Journal articles on the topic 'Dox-Induced Cardiotoxicity'
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1
Sumneang, Natticha, Pongpan Tanajak, and Thura Tun Oo. "Toll-like Receptor 4 Inflammatory Perspective on Doxorubicin-Induced Cardiotoxicity." Molecules 28, no. 11 (May 24, 2023): 4294. http://dx.doi.org/10.3390/molecules28114294.
Abstract:
Doxorubicin (Dox) is one of the most frequently used chemotherapeutic drugs in a variety of cancers, but Dox-induced cardiotoxicity diminishes its therapeutic efficacy. The underlying mechanisms of Dox-induced cardiotoxicity are still not fully understood. More significantly, there are no established therapeutic guidelines for Dox-induced cardiotoxicity. To date, Dox-induced cardiac inflammation is widely considered as one of the underlying mechanisms involved in Dox-induced cardiotoxicity. The Toll-like receptor 4 (TLR4) signaling pathway plays a key role in Dox-induced cardiac inflammation, and growing evidence reports that TLR4-induced cardiac inflammation is strongly linked to Dox-induced cardiotoxicity. In this review, we outline and address all the available evidence demonstrating the involvement of the TLR4 signaling pathway in different models of Dox-induced cardiotoxicity. This review also discusses the effect of the TLR4 signaling pathway on Dox-induced cardiotoxicity. Understanding the role of the TLR4 signaling pathway in Dox-induced cardiac inflammation might be beneficial for developing a potential therapeutic strategy for Dox-induced cardiotoxicity.
2
Ammar, El-Sayed M., Shehta A. Said, Ghada M. Suddek, and Sally L. El-Damarawy. "Amelioration of doxorubicin-induced cardiotoxicity by deferiprone in rats." Canadian Journal of Physiology and Pharmacology 89, no. 4 (April 2011): 269–76. http://dx.doi.org/10.1139/y11-020.
Abstract:
The therapeutic usefulness of doxorubicin (Dox), an anthracycline antibiotic used as an anticancer agent, is limited by its cardiotoxicity. Dox-induced cardiotoxicity is mainly attributed to accumulation of reactive oxygen species and interaction of Dox with cellular iron metabolism. The present study investigated the effects of the iron chelator deferiprone (Def) against Dox-induced cardiotoxicity in rats. Dox (15 mg/kg) was injected intraperitoneally as a single dose, and Def (10 mg/kg) was administered orally for 10 days. Dox showed cardiotoxicity as evidenced by increased heart rate, elevated ST segment, prolonged QTc interval, and increased T wave amplitude. In addition, Dox enhanced aconitine cardiotoxicity by decreasing its dose, producing ventricular tachycardia. Administration of Def significantly attenuated Dox-induced electrocardiographic changes. Cardiotoxicity of Dox was confirmed biochemically by a significant elevation in serum creatine kinase-MB and lactate dehydrogenase activities as well as by myocardial malondialdehyde and reduced glutathione contents. Moreover, Dox caused a significant decrease in myocardial superoxide dismutase activity. Administration of Def significantly attenuated the biochemical changes. These results suggest that Def might be a potential cardioprotective agent against Dox-induced cardiotoxicity.
3
Hamaamin, Karmand Salih, and Tavga Ahmed Aziz. "Doxorubicin-Induced Cardiotoxicity: Mechanisms and Management." Al-Rafidain Journal of Medical Sciences ( ISSN: 2789-3219 ) 3 (December 10, 2022): 87–97. http://dx.doi.org/10.54133/ajms.v3i.90.
Abstract:
Unfortunately, anticancer medications are extremely harmful to normal cells. Doxorubicin (DOX) is a highly cardiotoxic medication that can result in cardiomyopathy. The most significant mechanism for DOX-induced cardiotoxicity is oxidative stress, while other pathways have also been put forth. This review aims to highlight the mechanisms of DOX-induced cardiotoxicity and the most updated managements. Trustworthy sites such as Google Scholar, PubMed, and Research Gate were used to find the most updated articles. Many titles have been used for searching, such as "doxorubicin and cardiotoxicity," "cardioprotection," and "cardio-protective effects of phytochemicals." Preprints, review articles, and research with meta-analyses were disregarded. Three pathways, including oxidative stress, mitochondrial damage, and calcium excess, were responsible for DOX-induced cardiotoxicity. Cardiotoxicity may be partially caused by cell death, activation of the ubiquitin-ligase-proteasome system, and changes in its gene expression brought on by DOX. In the instance of DOX cardiotoxicity, medications and nutraceuticals with antioxidants and iron chelating properties have been found to have cardio-protective benefits. In conclusion, doxorubicin-treated cancer patients have been linked to cardiotoxicity, making cardioprotection extremely important in these patients. All of the mechanisms included in this review's discussion might provide light on fresh approaches to the treatment and/or prevention of DOX-induced cardiotoxicity.
4
Zheng, Dong, Yi Zhang, Ming Zheng, Ting Cao, Grace Wang, Lulu Zhang, Rui Ni, et al. "Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity." Clinical Science 133, no. 13 (July 2019): 1505–21. http://dx.doi.org/10.1042/cs20181022.
Abstract:
Abstract Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.
5
Zhang, Wei, Zhixing Fan, Fengyuan Wang, Lin Yin, Jinchun Wu, Dengke Li, Siwei Song, Xi Wang, Yanhong Tang, and Congxin Huang. "Tubeimoside I Ameliorates Doxorubicin-Induced Cardiotoxicity by Upregulating SIRT3." Oxidative Medicine and Cellular Longevity 2023 (January 14, 2023): 1–23. http://dx.doi.org/10.1155/2023/9966355.
Abstract:
Cardiotoxicity linked to doxorubicin (DOX) is primarily caused by inflammation, oxidative stress, and apoptosis. The role of tubeimoside I (TBM) in DOX-induced cardiotoxicity remains ambiguous, despite growing evidence that it could reduce inflammation, oxidative stress, and apoptosis in various diseases. This study was designed to investigate the role of TBM in DOX-induced cardiotoxicity and uncover the underlying mechanisms. H9c2 cell line and C57BL/6 mice were used to construct an in vitro and in vivo model of DOX-induced myocardial injury, respectively. We observed that DOX treatment provoked inflammation, oxidative stress, and cardiomyocyte apoptosis, which were significantly alleviated by TBM administration. Mechanistically, TBM attenuated DOX-induced downregulation of sirtuin 3 (SIRT3), and SIRT3 inhibition abrogated the beneficial effects of TBM both in vitro and in vivo. In conclusion, TBM eased inflammation, oxidative stress, and apoptosis in DOX-induced cardiotoxicity by increasing the expression of SIRT3, suggesting that it holds great promise for treating DOX-induced cardiac injury.
6
Mao, Jin Ning, Ai Jun Li, Liang Ping Zhao, Lan Gao, Wei Ting Xu, Xiao Su Hong, Wen Ping Jiang, and Jian Chang Chen. "PEG-PLGA Nanoparticles Entrapping Doxorubicin Reduced Doxorubicin-Induced Cardiotoxicity in Rats." Advanced Materials Research 912-914 (April 2014): 263–68. http://dx.doi.org/10.4028/www.scientific.net/amr.912-914.263.
Abstract:
Aim:Doxorubicin-induced cardiotoxicity limited its clinical utilization in oncology. In this study, Dox was entrapped into PEG-PLGA Nanoparticles, cardiotoxicity of Dox or PEG-PLGA-Dox was investigated in rats. Materials and methods :PEG-PLGA-Dox was prepared via modified single emulsion method. Its characterization including size, Drug loading capacity (DLC), entrapment efficiency (EE) were estimated. The cardiotoxicity of PEG-PLGA-Dox was assessed on SD rats via echocardiography and biochemical indicators compare to free Dox and physical sodium. Results:The average diameter of PEG-PLGA-Dox is around 200 nm, with DLC about 10%.After administered PEG-PLGA-Dox, the ratio of heart weight to body weight decreased not as significant as Dox group, level of serum parameters and echocardiography parameter also decreased little compared to the Dox group. Conclusions:After entrapped into PEG-PLGA nanoparticle, Dox-induced cardiotoxicity was reduced significantly.
7
Maneechote, Chayodom, Siriporn C. Chattipakorn, and Nipon Chattipakorn. "Recent Advances in Mitochondrial Fission/Fusion-Targeted Therapy in Doxorubicin-Induced Cardiotoxicity." Pharmaceutics 15, no. 4 (April 7, 2023): 1182. http://dx.doi.org/10.3390/pharmaceutics15041182.
Abstract:
Doxorubicin (DOX) has been recognized as one of the most effective chemotherapies and extensively used in the clinical settings of human cancer. However, DOX-mediated cardiotoxicity is known to compromise the clinical effectiveness of chemotherapy, resulting in cardiomyopathy and heart failure. Recently, accumulation of dysfunctional mitochondria via alteration of the mitochondrial fission/fusion dynamic processes has been identified as a potential mechanism underlying DOX cardiotoxicity. DOX-induced excessive fission in conjunction with impaired fusion could severely promote mitochondrial fragmentation and cardiomyocyte death, while modulation of mitochondrial dynamic proteins using either fission inhibitors (e.g., Mdivi-1) or fusion promoters (e.g., M1) can provide cardioprotection against DOX-induced cardiotoxicity. In this review, we focus particularly on the roles of mitochondrial dynamic pathways and the current advanced therapies in mitochondrial dynamics-targeted anti-cardiotoxicity of DOX. This review summarizes all the novel insights into the development of anti-cardiotoxic effects of DOX via the targeting of mitochondrial dynamic pathways, thereby encouraging and guiding future clinical investigations to focus on the potential application of mitochondrial dynamic modulators in the setting of DOX-induced cardiotoxicity.
8
Kitakata, Hiroki, Jin Endo, Hidehiko Ikura, Hidenori Moriyama, Kohsuke Shirakawa, Yoshinori Katsumata, and Motoaki Sano. "Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis." International Journal of Molecular Sciences 23, no. 3 (January 26, 2022): 1414. http://dx.doi.org/10.3390/ijms23031414.
Abstract:
Doxorubicin (DOX) is the most widely used anthracycline anticancer agent; however, its cardiotoxicity limits its clinical efficacy. Numerous studies have elucidated the mechanisms underlying DOX-induced cardiotoxicity, wherein apoptosis has been reported as the most common final step leading to cardiomyocyte death. However, in the past two years, the involvement of ferroptosis, a novel programmed cell death, has been proposed. The purpose of this review is to summarize the historical background that led to each form of cell death, focusing on DOX-induced cardiotoxicity and the molecular mechanisms that trigger each form of cell death. Furthermore, based on this understanding, possible therapeutic strategies to prevent DOX cardiotoxicity are outlined. DNA damage, oxidative stress, intracellular signaling, transcription factors, epigenetic regulators, autophagy, and metabolic inflammation are important factors in the molecular mechanisms of DOX-induced cardiomyocyte apoptosis. Conversely, the accumulation of lipid peroxides, iron ion accumulation, and decreased expression of glutathione and glutathione peroxidase 4 are important in ferroptosis. In both cascades, the mitochondria are an important site of DOX cardiotoxicity. The last part of this review focuses on the significance of the disruption of mitochondrial homeostasis in DOX cardiotoxicity.
9
da Cunha Menezes Souza, Leonardo, Meng Chen, Yuji Ikeno, Daisy Maria Fávero Salvadori, and Yidong Bai. "The implications of mitochondria in doxorubicin treatment of cancer in the context of traditional and modern medicine." Traditional Medicine and Modern Medicine 03, no. 04 (December 2020): 239–54. http://dx.doi.org/10.1142/s2575900020300076.
Abstract:
Doxorubicin (DOX) is an antibiotic anthracycline extensively used in the treatment of different malignancies, such as breast cancer, lymphomas and leukemias. The cardiotoxicity induced by DOX is one of the most important pathophysiological events that limit its clinical application. Accumulating evidence highlights mitochondria as a central role in this process. Modulation of mitochondrial functions as therapeutic strategy for DOX-induced cardiotoxicity has thus attracted much attention. In particular, emerging studies investigated the potential of natural mitochondria-targeting compounds from Traditional Chinese Medicine (TCM) as adjunct or alternative treatment for DOX-induced toxicity. This review summarizes studies about the mechanisms of DOX-induced cardiotoxicity, evidencing the importance of mitochondria and presenting TCM treatment alternatives for DOX-induced cardiomyopathy.
10
Jiang, Lai, Yanping Gong, Yida Hu, Yangyang You, Jiawu Wang, Zhetao Zhang, Zeyuan Wei, and Chaoliang Tang. "Peroxiredoxin-1 Overexpression Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Oxidative Stress and Cardiomyocyte Apoptosis." Oxidative Medicine and Cellular Longevity 2020 (July 29, 2020): 1–11. http://dx.doi.org/10.1155/2020/2405135.
Abstract:
Background. Previous research has shown that peroxiredoxin 1 (Prdx1) is an important modulator of physiological and pathophysiological cardiovascular events. This study is aimed at investigating the role and underlying mechanism of Prdx1 in doxorubicin- (DOX-) induced cardiotoxicity. Cardiac-specific expression of Prdx1 was induced in mice, and the mice received a single dose of DOX (15 mg/kg) to generate cardiotoxicity. First, our study demonstrated that Prdx1 expression was upregulated in the heart and in cardiomyocytes after DOX treatment. Second, we provided direct evidence that Prdx1 overexpression ameliorated DOX-induced cardiotoxicity by attenuating oxidative stress and cardiomyocyte apoptosis. Mechanistically, we found that DOX treatment increased the phosphorylation level of apoptosis signal-regulating kinase-1 (ASK1) and the downstream protein p38 in the heart and in cardiomyocytes, and these effects were decreased by Prdx1 overexpression. In contrast, inhibiting Prdx1 promoted DOX-induced cardiac injury via the ASK1/p38 pathway. These results suggest that Prdx1 may be an effective therapeutic option to prevent DOX-induced cardiotoxicity.
11
Cheng, Xiaoli, Dan Liu, Ruinan Xing, Haixu Song, Xiaoxiang Tian, Chenghui Yan, and Yaling Han. "Orosomucoid 1 Attenuates Doxorubicin-Induced Oxidative Stress and Apoptosis in Cardiomyocytes via Nrf2 Signaling." BioMed Research International 2020 (October 19, 2020): 1–13. http://dx.doi.org/10.1155/2020/5923572.
Abstract:
Doxorubicin (DOX) is an effective anticancer drug, but its therapeutic use is limited by its cardiotoxicity. The principal mechanisms of DOX-induced cardiotoxicity are oxidative stress and apoptosis in cardiomyocytes. Orosomucoid 1 (ORM1), an acute-phase protein, plays important roles in inflammation and ischemic stroke; however, the roles and mechanisms of ORM1 in DOX-induced cardiotoxicity remain unknown. Therefore, in the present study, we aimed to investigate the function of ORM1 in cardiomyocytes experiencing DOX-induced oxidative stress and apoptosis. A DOX-induced cardiotoxicity animal model was established in C57BL/6 mice by administering an intraperitoneal injection of DOX (20 mg/kg), and the control group was intraperitoneally injected with the same volume of sterilized saline. The effects were assessed after 7 d. Additionally, H9c2 cells were stimulated with DOX (10 μM) for 24 h. The results showed decreased ORM1 and increased oxidative stress and apoptosis after DOX stimulation in vivo and in vitro. ORM1 overexpression significantly reduced DOX-induced oxidative stress and apoptosis in H9c2 cells. ORM1 significantly increased the expression of nuclear factor-like 2 (Nrf2) and its downstream protein heme oxygenase 1 (HO-1) and reduced the expression of the lipid peroxidation end product 4-hydroxynonenal (4-HNE) and the level of cleaved caspase-3. In addition, Nrf2 silencing reversed the effects of ORM1 on DOX-induced oxidative stress and apoptosis in cardiomyocytes. In conclusion, ORM1 inhibited DOX-induced oxidative stress and apoptosis in cardiomyocytes by regulating the Nrf2/HO-1 pathway, which might provide a new treatment strategy for DOX-induced cardiotoxicity.
12
Miranda, Carlos J., Hortence Makui, Ricardo J. Soares, Marc Bilodeau, Jeannie Mui, Hajatollah Vali, Richard Bertrand, Nancy C. Andrews, and Manuela M. Santos. "Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin." Blood 102, no. 7 (October 1, 2003): 2574–80. http://dx.doi.org/10.1182/blood-2003-03-0869.
Abstract:
Abstract The clinical use of doxorubicin (DOX), an anthracycline chemotherapeutic agent, is limited by cardiotoxicity. The possible involvement of iron in DOX-induced cardiotoxicity became evident from studies in which iron chelators were shown to be cardioprotective. Iron overload is found in hereditary hemochromatosis, a genetic disorder prevalent in individuals of European descent. We hypothesized that Hfe deficiency may increase susceptibility to DOX-induced toxicity. Acute cardiotoxicity and iron changes were studied after treatment with DOX in Hfe knock-out (Hfe-/-) mice and wild-type mice. DOX-induced iron metabolism changes were intensified in Hfe-/- mice, which accumulated significantly more iron in the heart, liver, and pancreas, but less in the spleen compared with wild-type mice. In addition, Hfe-deficient mice exhibited significantly greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase. Increased mortality after chronic DOX treatment was observed in Hfe-/- mice and Hfe+/-mice compared with wild-type mice. DOX-treated Hfe-/- mice had a higher degree of mitochondrial damage and iron deposits in the heart than did wild-type mice. These data demonstrate that Hfe deficiency in mice increases susceptibility to DOX-induced cardiotoxicity and suggest that genetic mutations related to defects in iron metabolism may contribute to its cardiotoxicity in humans. (Blood. 2003;102:2574-2580)
13
Jiao, Yuheng, Yanyan Li, Jiayan Zhang, Song Zhang, Yafang Zha, and Jian Wang. "RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway." Biomolecules 12, no. 2 (February 12, 2022): 299. http://dx.doi.org/10.3390/biom12020299.
Abstract:
Doxorubicin (DOX) is an effective chemotherapeutic agent that plays an unparalleled role in cancer treatment. However, its serious dose-dependent cardiotoxicity, which eventually contributes to irreversible heart failure, has greatly limited the widespread clinical application of DOX. A previous study has demonstrated that the ribonucleotide reductase M2 subunit (RRM2) exerts salutary effects on promoting proliferation and inhibiting apoptosis and autophagy. However, the specific function of RRM2 in DOX-induced cardiotoxicity is yet to be determined. This study aimed to elucidate the role and potential mechanism of RRM2 on DOX-induced cardiotoxicity by investigating neonatal primary cardiomyocytes and mice treated with DOX. Subsequently, the results indicated that RRM2 expression was significantly reduced in mice hearts and primary cardiomyocytes. Apoptosis and autophagy-related proteins, such as cleaved-Caspase3 (C-Caspase3), LC3B, and beclin1, were distinctly upregulated. Additionally, RRM2 deficiency led to increased autophagy and apoptosis in cells. RRM2 overexpression, on the contrary, alleviated DOX-induced cardiotoxicity in vivo and in vitro. Consistently, DIDOX, an inhibitor of RRM2, attenuated the protective effect of RRM2. Mechanistically, we found that AKT/mTOR inhibitors could reverse the function of RRM2 overexpression on DOX-induced autophagy and apoptosis, which means that RRM2 could have regulated DOX-induced cardiotoxicity through the AKT/mTOR signaling pathway. In conclusion, our experiment established that RRM2 could be a potential treatment in reversing DOX-induced cardiac dysfunction.
14
Hu, Xiaoping, Huagang Liu, Zhiwei Wang, Zhipeng Hu, and Luocheng Li. "miR-200a Attenuated Doxorubicin-Induced Cardiotoxicity through Upregulation of Nrf2 in Mice." Oxidative Medicine and Cellular Longevity 2019 (November 3, 2019): 1–13. http://dx.doi.org/10.1155/2019/1512326.
Abstract:
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was closely involved in doxorubicin- (DOX-) induced cardiotoxicity. MicroRNA-200a (miR-200a) could target Keap1 mRNA and promote degradation of Keap1 mRNA, resulting in Nrf2 activation. However, the role of miR-200a in DOX-related cardiotoxicity remained unclear. Our study is aimed at investigating the effect of miR-200a on DOX-induced cardiotoxicity in mice. For cardiotropic expression, male mice received an injection of an adeno-associated virus 9 (AAV9) system carrying miR-200a or miR-scramble. Four weeks later, mice received a single intraperitoneal injection of DOX at 15 mg/kg. In our study, we found that miR-200a mRNA was the only microRNA that was significantly decreased in DOX-treated mice and H9c2 cells. miR-200a supplementation blocked whole-body wasting and heart atrophy caused by acute DOX injection, decreased the levels of cardiac troponin I and the N-terminal probrain natriuretic peptide, and improved cardiac and adult cardiomyocyte contractile function. Moreover, miR-200a reduced oxidative stress and cardiac apoptosis without affecting matrix metalloproteinase and inflammatory factors in mice with acute DOX injection. miR-200a also attenuated DOX-induced oxidative injury and cell loss in vitro. As expected, we found that miR-200a activated Nrf2 and Nrf2 deficiency abolished the protection provided by miR-200a supplementation in mice. miR-200a also provided cardiac benefits in a chronic model of DOX-induced cardiotoxicity. In conclusion, miR-200a protected against DOX-induced cardiotoxicity via activation of the Nrf2 signaling pathway. Our data suggest that miR-200a may represent a new cardioprotective strategy against DOX-induced cardiotoxicity.
15
Bhagat, Anchit, and Eugenie S. Kleinerman. "Neutrophils contribute to Doxorubicin-Induced Cardiotoxicity." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 111.23. http://dx.doi.org/10.4049/jimmunol.206.supp.111.23.
Abstract:
Abstract Doxorubicin (Dox) is a widely used chemotherapy agent for treating childhood cancer. However, Dox causes damage to the heart and as a result childhood cancer survivors are at higher risk of developing a cardiovascular disease at an earlier age. Elucidating the mechanisms by which Dox induces cardiotoxicity is crucial to identify therapeutic interventions. The innate immune system, in particular: neutrophils have been linked to several cardiac diseases. However, their role in Dox-induced cardiotoxicity has not been examined. Here, we hypothesize that neutrophils contribute to early damage caused by Dox treatment. We first evaluated whether Dox treatment induced neutrophil infiltration in heart. Mice were treated with Dox for 2 weeks and then neutrophil infiltration was quantified 24 hours after therapy by flow cytometry. There was an increase in neutrophils in heart tissue of Dox-treated mice as compared to controls. Additionally, when heart function was quantified by echocardiography, we found a decrease in ejection fraction [EF] and fractional shortening [FS]), and therefore decreased heart function. Next, we depleted neutrophils using an anti-Ly6G antibody and confirmed depletion in the blood and hearts of Dox-treated mice by flow cytometry. We found that neutrophil depletion prevented Dox-induced decrease in both EF and FS both short (24 hours after therapy) and long term (12 weeks after therapy) in the mice. Together these findings demonstrate that targeting neutrophils is a potential strategy to prevent Dox-induced cardiotoxicity.
16
Yu, Yangsheng, Degang Guo, and Lin Zhao. "MiR-199 Aggravates Doxorubicin-Induced Cardiotoxicity by Targeting TAF9b." Evidence-Based Complementary and Alternative Medicine 2022 (July 15, 2022): 1–13. http://dx.doi.org/10.1155/2022/4364779.
Abstract:
The clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. However, the pathogenic mechanism of DOX and the role of miRNA in DOX-induced cardiotoxicity remain to be further studied. This study aimed to investigate the role of miR-199 in DOX-mediated cardiotoxicity. A mouse model of myocardial cell injury induced by DOX was established. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression changes of miR-199 and TATA-binding protein associated factor 9B (TAF9b) in DOX-induced cardiac injury. Cell apoptosis was detected by TUNEL staining and flow cytometry. The expression levels of apoptosis-related proteins, namely, Bax and Bcl-2, were detected by qPCR. The expression of Beclin-1 and LC3b was detected by western blotting. The binding effect of miR-199 with TAF9b was verified by dual-luciferase reporter gene assay. In this study, overexpression of miR-199 could promote cardiotoxicity. Inhibition of miR-199 could alleviate DOX-mediated myocardial injury. Further studies showed that miR-199 targeted TAF9b. Moreover, miR-199 promoted apoptosis of myocardial cells and aggravated autophagy. Furthermore, we demonstrated that TAF9B knockdown reversed the myocardial protective effect of miR-199 inhibitors. Therefore, miR-199 promoted DOX-mediated cardiotoxicity by targeting TAF9b, thereby aggravating apoptosis and regulating autophagy.
17
Mao, Meijiao, Wang Zheng, Bin Deng, Youhua Wang, Duan Zhou, Lin Shen, Wankang Niku, and Na Zhang. "Cinnamaldehyde alleviates doxorubicin-induced cardiotoxicity by decreasing oxidative stress and ferroptosis in cardiomyocytes." PLOS ONE 18, no. 10 (October 12, 2023): e0292124. http://dx.doi.org/10.1371/journal.pone.0292124.
Abstract:
Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Cinnamaldehyde (CA), a bioactive component isolated from Cinnamonum cassia, possesses potent anti-oxidative and anti-apoptotic potentials. The major aim of this study was to evaluate the protective role of CA against DOX-induced cardiotoxicity. To this end, cardiomyocyte injury models were developed using DOX-treated H9c2 cells and DOX-treated rats, respectively. Herein, we found that CA treatment increased cardiomyocyte viability and attenuated DOX-induced cardiomyocyte death in vitro. CA further protected rats against DOX-induced cardiotoxicity, as indicated by elevated creatine kinase (CK) and lactate dehydrogenase (LDH) levels, myocardium injury, and myocardial fibrosis. CA alleviated DOX-induced myocardial oxidative stress by regulating reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels. Mechanistically, CA markedly accelerated nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2) and increased heme oxygenase-1 (HO-1) expression. Consequently, CA decreased DOX-induced cardiomyocyte ferroptosis, while Erastin (a ferroptosis agonist) treatment destroyed the effect of CA on increasing cardiomyocyte viability. Taken together, the current results demonstrate that CA alleviates DOX-induced cardiotoxicity, providing a promising opportunity to increase the clinical application of DOX.
18
Zhao, Yintao, Jingjing Sun, Wei Zhang, Meng Peng, Jun Chen, Lu Zheng, Xiangqin Zhang, Haibo Yang, and Yuan Liu. "Follistatin-Like 1 Protects against Doxorubicin-Induced Cardiomyopathy through Upregulation of Nrf2." Oxidative Medicine and Cellular Longevity 2020 (August 3, 2020): 1–11. http://dx.doi.org/10.1155/2020/3598715.
Abstract:
Doxorubicin- (DOX-) induced cardiomyocyte loss results in irreversible heart failure, which limits the clinical applications of DOX. Currently, there are no drugs that can effectively treat DOX-related cardiotoxicity. Follistatin-like 1 (FSTL1) has been reported to be a transforming growth factor-beta-inducible gene, and FSTL1 supplementation attenuated ischemic injury and cardiac apoptotic loss in mice. However, the effect of FSTL1 on DOX-induced cardiomyopathy has not been elucidated. We aimed to explore whether FSTL1 could prevent DOX-related cardiotoxicity in mice. Mice were intraperitoneally injected with a single dose of DOX to induce acute cardiotoxicity. We used an adeno-associated virus system to overexpress FSTL1 in the heart. DOX administration decreased FSTL1 mRNA and protein expression in the heart and in cells. FSTL1 prevented DOX-related cardiac injury and inhibited cardiac oxidative stress and apoptosis, thereby improving cardiac function in mice. FSTL1 also improved cardiomyocyte contractile functions in vitro. FSTL1 upregulated expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in DOX-treated hearts. FSTL1 was not capable of protecting against these toxic effects in Nrf2-deficient mice. In conclusion, FSTL1 protected against DOX-induced cardiotoxicity via upregulation of Nrf2 expression.
19
Wang, Tao, Chuqiao Yuan, Jia Liu, Liangyan Deng, Wei Li, Junling He, Honglin Liu, Liping Qu, Jianming Wu, and Wenjun Zou. "Targeting Energy Protection as a Novel Strategy to Disclose Di’ao Xinxuekang against the Cardiotoxicity Caused by Doxorubicin." International Journal of Molecular Sciences 24, no. 2 (January 4, 2023): 897. http://dx.doi.org/10.3390/ijms24020897.
Abstract:
Doxorubicin (DOX) can induce myocardial energy metabolism disorder and further worsen heart failure. “Energy protection” is proposed as a new cardiac protection strategy. Previous studies have found that Di’ao Xinxuekang (DXXK) can improve doxorubicin-induced cardiotoxicity in mice by inhibiting ferroptosis. However, there are very few studies associating DXXK and energy protection. This study aims to explore the “energy protection” effect of DXXK on cardiotoxicity induced by DOX. A DOX-induced cardiotoxicity model established in rats and H9c2 cells are used to analyze the therapeutic effects of DXXK on serum indexes, cardiac function indexes and cardiac histopathology. The metabonomic methods were used to explore the potential mechanism of DXXK in treating DOX-induced cardiotoxicity. In addition, we also observed the mitochondrial- and autophagy-related indicators of myocardial cells and the mRNA expression level of the core target regulating energy-metabolism-related pathways. Our results indicated that DXXK can improve cardiac function, reduce myocardial enzymes and alleviate the histological damage of heart tissue caused by DOX. In addition, DXXK can improve mitochondrial damage induced by DOX and inhibit excessive autophagy. Metabonomics analysis showed that DOX can significantly affects the pathways related to energy metabolism of myocardial cells, which are involved in the therapeutic mechanism of DXXK. In conclusion, DXXK can treat DOX-induced cardiotoxicity through the AMPK-mediated energy protection pathway.
20
Wang, Jingya, Lin Yao, Xiaoli Wu, Qi Guo, Shengxuan Sun, Jie Li, Guoqi Shi, Ruth B. Caldwell, R. William Caldwell, and Yongjun Chen. "Protection against Doxorubicin-Induced Cardiotoxicity through Modulating iNOS/ARG 2 Balance by Electroacupuncture at PC6." Oxidative Medicine and Cellular Longevity 2021 (March 20, 2021): 1–17. http://dx.doi.org/10.1155/2021/6628957.
Abstract:
Background. Doxorubicin (DOX) is a commonly used chemotherapeutic drug but is limited in clinical applications by its cardiotoxicity. Neiguan acupoint (PC6) is a well-recognized acupoint for the treatment of cardiothoracic disease. However, whether acupuncture at PC6 could be effective in preventing DOX-induced cardiotoxicity is still unknown. Methods. A set of experiments were performed with myocardial cells, wild type, inducible nitric oxide synthase knockout (iNOS-/-), and myocardial-specific ablation arginase 2 (Myh6-ARG 2-/-) mice. We investigated the protective effect and the underlying mechanisms for electroacupuncture (EA) against DOX-induced cardiotoxicity by echocardiography, immunostaining, biochemical analysis, and molecular biotechnology in vivo and in vitro analysis. Results. We found that DOX-mediated nitric oxide (NO) production was positively correlated with the iNOS level but has a negative correlation with the arginase 2 (ARG 2) level in both myocardial cells and tissues. Meanwhile, EA at PC6 alleviated cardiac dysfunction and cardiac hypertrophy in DOX-treated mice. EA at PC6 blocked the upregulation of NO production in accompanied with the downregulated iNOS and upregulated ARG 2 levels in myocardial tissue induced by DOX. Furthermore, knockout iNOS prevented cardiotoxicity and EA treatment did not cause the further improvement of cardiac function in iNOS-/- mice treated by DOX. In contrast, deficiency of myocardial ARG 2 aggravated DOX-induced cardiotoxicity and reduced EA protective effect. Conclusion. These results suggest that EA treatment at PC6 can prevent DOX-induced cardiotoxicity through modulating NO production by modulating the iNOS/ARG 2 balance in myocardial cells.
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Lue, Yanhe, Chen Gao, Ronald Swerdloff, James Hoang, Rozeta Avetisyan, Yue Jia, Meng Rao, et al. "Humanin analog enhances the protective effect of dexrazoxane against doxorubicin-induced cardiotoxicity." American Journal of Physiology-Heart and Circulatory Physiology 315, no. 3 (September 1, 2018): H634—H643. http://dx.doi.org/10.1152/ajpheart.00155.2018.
Abstract:
The chemotherapeutic effect of doxorubicin (Dox) is limited by cumulative dose-dependent cardiotoxicity in cancer survivors. Dexrazoxane (DRZ) is approved to prevent Dox-induced cardiotoxicity. Humanin and its synthetic analog HNG have a cytoprotective effect on the heart. To investigate the cardioprotective efficacy of HNG alone or in combination with DRZ against Dox-induced cardiotoxicity, 80 adult male mice were randomly divided into 8 groups to receive the following treatments via intraperitoneal injection: saline daily, HNG (5 mg/kg) daily, DRZ (60 mg/kg) weekly, Dox (3 mg/kg) weekly, DRZ + HNG, Dox + HNG, Dox + DRZ, and Dox + HNG + DRZ. Echocardiograms were performed before and at 4, 8, and 9.5 wk after the beginning of treatment. All mice were euthanized at 10 wk. In the absence of Dox, HNG, DRZ, or DRZ + HNG had no adverse effect on the heart. Dox treatment caused decreases in ejection fraction and cardiac mass and increases in cardiomyocyte apoptosis and intracardiac fibrosis. HNG or DRZ alone blunted the Dox-induced decrease in left ventricle posterior wall thickness and modestly ameliorated the Dox-induced decrease in ejection fraction. HNG + DRZ significantly ameliorated Dox-induced decreases in ejection function, cardiac fibrosis, and cardiac mass. Using a targeted analysis for the mitochondrial gene array and protein expression in heart tissues, we demonstrated that HNG + DRZ reversed DOX-induced altered transcripts that were biomarkers of cardiac damage and uncoupling protein-2. We conclude that HNG enhances the cardiac protective effect of DRZ against Dox-induced cardiotoxicity. HNG + DRZ protects mitochondria from Dox-induced cardiac damage and blunts the onset of cardiac dysfunction. Thus, HNG may be an adjuvant to DRZ in preventing Dox-induced cardiotoxicity. NEW & NOTEWORTHY Doxorubicin (Dox) is commonly used for treating a wide range of human cancers. However, cumulative dosage-dependent carditoxicity often limits its clinical applications. We demonstrated in this study that treating young adult male mice with synthetic humanin analog enhanced the cardiac protective effect of dexrazoxane against chemotherapeutic agent Dox-induced cardiac dysfunction. Thus, humanin analog can potentially serve as an adjuvant to dexrazoxane in more effectively preventing Dox-induced cardiac dysfunction and cardiomyopathy.
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Li, Jing, Huiping Liu, Srinivasan Ramachandran, Gregory B. Waypa, Jun-Jie Yin, Chang-Qing Li, Mei Han, et al. "Grape Seed Proanthocyanidins Ameliorate Doxorubicin-Induced Cardiotoxicity." American Journal of Chinese Medicine 38, no. 03 (January 2010): 569–84. http://dx.doi.org/10.1142/s0192415x10008068.
Abstract:
Doxorubicin (Dox) is one of the most widely used and successful chemotherapeutic antitumor drugs. Its clinical application is highly limited due to its cumulative dose-related cardiotoxicity. Proposed mechanisms include the generation of reactive oxygen species (ROS)-mediated oxidative stress. Therefore, reducing oxidative stress should be protective against Dox-induced cardiotoxicity. To determine whether antioxidant, grape seed proanthocyanidin extract (GSPE) attenuates Dox-induced ROS generation and protects cardiomyocytes from Dox-induced oxidant injury, cultured primary cardiomyocytes were treated with doxorubicin (Dox, 10 μM) alone or GSPE (50 μg/ml) with Dox (10 μM) for 24 hours. Dox increased intracellular ROS production as measured by 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate, induced significant cell death as assessed by propidium iodide, and declined the redox ratio of reduced glutathione (GSH)/oxidized glutathione (GSSG) and disrupted mitochondrial membrane potential as determined by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethlbenzimidazole-carbocyanide iodine (JC-1). Analysis of agarose gel electrophoresis revealed Dox-induced nuclear DNA damage with the ladder like fragmentation. GSPE treatment suppressed those alterations. Electron Spin Resonance (ESR) spectroscopy data also showed that GSPE strongly scavenged hydroxyl radical, superoxide and DPPH radicals. Together, these findings indicate that GSPE in combination with Dox has protective effect against Dox-induced toxicity in cardiomyocytes, which may be in part attributed to its antioxidative activity. Importantly, flow cytometric analysis demonstrated that co-treatment of Dox and GSPE did not decrease the proliferation-inhibitory effect of Dox in MCF-7 human breast carcinoma cells. Thus, GSPE may be a promising adjuvant to prevent cardiotoxicity without interfering with antineoplastic activity during chemotherapeutic treatment with Dox.
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Smuder, Ashley J., Andreas N. Kavazis, Kisuk Min, and Scott K. Powers. "Doxorubicin-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals." Journal of Applied Physiology 115, no. 2 (July 15, 2013): 176–85. http://dx.doi.org/10.1152/japplphysiol.00924.2012.
Abstract:
Doxorubicin (DOX) is an effective antitumor agent used in cancer treatment. However, its clinical use is limited due to cardiotoxicity. Indeed, the side effects of DOX are irreversible and include the development of cardiomyopathy and ultimately congestive heart failure. Although many studies have investigated the events leading to DOX-induced cardiotoxicity, the mechanisms responsible for DOX-induced cardiotoxicity remain unknown. In general, evidence suggests that DOX-induced cardiotoxicity is associated with an increased generation of reactive oxygen species and oxidative damage, leading to the activation of cellular proteolytic systems. In this regard, the autophagy/lysosomal proteolytic system is a constitutively active catabolic process that is responsible for the degradation of both organelles and cytosolic proteins. We tested the hypothesis that systemic DOX administration results in altered cardiac gene and protein expression of mediators of the autophagy/lysosomal system. Our results support this hypothesis, as DOX treatment increased both the mRNA and protein levels of numerous key autophagy genes. Because exercise training has been shown to be cardioprotective against DOX-induced damage, we also determined whether exercise training before DOX administration alters the expression of important components of the autophagy/lysosomal system in cardiac muscle. Our findings show that exercise training inhibits DOX-induced cardiac increases in autophagy signaling. Collectively, our results reveal that DOX administration promotes activation of the autophagy/lysosomal system pathway in the heart, and that endurance exercise training can be a cardioprotective intervention against myocardial DOX-induced toxicity.
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Ashour, Abdelkader E., Mohamed M. Sayed-Ahmed, Adel R. Abd-Allah, Hesham M. Korashy, Zaid H. Maayah, Hisham Alkhalidi, Mohammed Mubarak, and Abdulqader Alhaider. "Metformin Rescues the Myocardium from Doxorubicin-Induced Energy Starvation and Mitochondrial Damage in Rats." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/434195.
Abstract:
Clinical use of doxorubicin (DOX) is limited by its cardiotoxic side effects. Recent studies established that metformin (MET), an oral antidiabetic drug, possesses an antioxidant activity. However, whether it can protect against DOX-induced energy starvation and mitochondrial damage has not been reported. Our results, in a rat model of DOX-induced cardiotoxicity, show that DOX treatment significantly increased serum levels of LDH and CK-MB, indicators of cardiac injury, and induced expression of hypertrophic gene markers. DOX also caused marked decreases in the cardiac levels of glutathione, CoA-SH and ATP, and mRNA expression of catalase and NQO-1. These biochemical changes were associated with myocardial histopathological and ultrastructural deteriorations, as observed by light and electron microscopy, respectively. Cotreatment with MET (500 mg/kg) eliminated all DOX-induced biochemical, histopathological, and ultrastructural changes. These findings demonstrate that MET successfully prevents DOX-induced cardiotoxicityin vivoby inhibiting DOX-induced oxidative stress, energy starvation, and depletion of intramitochondrial CoA-SH.
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Li, Ling-Li, Li Wei, Ning Zhang, Wen-Ying Wei, Can Hu, Wei Deng, and Qi-Zhu Tang. "Levosimendan Protects against Doxorubicin-Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway." BioMed Research International 2020 (June 8, 2020): 1–11. http://dx.doi.org/10.1155/2020/8593617.
Abstract:
Background and Aims. Myocyte apoptosis plays a critical role in the development of doxorubicin- (DOX-) induced cardiotoxicity. In addition to its cardiotonic effect, laboratory evidence indicates that levosimendan can inhibit apoptosis, but its role in DOX-induced cardiac injury remains unclear. Therefore, the present study is aimed at exploring whether levosimendan could attenuate DOX-induced cardiotoxicity. Methods. Levosimendan (1 mg/kg) was administered to mice through oral gavage once daily for 4 weeks, and the mice were also subjected to an intraperitoneal injection of DOX (5 mg/kg) or saline, once a week for 4 weeks, to create a chronic model of DOX-induced cardiotoxicity. A morphological examination and biochemical analysis were used to evaluate the effects of levosimendan. H9C2 cells were used to verify the protective role of levosimendan in vitro. And an Akt inhibitor was utilized to verify the cardioprotection of levosimendan. Results. Levosimendan reduced the cardiac dysfunction and attenuated the myocardial apoptosis induced by DOX in vivo and in vitro. Levosimendan also inhibited the activation of phosphatase and tensin homolog (PTEN) and upregulated P-Akt expression both in vivo and in vitro. And inhibition of Akt abolished the cardioprotection of levosimendan in vitro. Conclusion. Levosimendan may protect against DOX-induced cardiotoxicity via modulation of the PTEN/Akt signaling pathway.
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Li, Siying, Wenjuan Wang, Ting Niu, Hui Wang, Bin Li, Lei Shao, Yimu Lai, et al. "Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/748524.
Abstract:
The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.
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Haesen, Sibren, Manon Marie Jager, Aline Brillouet, Iris de Laat, Lotte Vastmans, Eline Verghote, Anouk Delaet, et al. "Pyridoxamine Limits Cardiac Dysfunction in a Rat Model of Doxorubicin-Induced Cardiotoxicity." Antioxidants 13, no. 1 (January 17, 2024): 112. http://dx.doi.org/10.3390/antiox13010112.
Abstract:
The use of doxorubicin (DOX) chemotherapy is restricted due to dose-dependent cardiotoxicity. Pyridoxamine (PM) is a vitamin B6 derivative with favorable effects on diverse cardiovascular diseases, suggesting a cardioprotective effect on DOX-induced cardiotoxicity. The cardioprotective nature of PM was investigated in a rat model of DOX-induced cardiotoxicity. Six-week-old female Sprague Dawley rats were treated intravenously with 2 mg/kg DOX or saline (CTRL) weekly for eight weeks. Two other groups received PM via the drinking water next to DOX (DOX+PM) or saline (CTRL+PM). Echocardiography, strain analysis, and hemodynamic measurements were performed to evaluate cardiac function. Fibrotic remodeling, myocardial inflammation, oxidative stress, apoptosis, and ferroptosis were evaluated by various in vitro techniques. PM significantly attenuated DOX-induced left ventricular (LV) dilated cardiomyopathy and limited TGF-β1-related LV fibrotic remodeling and macrophage-driven myocardial inflammation. PM protected against DOX-induced ferroptosis, as evidenced by restored DOX-induced disturbance of redox balance, improved cytosolic and mitochondrial iron regulation, and reduced mitochondrial damage at the gene level. In conclusion, PM attenuated the development of cardiac damage after DOX treatment by reducing myocardial fibrosis, inflammation, and mitochondrial damage and by restoring redox and iron regulation at the gene level, suggesting that PM may be a novel cardioprotective strategy for DOX-induced cardiomyopathy.
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Shan, Lingling, Yulong Huo, Siyu Li, Wanrong Li, Jing Wang, Yang Yang, Langzi Wang, and Lin Chen. "Geraniin-Based Self-Assemble Nanoplatform for Antioxidation Reduced Cardiotoxicity and Tumor Synergistic Therapy." Journal of Biomedical Nanotechnology 19, no. 5 (May 1, 2023): 758–69. http://dx.doi.org/10.1166/jbn.2023.3580.
Abstract:
Reducing the cardiotoxicity caused by DOX is a difficult problem in clinical cancer therapy. The small hydrophobic polyphenolic compound geraniin (GE) was designed as a DOX nanocarrier to coordinate with Fe3+, forming DOX-Fe3+@GE-PEG (GDFP) nanoparticles (NPs). DOX-induced cardiotoxicity mediated by the Nrf2/HO-1 pathway was studied in vitro and in vivo. The targeting ability of GDFP NPs toward tumor cells or tissues was assessed using NIR imaging and pharmacokinetics studies. The synergistic therapeutic efficacy of the DOX and GE-based GDFP NPs was evaluated in vitro and in vivo. GE-based GDFP NPs promoted SOD and GSH-Px activities, inhibited Nrf2 protein expression, and enhance HO-1 protein expression, which contributed to the reduction of DOX-induced cardiotoxicity. The blood-circulation half-life of GDFP NPs was longer than 20 h determined by the NIR imaging and DOX plasma level calculations. The results indicated that high tumor accumulation of GDFP NPs could be achieved by retention (EPR) effect. The GDFP NPs showed an improved synergistic antitumor effect. Our work has explored a novel approach for overcoming DOX-induced cardiotoxicity and achieving synergistic chemotherapy, which holds great potential for future clinical application.
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Ono, Masaya, Yoichi Sunagawa, Saho Mochizuki, Takahiro Katagiri, Hidemichi Takai, Sonoka Iwashimizu, Kyoko Inai, et al. "Chrysanthemum morifolium Extract Ameliorates Doxorubicin-Induced Cardiotoxicity by Decreasing Apoptosis." Cancers 14, no. 3 (January 28, 2022): 683. http://dx.doi.org/10.3390/cancers14030683.
Abstract:
It is well known that the anthracycline anticancer drug doxorubicin (DOX) induces cardiotoxicity. Recently, Chrysanthemum morifolium extract (CME), an extract of the purple chrysanthemum flower, has been reported to possess various physiological activities such as antioxidant and anti-inflammatory effects. However, its effect on DOX-induced cardiotoxicity is still unknown. An 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT)assay revealed that 1 mg/mL of CME reduced DOX-induced cytotoxicity in H9C2 cells but not in MDA-MB-231 cells. A TUNEL assay indicated that CME treatment improved DOX-induced apoptosis in H9C2 cells. Moreover, DOX-induced increases in the expression levels of p53, phosphorylated p53, and cleaved caspase-3,9 were significantly suppressed by CME treatment. Next, we investigated the effect of CME in vivo. The results showed that CME treatment substantially reversed the DOX-induced decrease in survival rate. Echocardiography indicated that CME treatment also reduced DOX-induced left ventricular systolic dysfunction, and a TUNEL assay showed that CME treatment also suppressed apoptosis in the mouse heart. These results reveal that CME treatment ameliorated DOX-induced cardiotoxicity by suppressing apoptosis. Further study is needed to clarify the effect of CME on DOX-induced heart failure in humans.
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Jiang, Yu, Yanjuan Liu, Wen Xiao, Dandan Zhang, Xiehong Liu, Huiqiong Xiao, Sanli You, and Lili Yuan. "Xinmailong Attenuates Doxorubicin-Induced Lysosomal Dysfunction and Oxidative Stress in H9c2 Cells via HO-1." Oxidative Medicine and Cellular Longevity 2021 (March 27, 2021): 1–11. http://dx.doi.org/10.1155/2021/5896931.
Abstract:
The clinical use of doxorubicin (DOX) is limited by its cardiotoxicity, which is closely associated with oxidative stress. Xinmailong (XML) is a bioactive peptide extracted from American cockroaches, which has been mainly applied to treat chronic heart failure in China. Our previous study showed that XML attenuates DOX-induced oxidative stress. However, the mechanism of XML in DOX-induced cardiotoxicity remains unclear. Heme oxygenase-1 (HO-1), an enzyme that is ubiquitously expressed in all cell types, has been found to take antioxidant effects in many cardiovascular diseases, and its expression is protectively upregulated under DOX treatment. Lysosome and autophagy are closely involved in oxidative stress as well. It is still unknown whether XML could attenuate doxorubicin-induced lysosomal dysfunction and oxidative stress in H9c2 cells via HO-1. Thus, this study was aimed at investigating the involvement of HO-1-mediated lysosomal function and autophagy flux in DOX-induced oxidative stress and cardiotoxicity in H9c2 cells. Our results showed that XML treatment markedly increased cell proliferation and SOD activity, improved lysosomal function, and ameliorated autophagy flux block in DOX-treated H9c2 cells. Furthermore, XML significantly increased HO-1 expression following DOX treatment. Importantly, HO-1-specific inhibitor (Znpp) or HO-1 siRNA could significantly attenuate the protective effects of XML against DOX-induced cell injury, oxidative stress, lysosomal dysfunction, and autophagy flux block. These results suggest that XML protects against DOX-induced cardiotoxicity through HO-1-mediated recovery of lysosomal function and autophagy flux and decreases oxidative stress, providing a novel mechanism responsible for the protection of XML against DOX-induced cardiomyopathy.
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Taylor, Justin R., and Kyra Harames. "Abstract 4771: Prevention of doxorubicin-induced cardiotoxicity by benfotiamine." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4771. http://dx.doi.org/10.1158/1538-7445.am2023-4771.
Abstract:
Abstract Anthracyclines such as daunorubicin and doxorubicin (DOX) are currently used as chemotherapeutic agents in the prevention of various cancers including breast cancer, lung cancer, leukemia, and lymphoma. Although, anthracyclines are successful in controlling various cancers growth, the major drawback is the unwanted cardiotoxicity. Specifically, high doses of DOX used for the therapy of advanced cancers could cause life threating conditions. Therefore, specific interventions are required to decrease the cardiac toxicity associated with the DOX. Benfotiamine, a lipid soluble vitamin B1 derivative has shown be a potent anti-oxidant and anti-inflammatory agent. However, the efficacy of benfotiamine in the prevention of cardiotoxicity associated with the anthracyclines is not known. In this study, we examined the effect of benfotiamine in the prevention of DOX-induced cytotoxicity in the human umbilical vascular endothelial cells (HUVECs). Treatment of HUVECs with DOX caused significant endothelial cells death and benfotiamine in a concentration-dependent manner prevented the dox-induced endothelial cell death. Further, benfotiamine prevents the DOX-induced apoptosis in endothelial cells by preventing the activation of caspase-3. Benfotiamine also prevents DOX-induced reactive oxygen species generation. Our results also indicate that benfotiamine regulates DOX-induced expression of pro-apoptotic mediators such as BAD, phosphor-P53, and pro-caspase-3, and anti-apoptotic mediators such as BCL-2, BCL-x, IAPs, and HSP and others such as FADD, DR5, and SMAC/diablo. We plan to further explore how benfotiamine prevents DOX-induced cardiotoxicity using human cardiac myocytes and mouse models. Thus, based on our cell culture studies, benfotiamine through its potent anti-oxidative property could prevent endothelial cytotoxicity and suggests that it could be further developed as adjuvant therapy in controlling cardiotoxicity associated with the anthracycline chemotherapy. Citation Format: Justin R. Taylor, Kyra Harames. Prevention of doxorubicin-induced cardiotoxicity by benfotiamine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4771.
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Koczurkiewicz-Adamczyk, Paulina, Katarzyna Klaś, Agnieszka Gunia-Krzyżak, Kamil Piska, Kalina Andrysiak, Jacek Stępniewski, Sławomir Lasota, et al. "Cinnamic Acid Derivatives as Cardioprotective Agents against Oxidative and Structural Damage Induced by Doxorubicin." International Journal of Molecular Sciences 22, no. 12 (June 9, 2021): 6217. http://dx.doi.org/10.3390/ijms22126217.
Abstract:
Doxorubicin (DOX) is a widely used anticancer drug. However, its clinical use is severely limited due to drug-induced cumulative cardiotoxicity, which leads to progressive cardiomyocyte dysfunction and heart failure. Enormous efforts have been made to identify potential strategies to alleviate DOX-induced cardiotoxicity; however, to date, no universal and highly effective therapy has been introduced. Here we reported that cinnamic acid (CA) derivatives exert a multitarget protective effect against DOX-induced cardiotoxicity. The experiments were performed on rat cardiomyocytes (H9c2) and human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a well-established model for cardiac toxicity assessment. CA derivatives protected cardiomyocytes by ameliorating DOX-induced oxidative stress and viability reduction. Our data indicated that they attenuated the chemotherapeutic’s toxicity by downregulating levels of caspase-3 and -7. Pre-incubation of cardiomyocytes with CA derivatives prevented DOX-induced motility inhibition in a wound-healing assay and limited cytoskeleton rearrangement. Detailed safety analyses—including hepatotoxicity, mutagenic potential, and interaction with the hERG channel—were performed for the most promising compounds. We concluded that CA derivatives show a multidirectional protective effect against DOX-induced cardiotoxicity. The results should encourage further research to elucidate the exact molecular mechanism of the compounds’ activity. The lead structure of the analyzed CA derivatives may serve as a starting point for the development of novel therapeutics to support patients undergoing DOX therapy.
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Liu, Yuzhou, Liying Zhou, Binbin Du, Yuan Liu, Junhui Xing, Sen Guo, Ling Li, and Hongrui Chen. "Protection against Doxorubicin-Related Cardiotoxicity by Jaceosidin Involves the Sirt1 Signaling Pathway." Oxidative Medicine and Cellular Longevity 2021 (August 6, 2021): 1–18. http://dx.doi.org/10.1155/2021/9984330.
Abstract:
The clinical use of doxorubicin (DOX) is largely limited by its cardiotoxicity. Previous studies have shown that jaceosidin has many biological activities. However, little is known about whether jaceosidin can attenuate DOX-related acute cardiotoxicity. Here, we investigated the therapeutic effects of jaceosidin on DOX-induced acute cardiotoxicity. Mice were intraperitoneally injected with a single dose of DOX to establish an acute cardiac injury model. To explore the protective effects, mice were orally administered jaceosidin daily for 7 days, with dosing beginning 2 days before DOX injection. The results demonstrated that jaceosidin dose-dependently reduced free radical generation, inflammation accumulation, and cell loss induced by DOX in cardiomyocytes. Further studies showed that jaceosidin treatment inhibited myocardial oxidative damage and the inflammatory response and attenuated myocardial apoptotic death, thus improving cardiac function in mice injected with DOX. The inhibitory effects of jaceosidin on DOX-related acute cardiotoxicity were mediated by activation of the sirtuin1 (Sirt1) signaling pathway. Jaceosidin lost its protective effect against DOX-related injury in Sirt1-deficient cardiomyocytes and mice. In conclusion, jaceosidin has protective potential in treating DOX-related cardiac injury through activation of the Sirt1 signaling pathway.
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Lee, Eun Ji, Woong Bi Jang, Jaewoo Choi, Hye Ji Lim, Sangmi Park, Vinoth Kumar Rethineswaran, Jong Seong Ha, et al. "The Protective Role of Glutathione against Doxorubicin-Induced Cardiotoxicity in Human Cardiac Progenitor Cells." International Journal of Molecular Sciences 24, no. 15 (July 28, 2023): 12070. http://dx.doi.org/10.3390/ijms241512070.
Abstract:
This study investigated the protective effect of glutathione (GSH), an antioxidant drug, against doxorubicin (DOX)-induced cardiotoxicity. Human cardiac progenitor cells (hCPCs) treated with DOX (250 to 500 nM) showed increased viability and reduced ROS generation and apoptosis with GSH treatment (0.1 to 1 mM) for 24 h. In contrast to the 500 nM DOX group, pERK levels were restored in the group co-treated with GSH and suppression of ERK signaling improved hCPCs’ survival. Similarly to the previous results, the reduced potency of hCPCs in the 100 nM DOX group, which did not affect cell viability, was ameliorated by co-treatment with GSH (0.1 to 1 mM). Furthermore, GSH was protected against DOX-induced cardiotoxicity in the in vivo model (DOX 20 mg/kg, GSH 100 mg/kg). These results suggest that GSH is a potential therapeutic strategy for DOX-induced cardiotoxicity, which performs its function via ROS reduction and pERK signal regulation.
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Egwuatu, Ifeanyi Anthony, Chiadikobi Lawrence Ozoemena, Emeka Williams Ugwuishi, Christian Chiemeka Ozor, Augustine Oviosun, and Favour Onwene. "Deciphering the Ameliorative Potential of 5, 7-dihydroxyflavone (Chrysin) on Doxorubicin-Induced Cardiotoxicity by Modulating Oxidative Stress in Rats." Scholars International Journal of Anatomy and Physiology 6, no. 11 (November 23, 2023): 181–90. http://dx.doi.org/10.36348/sijap.2023.v06i11.005.
Abstract:
Doxorubicin-induced cardiotoxicity is the leading cause of morbidity and mortality among cancer survivors. The present study aimed to investigate the ameliorative effect of 5, 7-dihydroxyflavone (chrysin) against doxorubicin-induced cardiotoxicity in Wistar rats. Thirty-five adult male Wistar albino rats were randomly allocated into seven groups (n = 5 each) which consisted of normal control (group 1) receiving phosphate buffer saline (0.4 ml), positive control (Group 2) received 2mg\kg of doxorubicin (DOX) through an intraperitoneal route once weekly for 21 days, chrysin low dose and chrysin high dose (Group 3 and 4) received oral administration of chrysin 50&100mg/kg for 21 days, chrysin low dose and DOX, chrysin medium dose and DOX and chrysin high dose and DOX(group 5, 6, and 7) received 2mg/kg of DOX once weekly with 50, 100 and 150mg/kg of chrysin for 21 days. Significant elevations in cardiac troponin I (cTnI) and histological lesions, which corresponded with oxidative stress, inflammation, apoptotic indicators, and cardiotoxicity when compared to controls, were indicative of DOX-induced cardiotoxicity. Malondialdehyde (MDA), a sign of oxidative stress, SOD, CPK (creatinine phosphokinase), TBARS (thiobarbituric acid reactive substance), and CAT (catalase) were also elevated in the DOX group. The DOX group also had increased levels of cardiac inflammatory markers, including as interleukin-1 (IL-1), interleukin-6 (IL-6), and the apoptotic marker caspase-3. 5, 7-dihydroxyflavone (chrysin) significantly mitigated, but did not entirely reverse, the cardiotoxicity caused by DOX by reducing the histopathological scores of cardiomyopathies and lowering cTnI in comparison to the DOX group. Additionally, chrysin reduced MDA to substantially similar levels as the control. Following chrysin administration, significant decreases in IL-1, IL-6, and caspase-3 were also seen in comparison to the DOX-only group. All things considered, these findings point to chrysin's protective action against DOX-induced cardiotoxicity, which may have been rendered possible by oxidative stress, inflammatory, and apoptotic suppression.
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Abdul Karim, Lubna Zuhair, Inam Sameh Arif, and Fouad A. Al Saady. "Lipidomics application to explain acute cardiotoxicity induced by doxorubicin." Al Mustansiriyah Journal of Pharmaceutical Sciences 19, no. 4 (December 1, 2019): 161–69. http://dx.doi.org/10.32947/ajps.v19i4.647.
Abstract:
Doxorubicin (DOX) induced cardio-toxicity is one of the important limiting factors for the clinical use of this drug, the exact mechanism underlying the cardiotoxicity is still under debate and different experimental protocols were used. Lipidomics technology was used in this study to investigate the underlying
the cardiotoxicity is still under debate and different experimental protocols were used. Lipidomics technology was used in this study to investigate the underlying mechanism of cardiotoxicity induced by DOX. Lipidomics refers to the complete analysis of lipid profile of a cell or organism based on the principles and tools of analytical chemistry particularly mass spectrometry. This study was designed to investigate cardiotoxicity induced by doxorubicin using lipidomics technology.
Method: Twelve adult male rats divided randomly into two groups, each group comprising of six rats. 1: Control group (single dose (1ml) saline intraperitoneally); 2: DOX group (20 mg/ kg single dose intraperitoneally). After anesthesia, the myocardial tissue harvested and stored in liquid nitrogen, then the metabolites will be extracted from left ventricle of the heart tissue, derivatized using boron trifluride-methanol 10% and then the metabolites identified using GC-MS.
Results: The results showed that treatment with DOX produced significant (P<0.05) increase in the level of acetic acid, cholesterol, myristic acid, and stearic acid. Whereas the level of arachidonic acid, linolic acid, pentadecanoic acid, oleic acid and ricinoleic acid, decreased significantly (P<0.05) in DOX group. Lauric acid, palmitic acid, and methylcyclohexane, were found to be increased in DOX group.
Conclusion: This study showed that DOX induced cardiotoxicity can be identified by lipidomics technique by measuring lipid biomarkers of cardiotoxicity in heart tissue which include the saturated fatty acids (stearic acid, acetic acid and palmitic acid), unsaturated fatty acids (arachidonic acid, linoleic acid, and oleic acid) as well as cholesterol
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Chen, Sida, Yang Huang, Suiqing Huang, Zhuoming Zhou, Kaizheng Liu, Jinyu Pan, and Zhongkai Wu. "M2b macrophages protect against doxorubicin induced cardiotoxicity via alternating autophagy in cardiomyocytes." PLOS ONE 18, no. 7 (July 27, 2023): e0288422. http://dx.doi.org/10.1371/journal.pone.0288422.
Abstract:
Objective Doxorubicin (DOX) is an anthracycline antibiotic which is widely used for the treatment of various cancers, while the dose-related cardiotoxicity limits its potential therapeutic application. The underlying mechanism of DOX induced cardiotoxicity is complex and remains elusive. Our previous studies have shown that M2b macrophage plays an important role in reducing inflammation due to ischemic reperfusion injury in the myocardium. The purpose of this study was to investigate the potential protective role of M2b macrophages in DOX induced cardiotoxicity. Methods In vivo, we conducted DOX induced cardiac injury in C57BL/6 mice and treated them with M2b macrophages. Then, the mice were examined by echocardiography. The heart specimens were harvested for histological examination, transmission electron microscope analysis, and autophagy molecules evaluation. In vitro, HL-1 cardiac cell lines treated with DOX were cocultured with or without M2b macrophages. Then, Autophagy related genes and protein expression were assessed by real-time quantitative PCR and western blot; cell proliferation was assessed by cell counting kit-8. Results We found that M2b macrophages can improve cardiac function and alleviate cardiac injury in DOX induced cardiac injury mice. M2b macrophages can enhance cardiac autophagy levels both in vivo and in vitro in DOX induced cardiac injury model. In addition, this protective effect can be blocked by an autophagy inhibitor. Conclusion Our study shows that M2b macrophages can help attenuate the DOX induced cardiotoxicity by regulating the autophagy level of cardiomyocytes.
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Hamada, Juri, Altansarnai Baasanjav, Natsumi Ono, Kazuya Murata, Koichiro Kako, Junji Ishida, and Akiyoshi Fukamizu. "Possible involvement of downregulation of the apelin-APJ system in doxorubicin-induced cardiotoxicity." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 8 (April 15, 2015): H931—H941. http://dx.doi.org/10.1152/ajpheart.00703.2013.
Abstract:
Apelin peptide is an endogenous ligand of APJ (a putative receptor protein related to the angiotensin II type 1 receptor), which is a member of a G protein-coupled receptor superfamily with seven transmembrane domains. Recent findings have suggested that the apelin-APJ system plays a potential role in cardiac contraction and cardioprotection. In the present study, we show that the apelin-APJ system is disrupted in doxorubicin (Dox)-induced cardiotoxicity. We found downregulation of apelin and APJ mRNA expression in C57Bl/6J mouse hearts on days 1 and 5 after Dox administration (20 mg/kg ip). Plasma apelin levels and cardiac APJ protein expression were significantly decreased on day 5 after Dox injection. Cardiac apelin contents were reduced on day 1 but increased to basal levels on day 5 after Dox injection. We also examined the effects of APJ gene deletion on Dox-induced cardiotoxicity. Compared with wild-type mice, APJ knockout mice showed a significant depression in cardiac contractility on day 5 after Dox (15 mg/kg ip) treatment followed by a decrease in 14-day survival rates. Moreover, Dox-induced myocardial damage, cardiac protein carbonylation, and autophagic dysfunction were accelerated in APJ knockout mice. Rat cardiac H9c2 cells showed Dox-induced decreases in viability, which were prevented by APJ overexpression and the combination with apelin treatment. These results suggest that the suppression of APJ expression after Dox administration can exacerbate Dox-induced cardiotoxicity, which may be responsible for depressed protective function of the endogenous apelin-APJ system. Modulation of the apelin-APJ system may hold promise for the treatment of Dox-induced cardiotoxicity.
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Wang, Yuewen, Xu Chao, Fiaz ud Din Ahmad, Hailong Shi, Hania Mehboob, and Waseem Hassan. "Phoenix dactylifera Protects against Doxorubicin-Induced Cardiotoxicity and Nephrotoxicity." Cardiology Research and Practice 2019 (December 23, 2019): 1–8. http://dx.doi.org/10.1155/2019/7395239.
Abstract:
Doxorubicin (DOX) is an important anticancer drug used widely in the treatment of leukemia and lymphoma. The suitability of DOX is enhanced by its high therapeutic index, but its potential to cause cardiotoxicity and nephrotoxicity remains a prime concern in anticancer therapeutics. This study is designed to determine the effect of Phoenix dactylifera extract (PDE) on DOX-induced cardiotoxicity and nephrotoxicity. Experimental rats were divided into four groups, receiving normal saline 4 ml/kg, DOX alone, and crude extract of PDE at doses of 1 g/kg and 1.5 g/kg in the presence of DOX, respectively, for 21 days. Cardiac enzymes and serum and urinary sodium and potassium levels were evaluated which were analyzed statistically by using one-way ANOVA. Subsequently, DOX initiated changes in the level of cardiac markers CK-MB, LDH, and troponin I, which were notably reversed by PDE. PDE was also effective against serum and urinary sodium and urinary potassium and protected against DOX-induced nephrotoxicity. Groups treated with different doses of PDE showed marked decrease in levels of cardiac and renal markers. The study concluded that the PDE extract possesses protective effects against DOX-induced cardiotoxicity and nephrotoxicity.
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Li, Jun, Weiguo Wan, Tao Chen, Suiyang Tong, Xuejun Jiang, and Wanli Liu. "miR-451 Silencing Inhibited Doxorubicin Exposure-Induced Cardiotoxicity in Mice." BioMed Research International 2019 (July 4, 2019): 1–11. http://dx.doi.org/10.1155/2019/1528278.
Abstract:
Oxidative stress and cardiomyocytes apoptosis were closely involved in the pathological process of doxorubicin- (Dox-) induced cardiac injury. MicroRNA-451 (miR-451) was mainly expressed in cardiomyocytes. However, the role of miR-451 in Dox-induced cardiac injury remained unclear. Our study aimed to investigate the effect of miR-451 on Dox-induced cardiotoxicity in mice. We established a Dox-induced cardiotoxicity model in the mice and manipulated miR-451 expression in the heart using a miR-451 inhibitor, which was injected every other day beginning at one day before Dox injection. Oxidative stress and apoptosis in the hearts were evaluated. miR-451 levels were significantly increased in Dox-treated mice or cardiomyocytes. miR-451 inhibition attenuated Dox-induced whole-body wasting and heart atrophy, reduced cardiac injury, restored cardiac function, and improved cardiomyocyte contractile function. Moreover, miR-451 inhibition reduced oxidative stress and cardiomyocytes apoptosis in vivo and in vitro. miR-451 inhibition increased the expression of calcium binding protein 39 (Cab39) and activated adenosine monophosphate activated protein kinase (AMPK) signaling pathway. A specific inhibitor of AMPK abolished the protection provided by miR-451 inhibition against cell injury in vitro. In conclusion, miR-451 inhibition protected against Dox-induced cardiotoxicity via activation of AMPK signaling pathway.
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Gyongyosi, Alexandra, Nikolett Csaki, Agota Peto, Kitti Szoke, Ferenc Fenyvesi, Ildiko Bacskay, and Istvan Lekli. "BGP-15 Protects against Doxorubicin-Induced Cell Toxicity via Enhanced Mitochondrial Function." International Journal of Molecular Sciences 24, no. 6 (March 9, 2023): 5269. http://dx.doi.org/10.3390/ijms24065269.
Abstract:
Doxorubicin (DOX) is an efficacious and commonly used chemotherapeutic agent. However, its clinical use is limited due to dose-dependent cardiotoxicity. Several mechanisms have been proposed to play a role in DOX-induced cardiotoxicity, such as free radical generation, oxidative stress, mitochondrial dysfunction, altered apoptosis, and autophagy dysregulation. BGP-15 has a wide range of cytoprotective effects, including mitochondrial protection, but up to now, there is no information about any of its beneficial effects on DOX-induced cardiotoxicity. In this study, we investigated whether the protective effects of BGP-15 pretreatment are predominantly via preserving mitochondrial function, reducing mitochondrial ROS production, and if it has an influence on autophagy processes. H9c2 cardiomyocytes were pretreated with 50 μM of BGP-15 prior to different concentrations (0.1; 1; 3 μM) of DOX exposure. We found that BGP-15 pretreatment significantly improved the cell viability after 12 and 24 h DOX exposure. BGP-15 ameliorated lactate dehydrogenase (LDH) release and cell apoptosis induced by DOX. Additionally, BGP-15 pretreatment attenuated the level of mitochondrial oxidative stress and the loss of mitochondrial membrane potential. Moreover, BGP-15 further slightly modulated the autophagic flux, which was measurably decreased by DOX treatment. Hence, our findings clearly revealed that BGP-15 might be a promising agent for alleviating the cardiotoxicity of DOX. This critical mechanism appears to be given by the protective effect of BGP-15 on mitochondria.
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Al-Shabanah, Othman A., Abdulaziz M. Aleisa, Mohamed M. Hafez, Salim S. Al-Rejaie, Abdulaziz A. Al-Yahya, Saleh A. Bakheet, Mohamed M. Al-Harbi, and Mohamed M. Sayed-Ahmed. "Desferrioxamine Attenuates Doxorubicin-Induced Acute Cardiotoxicity through TFG-β/Smad p53 Pathway in Rat Model." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/619185.
Abstract:
Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.
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Räsänen, Markus, Joni Degerman, Tuuli A. Nissinen, Ilkka Miinalainen, Risto Kerkelä, Antti Siltanen, Janne T. Backman, et al. "VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection." Proceedings of the National Academy of Sciences 113, no. 46 (October 31, 2016): 13144–49. http://dx.doi.org/10.1073/pnas.1616168113.
Abstract:
Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.
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Haesen, Sibren, Eline Verghote, Ellen Heeren, Esther Wolfs, Dorien Deluyker, and Virginie Bito. "Pyridoxamine Attenuates Doxorubicin-Induced Cardiomyopathy without Affecting Its Antitumor Effect on Rat Mammary Tumor Cells." Cells 13, no. 2 (January 9, 2024): 120. http://dx.doi.org/10.3390/cells13020120.
Abstract:
Doxorubicin (DOX) is commonly used in cancer treatment but associated with cardiotoxicity. Pyridoxamine (PM), a vitamin B6 derivative, could be a cardioprotectant. This study investigated the effect of PM on DOX cardiotoxicity and DOX antitumor effectiveness. Sprague Dawley rats were treated intravenously with DOX (2 mg/kg/week) or saline over eight weeks. Two other groups received PM via oral intake (1 g/L in water bottles) next to DOX or saline. Echocardiography was performed after eight weeks. PM treatment significantly attenuated the DOX-induced reduction in left ventricular ejection fraction (72 ± 2% vs. 58 ± 3% in DOX; p < 0.001) and increase in left ventricular end-systolic volume (0.24 ± 0.02 µL/cm2 vs. 0.38 ± 0.03 µL/cm2 in DOX; p < 0.0001). Additionally, LA7 tumor cells were exposed to DOX, PM, or DOX and PM for 24 h, 48 h, and 72 h. Cell viability, proliferation, cytotoxicity, and apoptosis were assessed. DOX significantly reduced LA7 cell viability and proliferation (p < 0.0001) and increased cytotoxicity (p < 0.05) and cleaved caspase-3 (p < 0.001). Concomitant PM treatment did not alter the DOX effect on LA7 cells. In conclusion, PM attenuated DOX-induced cardiomyopathy in vivo without affecting the antitumor effect of DOX in vitro, highlighting PM as a promising cardioprotectant for DOX-induced cardiotoxicity.
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Law, David, Mitchel A. Magrini, Jacob A. Siedlik, Joan Eckerson, Kristen M. Drescher, and Eric C. Bredahl. "Creatine and Resistance Training: A Combined Approach to Attenuate Doxorubicin-Induced Cardiotoxicity." Nutrients 15, no. 18 (September 19, 2023): 4048. http://dx.doi.org/10.3390/nu15184048.
Abstract:
Doxorubicin (DOX), a potent chemotherapy agent, useful in the treatment of solid tumors, lymphomas, and leukemias, is limited by its potentially lethal cardiotoxicity. However, exercise has been consistently shown to mitigate the side effects of DOX, including cardiotoxicity. To date, most studies examining the relationship between exercise and DOX-induced cardiotoxicity have focused on aerobic exercise, with very few examining the role of anerobic activity. Therefore, this investigation explored the potential of creatine (CR) and resistance training (RT) in preserving cardiac health during DOX therapy. Male Sprague-Dawley rats were grouped into RT, RT + CR, sedentary (SED), and SED + CR, with each division further branching into saline (SAL) or DOX-treated subsets post-10 weeks of RT or SED activity. RT comprised progressive training utilizing specialized cages for bipedal stance feeding. CR-treated groups ingested water mixed with 1% CR monohydrate and 5% dextrose, while control animals received 5% dextrose. At week 10, DOX was administered (2 mg/kg/week) over 4-weeks to an 8 mg/kg cumulative dose. Cardiac function post-DOX treatment was assessed via transthoracic echocardiography. Left ventricular diameter during diastole was lower in DOX + CR, RT + DOX, and RT + CR + DOX compared to SED + DOX (p < 0.05). Additionally, cardiac mass was significantly greater in RT + CR + DOX SED + DOX animals (p < 0.05). These results suggest RT and CR supplementation, separately and in combination, could attenuate some measures of DOX-induced cardiotoxicity and may offer a cost-effective way to complement cancer treatments and enhance patient outcomes. More investigations are essential to better understand CR’s prolonged effects during DOX therapy and its clinical implications.
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Legi, Ashiq, Emma Rodriguez, Thomas K. Eckols, Cyrus Mistry, and Prema Robinson. "Substance P Antagonism Prevents Chemotherapy-Induced Cardiotoxicity." Cancers 13, no. 7 (April 6, 2021): 1732. http://dx.doi.org/10.3390/cancers13071732.
Abstract:
Background: Doxorubicin (DOX), used in chemotherapeutic regimens in many cancers, has been known to induce, cardiotoxicity and life-threatening heart failure or acute coronary syndromes in some patients. We determined the role of Substance P (SP), a neuropeptide and its high affinity receptor, NK-1R in chemotherapy associated cardiotoxicity in mice. We determined if NK-1R antagonism will prevent DOX-induced cardiotoxicity in vivo. Methods: C57BL/6 mice (6- week old male) were injected intraperitoneally with DOX (5 mg per kilogram of body weight once a week for 5 weeks) with or without treatment with aprepitant (a NK-1R antagonist, Emend, Merck & Co., Kenilworth, NJ, USA). Five different dosages of aprepitant were administered in the drinking water five days before the first injection of DOX and then continued until the end of the experiment. Each of these 5 doses are as follows; Dose 1 = 0.9 µg/mL, Dose 2 = 1.8 µg/mL, Dose 3 = 3.6 µg/mL, Dose 4 = 7.2 µg/mL, Dose 5 = 14.4 µg/mL. Controls consisted of mice injected with PBS (instead of DOX) with or without aprepitant treatment. The experiment was terminated 5 weeks post-DOX administration and various cardiac functional parameters were determined. Following euthanization, we measured heart weight to body weight ratios and the following in the hearts, of mice treated with and without DOX and aprepitant; (a) levels of SP and NK1R, (b) cardiomyocyte diameter (to determine evidence of cardiomyocyte hypertrophy), (c) Annexin V levels (to determine evidence of cardiac apoptosis), and (d) ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) (to determine evidence of oxidative stress). Results: We demonstrated that the levels of SP and NK1R were significantly increased respectively by 2.07 fold and 1.86 fold in the hearts of mice treated with versus without DOX. We determined that DOX-induced cardiac dysfunction was significantly attenuated by treatment with aprepitant. Cardiac functional parameters such as fractional shortening (FS), ejection fraction (EF) and stroke volume (SV) were respectively decreased by 27.6%, 21.02% and 21.20% compared to the vehicle treated group (All, p < 0.05, ANOVA). Importantly, compared to treatment with DOX alone, treatment with lower doses of aprepitant in DOX treated mice significantly reduced the effects of DOX on FS, EF and SV to values not significantly different from sham (vehicle treated) mice (All, p < 0.05, ANOVA). The levels of, apoptosis marker (Annexin V), oxidative stress (ratio of GSH with GSSG) and cardiomyocyte hypertrophy were respectively increased by 47.61%, 91.43% and 47.54% in the hearts of mice treated with versus without DOX. Compared to the DOX alone group, treatment with DOX and Dose 1, 2 and 3 of aprepitant significantly decreased the levels of each of these parameters (All p < 0.05, ANOVA). Conclusions: Our studies indicate that the SP/NK1-R system is a key mediator that induces, DOX-induced, cardiac dysfunction, cardiac apoptosis, cardiac oxidative stress and cardiomyocyte hypertrophy. These studies implicate that NK-1R antagonists may serve as a novel therapeutic tool for prevention of chemotherapy induced cardiotoxicity in cancer.
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Tao, Rong-Hua, Masato Kobayashi, Yuanzheng Yang, and Eugenie S. Kleinerman. "Exercise Inhibits Doxorubicin-Induced Damage to Cardiac Vessels and Activation of Hippo/YAP-Mediated Apoptosis." Cancers 13, no. 11 (June 1, 2021): 2740. http://dx.doi.org/10.3390/cancers13112740.
Abstract:
Dose-related cardiomyopathy is a major side effect following doxorubicin (Dox). To investigate whether exercise (Ex)-induced vasculogenesis plays a role in reducing Dox-induced cardiotoxicity, GFP+ bone marrow (BM) cells from GFP transgenic mice were transplanted into wild-type mice. Transplanted mice were treated with Dox, Ex, Dox+Ex, or control. We found Dox therapy resulted in decreased systolic and diastolic blood flow, decreased ejection fraction and fractional shortening, and decreased vascular endothelial cells and pericytes. These abnormalities were not seen in Dox+Ex hearts. Heart tissues from control-, Ex-, or Dox-treated mice showed a small number of GFP+ cells. By contrast, the Dox+Ex-treated hearts had a significant increase in GFP+ cells. Further analyses demonstrated these GFP+ BM cells had differentiated into vascular endothelial cells (GFP+CD31+) and pericytes (GFP+NG2+). Decreased cardiomyocytes were also seen in Dox-treated but not Dox+Ex-treated hearts. Ex induced an increase in GFP+c-Kit+ cells. However, these c-Kit+ BM stem cells had not differentiated into cardiomyocytes. Dox therapy induced phosphorylation of MST1/2, LATS1, and YAP; a decrease in total YAP; and cleavage of caspase-3 and PARP in the heart tissues. Dox+Ex prevented these effects. Our data demonstrated Dox-induced cardiotoxicity is mediated by vascular damage resulting in decreased cardiac blood flow and through activation of Hippo-YAP signaling resulting in cardiomyocyte apoptosis. Furthermore, Ex inhibited these effects by promoting migration of BM stem cells into the heart to repair the cardiac vessels damaged by Dox and through inhibiting Dox-induced Hippo-YAP signaling-mediated apoptosis. These data support the concept of using exercise as an intervention to decrease Dox-induced cardiotoxicity.
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Zhang, Wen-Bin, Xin Lai, and Xu-Feng Guo. "Activation of Nrf2 by miR-152 Inhibits Doxorubicin-Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis." Oxidative Medicine and Cellular Longevity 2021 (January 26, 2021): 1–14. http://dx.doi.org/10.1155/2021/8860883.
Abstract:
Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.
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Rong, Jing, Lizhong Li, Li Jing, Haiqin Fang, and Shuangqing Peng. "JAK2/STAT3 Pathway Mediates Protection of Metallothionein Against Doxorubicin-Induced Cytotoxicity in Mouse Cardiomyocytes." International Journal of Toxicology 35, no. 3 (November 2, 2015): 317–26. http://dx.doi.org/10.1177/1091581815614261.
Abstract:
Doxorubicin (Dox) is one of the most important anticancer agents; however, its clinical application is limited by its severe cardiotoxicity. In our previous study, we found that the gene expression levels of the Janus-activated kinase/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway were different between MT−/− cardiomyocytes and MT+/+ cardiomyocytes when they were treated with Dox. Thus, this study was intended to investigate the role of JAK2/STAT3 pathway in metallothionein (MT) protection of Dox-induced cardiotoxicity. Tyrphostin AG490 (α-cyano-(3,4-dihydroxy)-N-benzylcinnamide) is a synthetic protein tyrosine kinase inhibitor which at first has been considered as a specific JAK2 inhibitor and can inhibit the JAK2/STAT3 signaling pathway. In the present study, AG490 was used to assess the role of JAK2/STAT3 in MT protection against Dox-induced cardiotoxicity. The AG490 can attenuate the MT protection by increasing lactate dehydrogenase and the number of apoptotic cells. Interestingly, pretreated with AG490, MT−/− cardiomyocytes were more sensitive than MT+/+ to Dox-induced cytotoxicity as measured by reactive oxygen species generation, lipid peroxidation, and protein carbonylation. Metallothionein 1 and MT-2 messenger RNA were upregulated by Dox, and AG490 decreased the protein expression of MT-1 and MT-2. After Dox treatment, the protein expression of p-Jak2 and p-Stat3 levels was significantly increased in MT+/+ cardiomyocytes, suggesting that the JAK2/STAT3 pathway was partially involved in MT protection against Dox-induced cardiotoxicity.
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Ashour, Osama M., Ashraf B. Abdel-Naim, Hossam M. Abdallah, Ayman A. Nagy, Ahmed M. Mohamadin, and Essam A. Abdel-Sattar. "Evaluation of the Potential Cardioprotective Activity of Some Saudi Plants against Doxorubicin Toxicity." Zeitschrift für Naturforschung C 67, no. 5-6 (June 1, 2012): 297–307. http://dx.doi.org/10.1515/znc-2012-5-609.
Abstract:
Doxorubicin (DOX) is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumours. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. The local Saudi flora is very rich in a variety of plants of quite known folkloric or traditional medicinal uses. Tribulus macropterus Boiss., Olea europaea L. subsp. africana (Mill.) P. S. Green, Tamarix aphylla (L.) H. Karst., Cynomorium coccineum L., Cordia myxa L., Calligonum comosum L’ Hér, and Withania somnifera (L.) Dunal are Saudi plants known to have antioxidant activities. The aim of the current study was to explore the potential protective effects of methanolic extracts of these seven Saudi plants against DOX-induced cardiotoxicity in rats. Two plants showed promising cardioprotective potential in the order Calligonum comosum > Cordia myxa. The two plant extracts showed potent in vitro radical scavenging and antioxidant properties. They significantly protected against DOX-induced alterations in cardiac oxidative stress markers (GSH and MDA) and cardiac serum markers (CK-MB and LDH activities). Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. In conclusion, C. comosum and C. myxa exerted protective activity against DOX-induced cardiotoxicity, which is, at least partly, due to their antioxidant effect