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Chang, Meng-Ting, Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, and Lie-Fen Shyur. "Abstract PR05: Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target." Cancer Research 80, no. 19_Supplement (October 1, 2020): PR05. http://dx.doi.org/10.1158/1538-7445.mel2019-pr05.
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Abstract Melanoma is the most life-threatening skin cancer in the world. Advanced melanoma is highly metastatic, commonly develops drug resistance, and causes low survival rate in patients. PLX4032 (vemurafenib), a BRAFV600E inhibitor, is used to treat patients with late-stage melanoma. It showed initial good clinical responses but relapsed due to acquired drug resistance in tumors. The mechanism of PLX4032-induced resistance in melanoma is not well characterized; in particular, whether PLX4032-induced drug resistance in BRAF mutant melanoma would alter lipid metabolism in cancer is not clear. Understanding the status and role of lipid mediators (oxylipins) in melanoma pathology may be crucial for developing effective approach to overcome drug resistance. Our laboratory has demonstrated that plant sesquiterpene lactone deoxyelephantopin (DET) and its novel derivative DETD-35 effectively suppressed human A375 BRAFV600E melanoma with acquired drug resistance to PLX4032 in vitro and in xenograft mice. In this study we aimed to identify potential biomarkers associated with the resistant melanoma cells (A375-R) in the context of bioactive lipid mediators and to investigate whether DETD-35/DET effects against drug-resistant melanoma are through regulating their dynamics and contents. MS-based metabolomics was used to comprehensively analyze the oxylipin profiles in A375 and A375-R cells, mouse A375/A375-R tumor tissues, and respective sera with vehicle, drug, or compound treatment. We observed that PLX4032-resistant A375R melanoma cells or tumors produce significant and higher amounts of CYP450 enzyme-derived oxylipins than the parental A375, which were decreased after DETD-35 or DET treatment. This study proposes a role of CYP450-derived oxylipins in PLX4032-resistant melanoma cells and its potential to be a drug target. This abstract is also being presented as Poster B03. Citation Format: Meng-Ting Chang, Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. Unique lipid metabolite profiling in BRAFV600E inhibitor drug-resistant melanoma and their potential as drug target [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR05.
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Haasler, Lisa, Arun Kumar Kondadi, Thanos Tsigaras, Claudia von Montfort, Peter Graf, Wilhelm Stahl, and Peter Brenneisen. "The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro." Archives of Toxicology 95, no. 4 (February 1, 2021): 1349–65. http://dx.doi.org/10.1007/s00204-021-02987-4.
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AbstractA major challenge in current cancer therapy is still the treatment of metastatic melanomas of the skin. BH3 mimetics represent a novel group of substances inducing apoptosis. In this study, we investigated the cytotoxic effect of (±) gossypol (GP), a natural compound from cotton seed, on A375 melanoma cells and the underlying biochemical mechanisms. To prevent undesired side effects due to toxicity on normal (healthy) cells, concentrations only toxic for tumor cells have been elaborated. Viability assays were performed to determine the cytotoxicity of GP in A375 melanoma and normal (healthy) cells. For the majority of experiments, a concentration of 2.5 µM GP was used resulting in a ROS-independent but caspase-dependent cell death of A375 melanoma cells. At this level, GP was non-toxic for normal human epidermal melanocytes. GP has a very short half-life, however, it was demonstrated that only the “parent” compound and not decomposition products are responsible for the cytotoxic effect in A375 melanoma cells. GP significantly decreased mitochondrial membrane potential accompanied by a Drp1-dependent loss of mitochondrial integrity (fragmentation) in tumor cells. Taken together, GP induced a ROS-independent intrinsic apoptosis leading to the conclusion that within a specific concentration range, GP may work as effective anticancer drug without harmful side effects.
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Wu, Shih-Yen, Shih-Pin Huang, Yen-Chen Lo, Ren-Shyan Liu, Shyh-Jen Wang, Wuu-Jyh Lin, Chih-Chieh Shen, and Hsin-Ell Wang. "Synthesis and Preclinical Characterization of [18F]FPBZA: A Novel PET Probe for Melanoma." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/912498.
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Introduction. Benzamide can specifically bind to melanoma cells. A18F-labeled benzamide derivative, [18F]N-(2-diethylaminoethyl)-4-[2-(2-(2-fluoroethoxy) ethoxy)ethoxy]benzamide ([18F]FPBZA), was developed as a promising PET probe for primary and metastatic melanoma.Methods. [18F]FPBZA was synthesized via a one-step radiofluorination in this study. The specific uptake of [18F]FPBZA was studied in B16F0 melanoma cells, A375 amelanotic melanoma cells, and NB-DNJ-pretreated B16F0 melanoma cells. The biological characterization of [18F]FPBZA was performed on mice bearing B16F0 melanoma, A375 amelanotic melanoma, or inflammation lesion.Results. [18F]FPBZA can be prepared efficiently with a yield of 40–50%. The uptake of [18F]FPBZA by B16F0 melanoma cells was significantly higher than those by A375 tumor cells and NB-DNJ-pretreated B16F0 melanoma cells. B16F0 melanoma displayed prominent uptake of [18F]FPBZA at 2 h (7.81±0.82 %ID/g), compared with A375 tumor and inflammation lesion (3.00±0.71and1.67±0.56 %ID/g, resp.). [18F]FPBZA microPET scan clearly delineated B16F0 melanoma but not A375 tumor and inflammation lesion. In mice bearing pulmonary metastases, the lung radioactivity reached4.77±0.36 %ID/g at 2 h (versus1.16±0.23 %ID/g in normal mice).Conclusions. Our results suggested that [18F]FPBZA PET would provide a promising and specific approach for the detection of primary and metastatic melanoma lesions.
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Liu, Jia-Fang, Kuang Lai, Shu-Fen Peng, Pornsuda Maraming, Yi-Ping Huang, An-Cheng Huang, Fu-Shin Chueh, Wen-Wen Huang, and Jing-Gung Chung. "Berberine Inhibits Human Melanoma A375.S2 Cell Migration and Invasion via Affecting the FAK, uPA, and NF-κB Signaling Pathways and Inhibits PLX4032 Resistant A375.S2 Cell Migration In Vitro." Molecules 23, no. 8 (August 13, 2018): 2019. http://dx.doi.org/10.3390/molecules23082019.
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Many studies have demonstrated that berberine inhibited the cell migration and invasion in human cancer cell lines. However, the exact molecular mechanism of berberine inhibiting the cell migration and invasion of human melanoma A375.S2 and A375.S2/PLX (PLX4032 induced resistant A375.S2) skin cancer cells remains unknown. In this study, we investigated the anti-metastasis mechanisms of berberine in human melanoma cancer A375.S2 cells and A375.S2/PLX resistant cells in vitro. Berberine at low concentrations (0, 1, 1.5 and 2 μM) induced cell morphological changes and reduced the viable cell number and inhibited the mobility, migration, and invasion of A375.S2 cells that were assayed by wound healing and transwell filter. The gelatin zymography assay showed that berberine slightly inhibited MMP-9 activity in A375.S2 cells. Results from western blotting indicated that berberine inhibited the expression of MMP-1, MMP-13, E-cadherin, N-cadherin, RhoA, ROCK1, SOS-1, GRB2, Ras, p-ERK1/2, p-c-Jun, p-FAK, p-AKT, NF-κB, and uPA after 24 h of treatment, but increased the PKC and PI3K in A375.S2 cells. PLX4032 is an inhibitor of the BRAFV600E mutation and used for the treatment of cancer cells harboring activated BRAF mutations. Berberine decrease cell number and inhibited the cell mobility in the resistant A375.S2 (A375.S2/PLX, PLX4032 generated resistant A375.S2 cells). Based on these observations, we suggest that the potential of berberine as an anti-metastatic agent in melanoma that deserves to be investigated in more detail, including in vivo studies in future.
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Huang, Dao Chao, Xian Fang Yang, Benoît Ochietti, Ibtihal Fadhil, Anne Camirand, and Richard Kremer. "Parathyroid Hormone-Related Protein: Potential Therapeutic Target for Melanoma Invasion and Metastasis." Endocrinology 155, no. 10 (October 1, 2014): 3739–49. http://dx.doi.org/10.1210/en.2013-1803.
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Abstract The role of PTHrP in the highly metastatic human melanoma disease is not known. This study investigates the mechanisms of action of this secreted factor through homozygous inactivation of the Pthrp gene in A375 human melanoma cells. In vitro, Pthrp-ablated cells (knockout [KO]-A375, −/−) showed decreased motility and anchorage-independent growth, rounder morphology, and a significant reduction in invasion capacity compared with nonablated A375 cells (wild-type [WT]-A375, +/+). PTHrP peptide 1–34 and conditioned medium from WT-A375 cells partially restored the invasive phenotype in KO-A375. Pthrp ablation substantially decreased actin polymerization, matrix metallopeptidase 9 expression and focal adhesion kinase phosphorylation. In vivo, green fluorescent protein-transduced ablated and nonablated A375 cells were injected intracardially or sc into nude mice to study proliferation and multiorgan metastasis. Dissemination of injected Pthrp-ablated cells to lung and liver was reduced by 85% and 50%, respectively, compared with nonablated controls (120 hours after injection). The number of metastatic lesions and the percentage of animals with metastasis were markedly lower in mice injected with Pthrp-ablated A375, and 45% of these animals survived a 7-week period compared with 15% of mice injected with nonablated WT-A375. When mice injected with WT-A375 were treated with our blocking anti-PTHrP monoclonal antibody raised against the first 33 amino acids of human PTHrP, tumor size was decreased by more than 80% over 4 weeks and survival was significantly improved over 8 months. This study provides direct evidence of the major role for PTHrP in melanoma invasion and metastasis and suggests that agents that suppress PTHrP may be beneficial against melanoma progression.
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Lachman, L. B., C. A. Dinarello, N. D. Llansa, and I. J. Fidler. "Natural and recombinant human interleukin 1-beta is cytotoxic for human melanoma cells." Journal of Immunology 136, no. 8 (April 15, 1986): 3098–102. http://dx.doi.org/10.4049/jimmunol.136.8.3098.
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Abstract Human peripheral blood monocytes stimulated with LPS were found to release an activity that was cytotoxic for the A375 melanoma. Biochemical and immunological characterization of the activity indicated that IL 1-beta was the cytotoxic agent. Human recombinant IL 1-beta, purified to homogeneity, was directly cytotoxic for A375. Tumor necrosis factor, also released by activated monocytes, was not cytotoxic for the A375 melanoma.
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Ge, Lan, Yaguang Wu, Ming Wan, Yi You, Zhifang Zhai, and Zhiqiang Song. "Metformin Increases Sensitivity of Melanoma Cells to Cisplatin by Blocking Exosomal-Mediated miR-34a Secretion." Journal of Oncology 2021 (November 29, 2021): 1–7. http://dx.doi.org/10.1155/2021/5525231.
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Melanoma, also known as malignant melanoma, is a type of cancer derived from the pigment-containing cells known as melanocytes. Cisplatin (CDDP) is widely used in the treatment of different types of tumors with high response rates, but it generally has low efficiency in melanoma. This study aimed to investigate whether metformin could sensitize the melanoma cell line A375 to cisplatin. Our results for the first time indicated that CDDP increased the miR-34a secretion by exosomes in melanoma A375 cells, which was, at least partially, related to the cisplatin resistance of melanoma cells. Moreover, metformin significantly sensitized A375 cells to cisplatin. Mechanistically, metformin significantly blocked the exosome-mediated miR-34a secretion induced by cisplatin. Our study not only reveals a novel mechanism that exosomal secretion of miR-34a is involved in the cisplatin resistance of melanoma cells but also provides a promising therapeutic strategy by synergistic addition of metformin.
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Freeman, Taylor, Samar Sayedyahossein, Danielle Johnston, Rafael Sanchez-Pupo, Brooke O’Donnell, Kenneth Huang, Zameena Lakhani, et al. "Inhibition of Pannexin 1 Reduces the Tumorigenic Properties of Human Melanoma Cells." Cancers 11, no. 1 (January 16, 2019): 102. http://dx.doi.org/10.3390/cancers11010102.
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Pannexin 1 (PANX1) is a channel-forming glycoprotein expressed in many tissues including the skin. PANX1 channels allow the passage of ions and molecules up to 1 kDa, including ATP and other metabolites. In this study, we show that PANX1 is highly expressed in human melanoma tumors at all stages of disease progression, as well as in patient-derived cells and established melanoma cell lines. Reducing PANX1 protein levels using shRNA or inhibiting channel function with the channel blockers, carbenoxolone (CBX) and probenecid (PBN), significantly decreased cell growth and migration, and increased melanin production in A375-P and A375-MA2 cell lines. Further, treatment of A375-MA2 tumors in chicken embryo xenografts with CBX or PBN significantly reduced melanoma tumor weight and invasiveness. Blocking PANX1 channels with PBN reduced ATP release in A375-P cells, suggesting a potential role for PANX1 in purinergic signaling of melanoma cells. In addition, cell-surface biotinylation assays indicate that there is an intracellular pool of PANX1 in melanoma cells. PANX1 likely modulates signaling through the Wnt/β-catenin pathway, because β-catenin levels were significantly decreased upon PANX1 silencing. Collectively, our findings identify a role for PANX1 in controlling growth and tumorigenic properties of melanoma cells contributing to signaling pathways that modulate melanoma progression.
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Liu, Wenjing, Xiaona Liu, Zhaohai Pan, Dan Wang, Minjing Li, Xiaoyu Chen, Ling Zhou, Maolei Xu, Defang Li, and Qiusheng Zheng. "Ailanthone Induces Cell Cycle Arrest and Apoptosis in Melanoma B16 and A375 Cells." Biomolecules 9, no. 7 (July 11, 2019): 275. http://dx.doi.org/10.3390/biom9070275.
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Malignant melanoma is the most lethal type of skin cancer. Previous studies have shown that ailanthone has potent antitumor activity in a variety of cell lines. However, the anti-tumor effect of ailanthone on malignant melanoma remains unclear. To investigate the anti-tumor mechanisms of ailanthone in human melanoma B16 and mouse melanoma A375 cells, the cell counting kit-8 assay, colony formation assay, DNA content analysis, Hoechst 33258, and Annexin V-FITC/PI staining were used to assess cell proliferation, cell cycle distribution, and cell apoptosis, respectively. Western blotting was performed to evaluate the expression of cell cycle- and apoptosis-related proteins and regulatory molecules. The results showed that ailanthone significantly inhibited melanoma B16 and A375 cell proliferation as well as remarkably induced cell cycle arrest at the G0–G1 phase in B16 cells and the G2–M phase in A375 cells in a dose-dependent manner. Further investigation revealed that ailanthone promoted the expression of p21 and suppressed the expression of cyclin E in B16 cells or cyclin B in A375 cells through the PI3K-Akt signaling pathway. In addition, ailanthone induced B16 and A375 cell apoptosis via a caspase-dependent mechanism. Further studies showed that ailanthone remarkably downregulated Bcl-2 and upregulated Apaf-1 and Bax, and subsequently increased mitochondrial membrane permeabilization and released cytochrome c from the mitochondria in B16 cells and A375 cells. Taken together, ailanthone induces cell cycle arrest via the PI3K-Akt signaling pathway as well as cell apoptosis via the mitochondria-mediated apoptotic signaling pathway. Ailanthone may be potentially utilized as an anti-tumor agent in the management of malignant melanoma.
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Park, Jaehyun, Mijin Kwon, Jaehoon Lee, Sangkyu Park, Jeongmin Seo, and Sangho Roh. "Anti-Cancer Effects of Lactobacillus plantarum L-14 Cell-Free Extract on Human Malignant Melanoma A375 Cells." Molecules 25, no. 17 (August 26, 2020): 3895. http://dx.doi.org/10.3390/molecules25173895.
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Human malignant melanoma is the most aggressive type of skin cancer with high metastatic ability. Despite several traditional therapies, the mortality rate remains high. Lactobacillus plantarum (L. plantarum), a species of lactic acid bacteria (LAB), is being studied for human health, including cancer treatment. However, few studies have elucidated the relationship between L. plantarum extract and human malignant melanoma. To investigate the effects of L. plantarum on human melanoma cells, A375 human melanoma cells were used and treated with L. plantarum L-14 extract. After the treatment, viability, migration ability, molecular changes of migration- and apoptosis-related genes, and the location of cytochrome c was evaluated. The L-14 extract inhibited the viability, migration of A375 cells as well as reduced expression of migration-related genes. In addition, it was confirmed that the L-14 extract induced intrinsic apoptosis in A375 cells. This study demonstrated that the L-14 extract exerted anticancer effects on A375 cells. Therefore, these data suggest that the L-14 extract is worth studying for the development of melanoma drugs using LAB.
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Jandova, Jana, Jessica Perer, Anh Hua, Jeremy A. Snell, and Georg T. Wondrak. "Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo." Cancers 12, no. 6 (May 26, 2020): 1369. http://dx.doi.org/10.3390/cancers12061369.
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Metabolic reprogramming is a molecular hallmark of cancer. Recently, we have reported the overexpression of glyoxalase 1 (encoded by GLO1), a glutathione-dependent enzyme involved in detoxification of the reactive glycolytic byproduct methylglyoxal, in human malignant melanoma cell culture models and clinical samples. However, the specific role of GLO1 in melanomagenesis remains largely unexplored. Here, using genetic target modulation, we report the identification of GLO1 as a novel molecular determinant of invasion and metastasis in malignant melanoma. First, A375 human malignant melanoma cells with GLO1 deletion (A375-GLO1_KO) were engineered using CRISPR/Cas9, and genetic rescue clones were generated by stable transfection of KO clones employing a CMV-driven GLO1 construct (A375-GLO1_R). After confirming GLO1 target modulation at the mRNA and protein levels (RT-qPCR, immunodetection, enzymatic activity), phenotypic characterization indicated that deletion of GLO1 does not impact proliferative capacity while causing significant sensitization to methylglyoxal-, chemotherapy-, and starvation-induced cytotoxic stress. Employing differential gene expression array analysis (A375-GLO1_KO versus A375-GLO1_WT), pronounced modulation of epithelial mesenchymal transition (EMT)-related genes [upregulated: CDH1, OCLN, IL1RN, PDGFRB, SNAI3; (downregulated): BMP1, CDH2, CTNNB1, FN1, FTH1, FZD7, MELTF, MMP2, MMP9, MYC, PTGS2, SNAI2, TFRC, TWIST1, VIM, WNT5A, ZEB1, and ZEB2 (up to tenfold; p < 0.05)] was observed—all of which are consistent with EMT suppression as a result of GLO1 deletion. Importantly, these expression changes were largely reversed upon genetic rescue employing A375-GLO1_R cells. Differential expression of MMP9 as a function of GLO1 status was further substantiated by enzymatic activity and ELISA analysis; phenotypic assessment revealed the pronounced attenuation of morphological potential, transwell migration, and matrigel 3D-invasion capacity displayed by A375-GLO1_KO cells, reversed again in genetic rescue clones. Strikingly, in a SCID mouse metastasis model, lung tumor burden imposed by A375-GLO1_KO cells was strongly attenuated as compared to A375-GLO1_WT cells. Taken together, these prototype data provide evidence in support of a novel function of GLO1 in melanoma cell invasiveness and metastasis, and ongoing investigations explore the function and therapeutic potential of GLO1 as a novel melanoma target.
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Bai, Ming, Nan-Ze Yu, Fei Long, Cheng Feng, and Xiao-Jun Wang. "Effects of CDKN2A (p16INK4A/p14ARF) Over-Expression on Proliferation and Migration of Human Melanoma A375 Cells." Cellular Physiology and Biochemistry 40, no. 6 (2016): 1367–76. http://dx.doi.org/10.1159/000453189.
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Objective: This study aims to investigate the effects of CDKN2A (p16INK4A/p14ARF) over-expression on the proliferation and migration of human melanoma A375 cells. Methods: Melanoma tissues and pigmented nevi tissues were collected. Human melanoma A375 cells were transfected by CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expressing vectors and then assigned into blank, negative control (NC), p16INK4A and p14ARF groups. The expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein was detected by qRT-PCR and Western blotting. CCK-8, flow cytometry and Transwell assays were applied to observe cell proliferation, the cell cycle and apoptosis, and migration and invasion, respectively. The model of subcutaneous xenografts in nude mice was established to measure cell growth in vivo. Results: Compared with pigmented nevi tissues, CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein expression were significantly decreased in melanoma tissues. CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expression inhibited proliferation, migration, invasion and progression from G0/G1 to S phase of A375 cells and xenograft tumor growth, but promoted apoptosis. Conclusion: Our study demonstrated that over-expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) suppressed proliferation and migration of human melanoma A375 cells.
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Peng, Zhi-Peng, Shan-Fu Huang, Jun-Jun Li, Xi-Ke Tang, Xi-Yue Wang, and Hong-Mian Li. "The Effects of Hedgehog Signaling Pathway on the Proliferation and Apoptosis of Melanoma Cells." Journal of Oncology 2022 (January 4, 2022): 1–9. http://dx.doi.org/10.1155/2022/4984866.
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Background. Studies have found that the abnormality of the Hedgehog signaling pathway is related to the occurrence and development of a variety of tumors, but the effect of this signaling pathway on melanoma cells is still unclear. Methods. This study aimed to discuss the effect of Hedgehog signaling pathway on the proliferation and apoptosis of human malignant melanoma A375 cells and explore its possible mechanism in the proliferation and apoptosis of melanoma cells. Different concentrations of Hedgehog signaling pathway inhibitor cyclopamine (5, 10, 20 and 40 μM) were used to treat human melanoma A375 cells for 24, 48, and 72 h, and set a blank control group (0 μM). Trypan blue cell counting method was used to detect cell viability. MTT method was used to detect the inhibition rate of cell proliferation. Transwell was used to detect cell invasion, and flow cytometry was used to detect cell apoptosis. Results. Through the trypan blue cell counting method and MTT experiment, it was found that the Hedgehog signaling pathway inhibitor cyclopamine has an inhibitory effect on the proliferation and viability of melanoma A375 cells ( P < 0.05 ), and the proliferation inhibitory effect is enhanced with prolonged action time in a dose- and time-dependent manner. Transwell experiment showed that compared with the blank control group, the invasion and migration ability of the treated melanoma A375 cells are significantly reduced, and the difference is statistically significant ( P < 0.05 ). Cell apoptosis experiment showed that compared with the blank control group, the apoptosis rate of A375 cells is significantly higher after treated by 40 μM cyclopamine for 24 h, and the difference is statistically significant ( P < 0.05 ). Gli1 and Bcl-2 protein are highly expressed in melanoma A375 cells, and their expressions show a downward trend ( P < 0.05 ) after being treated by cyclopamine. Conclusion. Cyclopamine inhibits cell proliferation and induces cell apoptosis by downregulating Gli1. Hedgehog signaling pathway can be used as a new target for the treatment of malignant melanoma, and multiple measures can be used to inhibit the signaling pathway to achieve a therapeutic effect.
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Cheng, Sun-Long, Rosa Huang-Liu, Jin-Nan Sheu, Shui-Tein Chen, Supachok Sinchaikul, and Gregory J. Tsay. "Toxicogenomics of A375 human malignant melanoma cells." Pharmacogenomics 8, no. 8 (August 2007): 1017–36. http://dx.doi.org/10.2217/14622416.8.8.1017.
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Okazawa, Makoto, Takuma Shiraki, Haruaki Ninomiya, Shigeo Kobavashi, Soichi Miwa, and Tomoh Masaki. "EndothelinB-mediated apoptosis of A375 melanoma cells." Japanese Journal of Pharmacology 76 (1998): 100. http://dx.doi.org/10.1016/s0021-5198(19)40521-0.
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Jiang, Qun-Qun, and Wei-Bing Liu. "Lycorine inhibits melanoma A375 cell growth and metastasis through the inactivation of the PI3K/AKT signaling pathway." médecine/sciences 34 (October 2018): 33–38. http://dx.doi.org/10.1051/medsci/201834f106.
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Malignant melanoma, one of the most aggressive skin cancers, has a very high mortality rate. Currently, the number of drugs to treat melanoma is low. Although new immunotherapeutic approaches based on the use of antibodies against immune checkpoints have shown long term responses, it is urgent to develop novel anti-melanoma drugs with a high efficiency and a low toxicity in a large number of patients. Lycorine, a natural product, has been reported to exert antitumor effects on some cancers. However, the impact of lycorine on melanoma cells is still unknown. Using the CCK8 assay, we found that lycorine can suppress the proliferation of melanoma A375 cells in a dose-time-dependent manner. Moreover, a transwell assay showed that lycorine inhibited the migration and invasion of A375 cells significantly. Further, lycorine treatment could induce the apoptosis of the A375 cells. Biochemical analyses showed that the expression level of the anti-apoptosis Bcl-2 protein decreased, while the expression of the pro-apoptosis protein Bax and active caspase-3 increased after lycorine treatment. Finally, using western blot assay, we found that the antitumor effects of lycorine on A375 cells might be through the inactivation of the PI3K/Akt signaling pathway. Based on these observations, we suggest that lycorine may be an interesting candidate for further studies on its ability to represent a novel antitumor drug for human melanoma treatment in the future.
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Skoniecka, A., M. Cichorek, A. Tyminska, I. Pelikant-Malecka, and J. Dziewiatkowski. "Melanization as unfavorable factor in amelanotic melanoma cell biology." Protoplasma 258, no. 5 (January 27, 2021): 935–48. http://dx.doi.org/10.1007/s00709-021-01613-5.
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AbstractThe biology of three amelanotic melanoma cell lines (Ab, B16F10, and A375) of different species origin was analyzed during in vitro induced melanization in these cells. Melanin production was induced by DMEM medium characterized by a high level of L-tyrosine (a basic amino acid for melanogenesis). The biodiversity of amelanotic melanoma cells was confirmed by their different responses to melanogenesis induction; Ab hamster melanomas underwent intensive melanization, mouse B16F10 darkened slightly, while human A375 cells did not show any change in melanin content. Highly melanized Ab cells entered a cell death pathway, while slight melanization did not influence cell biology in a significant way. The rapid and high melanization of Ab cells induced apoptosis documented by phosphatidylserine externalization, caspase activation, and mitochondrial energetic state decrease. Melanoma cell type, culture medium, and time of incubation should be taken into consideration during amelanotic melanoma cell culture in vitro. L-tyrosine, as a concentration-dependent factor presented in the culture media, could stimulate some amelanotic melanoma cell lines (Ab, B16F10) to melanin production. The presence of melanin should be considered in the examination of antimelanoma compounds in vitro, because induction of melanin may interfere or be helpful in the treatment of amelanotic melanoma.
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Zheng, Yufei, Yuqi Wu, Xi Chen, Xiasen Jiang, Kai Wang, and Fuliang Hu. "Chinese Propolis Exerts Anti-Proliferation Effects in Human Melanoma Cells by Targeting NLRP1 Inflammatory Pathway, Inducing Apoptosis, Cell Cycle Arrest, and Autophagy." Nutrients 10, no. 9 (August 26, 2018): 1170. http://dx.doi.org/10.3390/nu10091170.
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Melanoma is a malignant tumor that begins in the melanocyte and has the highest mortality rate among all cutaneous tumors. Chinese propolis (CP) has been shown to have a potent antitumor effect against various cancers. In this study, we uncovered the combined effects of antiproliferation and anti-inflammation of CP on suppressing the progression of human melanoma cell line A375. We evaluated the alterations of protein expression after CP treatment by Western blot. After CP treatment, A375 cells underwent intrinsic apoptosis and cell cycle arrest. Furthermore, we found that CP suppressed inflammation in A375 cells. NLRP1 (NLR family pyrin domain containing 1), confirmed as a proinflammatory protein in melanoma progression, was downregulated significantly by CP, as were the NLRP1-related caspase activation and recruitment domains (CARD) proteins, including caspase-1 and caspase-4. Additionally, decreasing mRNA levels of IL-1α, IL-1β, and IL-18 further proved the negative regulation of CP on the melanoma inflammatory environment. We also discovered that CP induced autophagy in A375 cells. Interestingly, inhibiting autophagy in CP-treated cells diminished its antitumor effect, suggesting that the autophagy was attributed to CP-induced apoptosis. Collectively, CP is a promising candidate for drug development for melanoma therapy.
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Zanrè, Valentina, Rachele Campagnari, Antonietta Cerulli, Milena Masullo, Alessia Cardile, Sonia Piacente, and Marta Menegazzi. "Salviolone from Salvia miltiorrhiza Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation." International Journal of Molecular Sciences 23, no. 3 (January 20, 2022): 1121. http://dx.doi.org/10.3390/ijms23031121.
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Melanoma is a highly malignant solid tumor characterized by an elevated growth and propagation rate. Since, often, melanoma treatment cannot prevent recurrences and the appearance of metastasis, new anti-melanoma agents need to be discovered. Salvia miltiorrhiza roots are a source of diterpenoid derivatives, natural compounds with several biological activities, including antiproliferative and anticancer effects. Seven diterpenoid derivatives were purified from S. miltiorrhiza roots and identified by NMR and MS analysis. Tanshinone IIA and cryptotanshinone were detected as the main components of S. miltiorrhiza root ethanol extract. Although their antitumor activity is already known, they have been confirmed to induce a reduction in A375 and MeWo melanoma cell growth. Likewise, salviolone has been shown to impair the viability of melanoma cells without affecting the growth of normal melanocytes. The underlying anticancer activity of salviolone has been investigated and compared to that of cryptotanshinone in A375 cells, showing an increased P21 protein expression in a P53-dependent manner. In that way, salviolone, even more than cryptotanshinone, displays a multitarget effect on cell-cycle-related proteins. Besides, it modulates the phosphorylation level of the signal transducer and activator of transcription (STAT)3. Unexpectedly, salviolone and cryptotanshinone induce sustained activation of the extracellular signal-regulated kinases (ERK)1/2 and the protein kinase B (Akt). However, the blockage of ERK1/2 or Akt activities suggests that kinase activation does not hinder their ability to inhibit A375 cell growth. Finally, salviolone and cryptotanshinone inhibit to a comparable extent some crucial malignancy features of A375 melanoma cells, such as colony formation in soft agar and metalloproteinase-2 activity. In conclusion, it has been shown for the first time that salviolone, harboring a different molecular structure than tanshinone IIA and cryptotanshinone, exhibits a pleiotropic effect against melanoma by hampering cell cycle progression, STAT3 signaling, and malignant phenotype of A375 melanoma cells.
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Long, Jianwen, and Xianming Pi. "Polyphyllin I Promoted Melanoma Cells Autophagy and Apoptosis via PI3K/Akt/mTOR Signaling Pathway." BioMed Research International 2020 (July 18, 2020): 1–9. http://dx.doi.org/10.1155/2020/5149417.
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To investigate whether Polyphyllin I (PPI) might induce the autophagy and apoptosis of melanoma cells by regulating PI3K/Akt/mTOR signal pathway. Melanoma A375 cells were incubated with different concentrations of Polyphyllin I (0, 1.5, 3.0, and 6.0 mg/L) and PI3K/Akt/mTOR signaling pathway activator IGF-1(20 mg/L). CCK-8 assay was utilized to detect cell proliferation; Cell apoptosis and cell cycle were measured by flow cytometry; Western blot was used to examine the expressions of proteins. Immunofluorescence analysis was performed to evaluate autophagy of A375 cells; In addition, xenograft-bearing nude mice were applied to study the role of Polyphyllin I on melanoma development, melanoma cell proliferation, as well as melanoma cell apoptosis in vivo. The outcomes represented that Polyphyllin I promoted A375 cell apoptosis via upregulating Bax level and cleaved caspase-3 level and downregulating Bcl-2 level, inhibited the growth of A375 cells at the G0/G1 phase, and enhanced cell autophagy via regulating the levels of Beclin 1, LC3II, and p62. However, IGF-1 (an activator of PI3K/Akt/mTOR signal pathway) attenuated these changes that Polyphyllin I induced. Furthermore, the xenograft model experiment confirmed that Polyphyllin I treatment suppressed xenograft tumor growth, increased apoptotic index evaluated by the TUNEL method, and reduced the level of Ki67 in tumor tissues in vivo. In conclusion, Polyphyllin I treatment enhanced melanoma cell autophagy and apoptosis, as well as blocked melanoma cell cycle via suppressing PI3K/Akt/mTOR signal pathway. Meanwhile, Polyphyllin I treatment suppressed the development of melanoma in vivo. Therefore, Polyphyllin I possibly is a promising molecular targeted agent used in melanoma therapy.
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Sciarretta, Francesca, Chiara Fulci, Camilla Palumbo, Dante Rotili, Lucio Tentori, Grazia Graziani, and Anna Maria Caccuri. "Effects of Glutathione Transferase-Targeting Nitrobenzoxadiazole Compounds in Relation to PD-L1 Status in Human Melanoma Cells." Chemotherapy 64, no. 3 (2019): 138–45. http://dx.doi.org/10.1159/000503339.
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Background: PD-L1 is a membrane protein with inhibitory effects on immune responses, whose expression has been correlated with high aggressiveness and the propensity of melanoma to metastasize. The nitrobenzoxadiazole (NBD) NBDHEX and its analog MC3181 are endowed with strong antitumor activity towards melanoma and a significant ability to reduce its adhesion and invasiveness. Therefore, we investigated whether PD-L1 status could affect cell sensitivity to the cytotoxic effects of NBDs. We then evaluated the effects of NBDHEX on PD-L1 expression and autophagy in melanoma cells. We used the BRAF-mutated A375 melanoma cell line and an A375 variant population enriched for PD-L1+ cells as a model. The cytotoxic effects of NBDs were evaluated in comparison to those of the BRAF inhibitor vemurafenib and the autophagy inhibitor chloroquine. Methods: The effect of NBDHEX on autophagy was determined by measuring LC3-II and p62 protein levels by Western blot. The cytotoxic activity of the compounds was evaluated by sulforhodamine B assay. PD-L1 expression and plasma membrane localization were analyzed by FACS and Western blot analysis. Results: NBDHEX behaves as a late-autophagy inhibitor in A375 melanoma cells, as previously found in other tumor cell lines. NBDHEX and MC3181 showed strong and comparable cytotoxic activity in both parental and PD-L1+ A375 cells, with IC50 values in the sub-micromolar range. Conversely, cells sorted for high PD-L1 expression had lower sensitivity to both the BRAF inhibitor vemurafenib and the autophagy inhibitor chloroquine. NBDHEX treatment did not change the total expression and cell surface localization of PD-L1 in both parental and PD-L1+ A375 cells. Conclusions: Our data suggest that NBDs may represent a promising treatment strategy for melanoma with elevated PD-L1 expression.
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El Abdaimi, Khadija, Vasilios Papavasiliou, David Goltzman, and Richard Kremer. "Expression and regulation of parathyroid hormone-related peptide in normal and malignant melanocytes." American Journal of Physiology-Cell Physiology 279, no. 4 (October 1, 2000): C1230—C1238. http://dx.doi.org/10.1152/ajpcell.2000.279.4.c1230.
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We examined parathyroid hormone-related peptide (PTHrP) production and regulation in both normal human melanocytes and in a human amelanotic melanoma cell line (A375). Northern blot and immunocytochemical analysis demonstrated that both cultured A375 cells and normal human melanocytes express PTHrP, but A375 cells expressed much higher levels of the peptide. PTHrP secretory rate increased at least 10-fold after treatment with 10% fetal bovine serum (100.2 ± 2.8 pmol/106 cells vs. basal <15 pmol/106 cells) in proliferating A375 cells but only twofold in confluent cells. Treatment of A375 cells with increasing concentrations of 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] or its low-calcemic analog EB-1089 revealed that EB-1089 was 10-fold more potent than 1,25-(OH)2D3 on inhibition of both cell proliferation and PTHrP expression. Furthermore, inoculation of A375 cells into the mammary fat pad of female severe combined immunodeficiency mice resulted in the development of hypercalcemia and elevated concentrations of plasma immunoreactive PTHrP in the absence of detectable skeletal metastases. Our study, therefore, demonstrates a stepwise increase in PTHrP expression when cells progress from normal to malignant phenotype and suggests that EB-1089 should be further evaluated as a therapeutic agent in human melanoma.
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Anselmi, Martina, Fabrizio Fontana, Monica Marzagalli, Nicoletta Gagliano, Michele Sommariva, and Patrizia Limonta. "Melanoma Stem Cells Educate Neutrophils to Support Cancer Progression." Cancers 14, no. 14 (July 13, 2022): 3391. http://dx.doi.org/10.3390/cancers14143391.
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Background: It is now well-established that cancer stem cells (CSCs) can support melanoma progression by reshaping the tumor immune microenvironment. However, the molecular mechanisms underlying the crosstalk between melanoma SCs and cancer-associated neutrophils have not been elucidated yet. Methods: The aim of the present study was to unravel the role of melanoma SCs in neutrophil polarization. HL60 neutrophil-like (dHL60) cells were treated with conditioned medium from A375 melanoma SCs (CSC-CM), and their phenotype was investigated. Results: We demonstrated that CSC-CM could specifically activate immune cells by increasing CD66b and CD11b expression. In particular, we revealed that A375 CSCs could release various soluble factors, namely TGF-β, IL-6, and IL-8, able to promote the recruitment of neutrophils and their switch toward an N2 phenotype characterized by the activation of ERK, STAT3, and P38 pathways and the overexpression of CXCR2 and NF-kB. Moreover, after exposure to CSC-CM, dHL60 cells exhibited enhanced ROS production and NET release, without undergoing cell death; increased secretion of MMP-9 and pro-inflammatory cytokines was also observed. Finally, CSC-CM-activated neutrophils endowed A375 cells with stemness traits, stimulating both sphere formation and ABCG2 expression. Conclusion: Collectively, our results suggest that melanoma SCs can prime neutrophils to support cancer progression.
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Ichinose, Y., O. Bakouche, J. Y. Tsao, and I. J. Fidler. "Tumor necrosis factor and IL-1 associated with plasma membranes of activated human monocytes lyse monokine-sensitive but not monokine-resistant tumor cells whereas viable activated monocytes lyse both." Journal of Immunology 141, no. 2 (July 15, 1988): 512–18. http://dx.doi.org/10.4049/jimmunol.141.2.512.
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Abstract The purpose of our study was to determine some of the mechanisms involved in macrophage-mediated lysis of tumorigenic cells. A375 human melanoma cells (A375-R) resistant to lysis mediated by TNF and IL-1 were selected from the TNF- and IL-1-sensitive A375 parental melanoma cells subsequent to continuous (2 mo) exposure to rTNF. Peripheral blood monocytes isolated by centrifugal elutriation from healthy donors were incubated with rIFN-gamma and muramyl dipeptide, with a lipoprotein derived from Escherichia coli (CG-31362) or with LPS for 24 h. These activated monocytes lysed both the A375 (monokine-sensitive) and A375-R (monokine-resistant) melanoma cells. Activated tumoricidal macrophages fixed in 2% paraformaldehyde lysed only the TNF- and IL-1-sensitive A375 cells. These fixed monocytes contained both IL-1 and TNF activities as determined by D10 cell proliferation and L929 cytolysis assays, respectively. Nearly identical results were obtained with preparations of plasma membranes from activated human monocytes. Anti-IL-1 and/or anti-TNF sera neutralized the cytolysis of tumor cells mediated by free monokines, by fixed monocytes, or by plasma membrane preparations. In contrast, anti-TNF and/or anti-IL-1 sera did not inhibit tumor cell lysis by viable activated monocytes. We conclude that IL-1 and TNF molecules associated with the plasma membranes of activated monocytes mediate lysis of susceptible target cells. However, because activated monocytes lysed IL-1-and TNF-resistant target cells, molecules other than these monokines must also be involved in the antitumor activity of monocytes.
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Fan, Yuqi, Yiwei Mao, Shijie Cao, Guiyang Xia, Qiang Zhang, Hongyang Zhang, Feng Qiu, and Ning Kang. "S5, a Withanolide Isolated from Physalis Pubescens L., Induces G2/M Cell Cycle Arrest via the EGFR/P38 Pathway in Human Melanoma A375 Cells." Molecules 23, no. 12 (December 1, 2018): 3175. http://dx.doi.org/10.3390/molecules23123175.
Full textAbstract:
S5 is a withanolide natural product isolated from Physalis pubescens L. Our previous experimental studies found that it has significant antitumor activity on renal cell carcinoma. In the present study, the anti-melanoma effect of S5 and the related molecular mechanism was first investigated. It was found that S5 induced an obvious growth inhibitory effect on human melanoma A375 cells with low toxicity to human peripheral blood cells. Furthermore, the results demonstrated that the cell death mode of S5 on A375 cells is not due to inducing apoptosis and autophagy. However, there was a significant time-dependent increase in G2/M phase after treatment of A375 with S5. Meanwhile, S5 could also decrease the protein expression of Cdc25c, Cdc2, and CyclinB1, and increased the expression of p-P53 and P21, suggesting that S5 inhibited A375 cell death through G2/M phase arrest. Moreover, the signal pathway factors P38, extracellular regulated protein kinases (ERK), and epidermal growth factor receptor (EGFR) were observed taking part in the S5-induced A375 cells growth inhibitory effect. In addition, suppressing P38 and EGFR reversed the cell proliferation inhibitory effect and G2/M cell cycle arrest induced by S5 and inhibition of EGFR enhanced the downregulation of the expression of P38 and p-P38, indicating that S5 induced A375 G2/M arrest through the EGFR/P38 pathway. Briefly, this study explained for the first time the mechanism of S5-induced A375 cell growth inhibition in order to provide the basis for its clinical application in melanoma.
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Rok, Jakub, Zuzanna Rzepka, Justyna Kowalska, Klaudia Banach, Artur Beberok, and Dorota Wrześniok. "The Anticancer Potential of Doxycycline and Minocycline—A Comparative Study on Amelanotic Melanoma Cell Lines." International Journal of Molecular Sciences 23, no. 2 (January 13, 2022): 831. http://dx.doi.org/10.3390/ijms23020831.
Full textAbstract:
Malignant melanoma is still a serious medical problem. Relatively high mortality, a still-growing number of newly diagnosed cases, and insufficiently effective methods of therapy necessitate melanoma research. Tetracyclines are compounds with pleiotropic pharmacological properties. Previously published studies on melanotic melanoma cells ascertained that minocycline and doxycycline exerted an anti-melanoma effect. The purpose of the study was to assess the anti-melanoma potential and mechanisms of action of minocycline and doxycycline using A375 and C32 human amelanotic melanoma cell lines. The obtained results indicate that the tested drugs inhibited proliferation, decreased cell viability, and induced apoptosis in amelanotic melanoma cells. The treatment caused changes in the cell cycle profile and decreased the intracellular level of reduced thiols and mitochondrial membrane potential. The exposure of A375 and C32 cells to minocycline and doxycycline triggered the release of cytochrome c and activated initiator and effector caspases. The anti-melanoma effect of analyzed drugs appeared to be related to the up-regulation of ERK1/2 and MITF. Moreover, it was noticed that minocycline and doxycycline increased the level of LC3A/B, an autophagy marker, in A375 cells. In summary, the study showed the pleiotropic anti-cancer action of minocycline and doxycycline against amelanotic melanoma cells. Considering all results, it could be concluded that doxycycline was a more potent drug than minocycline.
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Zhang, Haoran, Aijun Zhang, Anisha A. Gupte, and Dale J. Hamilton. "Plumbagin Elicits Cell-Specific Cytotoxic Effects and Metabolic Responses in Melanoma Cells." Pharmaceutics 13, no. 5 (May 12, 2021): 706. http://dx.doi.org/10.3390/pharmaceutics13050706.
Full textAbstract:
Melanoma is one of the most malignant skin cancers that require comprehensive therapies, including chemotherapy. A plant-derived drug, plumbagin (PLB), exhibits an anticancer property in several cancers. We compared the cytotoxic and metabolic roles of PLB in A375 and SK-MEL-28 cells, each with different aggressiveness. In our results, they were observed to have distinctive mitochondrial respiratory functions. The primary reactive oxygen species (ROS) source of A375 can be robustly attenuated by cell membrane permeabilization. A375 cell viability and proliferation, migration, and apoptosis induction are more sensitive to PLB treatment. PLB induced metabolic alternations in SK-MEL-28 cells, which included increasing mitochondrial oxidative phosphorylation (OXPHOS), mitochondrial ATP production, and mitochondrial mass. Decreasing mitochondrial OXPHOS and total ATP production with elevated mitochondrial membrane potential (MMP) were observed in PLB-induced A375 cells. PLB also induced ROS production and increased proton leak and non-mitochondria respiration in both cells. This study reveals the relationship between metabolism and cytotoxic effects of PLB in melanoma. PLB displays stronger cytotoxic effects on A375 cells, which exhibit lower respiratory function than SK-MEL-28 cells with higher respiratory function, and triggers cell-specific metabolic changes in accordance with its cytotoxic effects. These findings indicate that PLB might serve as a promising anticancer drug, targeting metabolism.
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Zhu, Jinjin, and Pan Xu. "Long Noncoding RNA Small Nucleolar RNA Host Gene 6 Promotes Cell Proliferation, Migration and Invasion in Melanoma by Sponging miR-944." Journal of Biomaterials and Tissue Engineering 11, no. 8 (August 1, 2021): 1459–65. http://dx.doi.org/10.1166/jbt.2021.2615.
Full textAbstract:
Long noncoding RNA small nucleolar RNA host gene 6 (SNHG6) has been reported to be a tumor promoter in various human cancers. Nevertheless, the detailed functions and clinical value of SNHG6 in melanoma remain elusive. The study aimed to investigate the role and potential mechanism of SNHG6 in melanoma metastasis. Quantitative real-time PCR (qRT-PCR) was used to detect the expressions of SNHG6 and miR-944 in melanoma cells. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) assay, and cell migration and invasion were measured by wound healing assay and cell invasion assay, respectively. In addition, dual luciferase reporter assay was performed to verify the interaction between SNHG6 and miR-944. The protein expressions of PI3K/Akt pathway were evaluated by western blot assay. The results revealed that SNHG6 expression was significantly increased in melanoma cells. Knockdown of SNHG6 suppressed cell proliferation, migration and invasion in A375 cells. Moreover, miR-944 was identified as a direct target of SNHG6 in melanoma. miR-944 was downregulated in melanoma cells, while SNHG6 silencing improved miR-944 level in A375 cells. Rescue experiments demonstrated that miR-944 overexpression reversed the effects of SNHG6 on A375 cell proliferation, migration and invasion. Altogether, SNHG6 exerted oncogenic effects in melanoma cells, providing a novel promising target for the treatment of melanoma.
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Alateng, Chulu, Yulei Liu, Gaowa Saren, and Jun Ren. "Diminution of Proliferation, Migration, and Invasion of Melanoma Cells by Arctium Lappa L. Extracts." Current Topics in Nutraceutical Research 19, no. 2 (November 16, 2020): 188–93. http://dx.doi.org/10.37290/ctnr2641-452x.19:188-193.
Full textAbstract:
As a highly aggressive form of human cancer, melanoma is prone to metastasis, leading to 75% of all skin cancer deaths. The 5-year-survival rate of melanoma is below 20%. Therefore, new therapies for melanoma are urgently needed. Burdock (Arctium lappa L) root - known for its antitumor, antioxidant, anti-inflammatory, antiviral, neuroprotective, and endoplasmic reticulum stress regulatory effects - was evaluated for its effects on the proliferation and apoptosis of melanoma cells and its possible mechanism. The results show suppression of the proliferation and stimulation of apoptosis of A375 cells in vitro. Additionally, it suppressed the PI3K/AKT pathway in A375 cells. These data suggest burdock (A. lappa L) root preparation as a promising drug for the treatment of melanoma.
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Wu, Shenglin, Shan Nie, and Jian Wang. "MiR 206 inhibits reorganization of the cytoskeleton in melanoma cells by targeting DDX5." Tropical Journal of Pharmaceutical Research 20, no. 11 (December 11, 2021): 2279–85. http://dx.doi.org/10.4314/tjpr.v20i11.7.
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Purpose: To investigate the role and mechanism of microRNA-206 (miR-206) in cytoskeleton reorganization in melanoma cells.
Methods: MiR-206 and RNA helicase p68 (DDX5) expression levels were measured in A375, A875, and HEM-M cells by quantitative real time polymerase chain reaction (qRT-PCR). A DDX5 overexpression cell line was constructed, and DDX5 overexpression, A375, and A875 cells were transfected with miR-206 mimic or DDX5 small interfering RNA (siRNA). Transwell assay was used to assess cell migration and invasion of A375 and A875 cells, while Luciferase reporter assay was used to determine the putative target of miR-206. DDX5, miR-206, vinculin, coronin3, and ezrin expression levels were evaluated by qRT-PCR. Protein expressions of DDX5, vinculin, coronin3, and ezrin were evaluated by western blot analysis.
Results: DDX5 expression was higher and miR-206 expression lower in A375 and A875 cells when compared to HEM-M cells (p < 0.05). Knockdown of DDX5 and overexpression of miR-206 repressed invasion and migration, and inhibited expression of vinculin, coronin3, and ezrin in A375 and A875 cells (p < 0.05). However, overexpression of DDX5 reversed the effect of miR-206 on cytoskeletal protein expression. Luciferase reporter assay data confirmed that DDX5 is a direct target of miR-206 (p < 0.05).
Conclusion: MiR-206 suppresses reorganization of the cytoskeleton in melanoma cells by targeting DDX5, and is thus, a promising target for the treatment of melanoma.
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Chatterjee, S. J., P. Ovadje, M. Mousa, C. Hamm, and S. Pandey. "The Efficacy of Dandelion Root Extract in Inducing Apoptosis in Drug-Resistant Human Melanoma Cells." Evidence-Based Complementary and Alternative Medicine 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/129045.
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Notoriously chemoresistant melanoma has become the most prevalent form of cancer for the 25–29 North American age demographic. Standard treatment after early detection involves surgical excision (recurrence is possible), and metastatic melanoma is refractory to immuno-, radio-, and most harmful chemotherapies. Various natural compounds have shown efficacy in killing different cancers, albeit not always specifically. In this study, we show that dandelion root extract (DRE) specifically and effectively induces apoptosis in human melanoma cells without inducing toxicity in noncancerous cells. Characteristic apoptotic morphology of nuclear condensation and phosphatidylserine flipping to the outer leaflet of the plasma membrane of A375 human melanoma cells was observed within 48 hours. DRE-induced apoptosis activates caspase-8 in A375 cells early on, demonstrating employment of an extrinsic apoptotic pathway to kill A375 cells. Reactive Oxygen Species (ROS) generated from DRE-treated isolated mitochondria indicates that natural compounds in DRE can also directly target mitochondria. Interestingly, the relatively resistant G361 human melanoma cell line responded to DRE when combined with the metabolism interfering antitype II diabetic drug metformin. Therefore, treatment with this common, yet potent extract of natural compounds has proven novel in specifically inducing apoptosis in chemoresistant melanoma, without toxicity to healthy cells.
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Xie, Zhi, Chen Wang, Li Li, Xianfeng Chen, Guanjing Wei, Yan Chi, Yanping Liang, Lizhen Lan, Jiqiong Hong, and Lili Li. "lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma." Open Medicine 17, no. 1 (January 1, 2022): 1612–22. http://dx.doi.org/10.1515/med-2022-0587.
Full textAbstract:
Abstract Invasion and metastasis of melanoma are a series of complicated biological events regulated by multiple factors. The coregulation of many molecules involved in the development and progression of melanoma contributes to invasion and migration. mGluR1 is a metabotropic glutamate receptor that is overexpressed in melanocytes and is sufficient to induce melanoma. In our study, we found that mGluR1 was obviously increased in melanoma. Furthermore, we found that miR-129-5p could directly target and regulate mGluR1 mRNA, which was significantly reduced in A375 cells. Overexpression of miR-129-5p inhibited cell migration, invasion and clonal formation. lncRNA-AC130710 directly targeted and suppressed miR-129-5p in A375 cells. Downregulation of lncRNA-AC130710 suppressed the levels of mGluR1 mRNA by promoting miR-129-5p expression and further inhibiting migration, invasion and colony formation in A375 cells, which was associated with the activation of the PKCα-MAPK signaling pathway. Taken together, our study showed that the lncRNA-AC130710/miR-129-5p/mGluR1 axis plays an important role in the invasion and metastasis of melanoma.
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Liu, Wenfang, Qianying Yu, Fei Wang, Yunxia Li, Guohua Zhang, and Sirui Tao. "Taraxasterol attenuates melanoma progression via inactivation of reactive oxygen species-mediated PI3K/Akt signaling pathway." Human & Experimental Toxicology 41 (January 2022): 096032712110690. http://dx.doi.org/10.1177/09603271211069034.
Full textAbstract:
Background: Taraxasterol (TX), a pentacyclic triterpene, is one of the main active constituents isolated from Taraxacum officinale. A growing number of studies have reported that TX exhibits a wide range of biological activities such as anti-oxidative, anti-inflammatory, and neuro-protective effects. Recently, TX has been demonstrated to be a potential drug candidate for treatment of some types of cancers. However, the specific role of TX in melanoma remains unclear. Purpose: In this study, we aimed at exploration of the effect of TX on melanoma cell viability, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) as well as the underlying mechanisms. Research design: A375 and SK-MEL-28 cells were treated with various concentrations of TX for different times. Cell viability was measured using CCK-8 assay. Cell apoptosis was determined by flow cytometry. Transwell assays were performed to measure cell migration and invasion. The expression of E-cadherin, α-catenin, N-cadherin, vimentin, p-PI3K, PI3K, p-Akt and Akt was detected using western blot. Results: The study showed that TX induced A375 and SK-MEL-28 cell apoptosis. Furthermore, exposure to TX inhibited A375 and SK-MEL-28 cell migration and invasion. Besides, the EMT process was reversed in A375 and SK-MEL-28 cells after TX treatment. We also observed that TX reduced the protein expression of p-PI3K and p-Akt; thus, inhibiting activity of the PI3K/Akt pathway in A375 and SK-MEL-28 cells. In addition, TX treatment increased the levels of reactive oxygen species (ROS) in A375 and SK-MEL-28 cells, and treatment with the ROS scavenger NAC significantly rescued TX-induced down-regulation of p-PI3K and p-Akt in A375 and SK-MEL-28 cells. Conclusions: In conclusion, our study demonstrated that TX induced ROS accumulation followed by inactivation of the PI3K/Akt pathway and subsequently attenuated melanoma progression, suggesting that TX may be a potential candidate for treatment of melanoma.
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Wang, Mei, Guangwei Shi, Chunxiang Bian, Muhammad Farrukh Nisar, Yingying Guo, Yan Wu, Wei Li, et al. "UVA Irradiation Enhances Brusatol-Mediated Inhibition of Melanoma Growth by Downregulation of the Nrf2-Mediated Antioxidant Response." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–15. http://dx.doi.org/10.1155/2018/9742154.
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Brusatol (BR) is a potent inhibitor of Nrf2, a transcription factor that is highly expressed in cancer tissues and confers chemoresistance. UVA-generated reactive oxygen species (ROS) can damage both normal and cancer cells and may be of potential use in phototherapy. In order to provide an alternative method to treat the aggressive melanoma, we sought to investigate whether low-dose UVA with BR is more effective in eliminating melanoma cells than the respective single treatments. We found that BR combined with UVA led to inhibition of A375 melanoma cell proliferation by cell cycle arrest in the G1 phase and triggers cell apoptosis. Furthermore, inhibition of Nrf2 expression attenuated colony formation and tumor development from A375 cells in heterotopic mouse models. In addition, cotreatment of UVA and BR partially suppressed Nrf2 and its downstream target genes such as HO-1 along with the PI3K/AKT pathway. We propose that cotreatment increased ROS-induced cell cycle arrest and cellular apoptosis and inhibits melanoma growth by regulating the AKT-Nrf2 pathway in A375 cells which offers a possible therapeutic intervention strategy for the treatment of human melanoma.
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Lieser, Elizabeth Ann Teresa, Alexey A. Leontovich, Shernan G. Holtan, Wendy Kay Nevala, and Svetomir Markovic. "Exhibition of a stem-cell like phenotype with the expression of CD271 in drug-resistant melanoma cells." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 8599. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8599.
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8599 Background: Chemotherapy resistance is a common, difficult problem for melanoma patients needing long term care and those suffering from recurrence. Neural growth factor receptor (NGFR), also known as CD271, is commonly expressed on mesenchymal stem cells and is important for development, survival and differentiation of cells. This has previously shown to be expressed on melanoma stem cells. We hypothesized that treatment with carboplatin enriches the population of tumor cells for cancer stem cells (CSC) as a mechanism of chemotherapy resistance. Methods: Core tumor samples from 118 patients with metastatic melanoma were obtained from formalin-fixed paraffin embedded specimens. Slides were stained using an anti-CD271 antibody for IHC. A375 melanoma cells were treated with increasing concentrations of carboplatin for approximately 1 year. WT, 6 mg/mL and 10 mg/mL resistant cells were tagged with CD271-PE antibody and run on a flow cytometer. These cells were then tested for gene expression by microarray using an Affymetrix human 133 plus 2.0 chip, and analyzed on Partek software. Pathway analysis of these carboplatin resistant cells was preformed using Ingenuity. Results: Virtually all melanoma tumor samples stained positively for CD271 by IHC, with a median of 50% cells within tumor samples expressing the cytoplasmic marker. Flow cytometry demonstrated an increase in the percentage of cells expressing CD271 as resistance to carboplatin increased. Wild type A375 cells contained 30% positive CD271, A375 6mg/mL resistant contained 42% positive and A375 10mg/mL resistant showed 66% positive. Microarray also exhibited a direct correlation between CD271 gene expression with increasing carboplatin resistance. Functional ontology enrichment revealed development and regulation of the EMT pathway as an important process impacted by our resistant cell line. Conclusions: The data suggests that as melanoma cells become resistant to certain chemotherapy drugs they essentially loose their differentiated phenotype and become more stem cell-like. Monitoring melanoma expression of CD271 could help individualize therapy and anticipate chemotherapeutic resistance in this high-risk group of patients.
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Chen, Xianjin, Lili Chang, Yan Qu, Jinning Liang, Waishu Jin, and Xiujuan Xia. "Tea polyphenols inhibit the proliferation, migration, and invasion of melanoma cells through the down-regulation of TLR4." International Journal of Immunopathology and Pharmacology 31 (January 1, 2018): 039463201773953. http://dx.doi.org/10.1177/0394632017739531.
Full textAbstract:
Melanoma is the most common skin cancer and malignant melanoma which can cause skin cancer-related deaths. Toll-like receptor 4 (TLR4) had been reported to play an important role in melanoma, and tea polyphenol (TP) is regarded as an anticancer substance. However, the relationship between TP and TLR4 in melanoma is not well explored. Therefore, our aim is to figure out how TP has an influence on melanoma. Melanoma cell lines (B16F10 and A375) were treated with TP and lipopolysaccharides (LPS). Western blot assay was used to examine TLR4 expression, and MTT assay was conducted to assess proliferation. Wound healing assay was conducted to evaluate the migration of melanoma cells, and transwell assay was used to examine the melanoma cells’ invasiveness. Besides, in vivo experiments were practiced for TP function in mice with melanoma cells. TP inhibited the proliferation, migration and invasion ability of melanoma cells, which displayed a dosage and time dependence. TLR4 was highly expressed in melanoma cells compared with normal skin cells. TP could suppress TLR4 expression both in normal melanomas and in stimulated melanomas by TLR4 agonist LPS. Suppressing TLR4 in melanomas could inhibit cell function (proliferation, migration, and invasion), and blocking the expression of 67LR could abolish TP function on TLR4. TP can inhibit melanoma (B16F10) growth in vivo.
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Mioc, Marius, Alexandra Mioc, Roxana Racoviceanu, Roxana Ghiulai, Alexandra Prodea, Andreea Milan, Lucian Barbu Tudoran, Camelia Oprean, Viviana Ivan, and Codruța Șoica. "The Antimelanoma Biological Assessment of Triterpenic Acid Functionalized Gold Nanoparticles." Molecules 28, no. 1 (January 3, 2023): 421. http://dx.doi.org/10.3390/molecules28010421.
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One of several promising strategies for increasing the bioavailability and therapeutic potential of high-lipophilic biologically active compounds is gold nanoparticle formulation. The current study describes the synthesis and biological antimelanoma evaluation of three triterpen-functionalized gold nanoparticles, obtained using our previously reported antimelanoma benzotriazole-triterpenic acid esters. Functionalized gold nanoparticle (GNP) formation was validated through UV-VIS and FTIR spectroscopy. The conjugate’s cytotoxic effects were investigated using HaCaT healthy keratinocytes and A375 human melanoma cells. On A375 cells, all three conjugates demonstrated dose-dependent cytotoxic activity, but no significant cytotoxic effects were observed on normal HaCaT keratinocytes. GNP-conjugates were found to be more cytotoxic than their parent compounds. After treatment with all three GNP-conjugates, 4,6′-diamidino-2-phenylindole (DAPI) staining revealed morphological changes consistent with apoptosis in A375 melanoma cells. Quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed that the triterpene-GNP conjugate treated A375 melanoma cells had a fold change increase in Bcl-2-associated X protein (BAX) expression and a fold change decrease in B-cell lymphoma 2 (Bcl-2) expression. In A735 melanoma cells, high-resolution respirometry studies revealed that all three GNP-conjugates act as selective inhibitors of mitochondrial function. Furthermore, by examining the effect on each mitochondrial respiratory rate, the results indicate that all three conjugates are capable of increasing the production of reactive oxygen species (ROS), an apoptosis trigger in cancer cells.
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Okazawa, Makoto, Takuma Shiraki, Haruaki Ninomiya, Shigeo Kobayashi, and Tomoh Masaki. "Endothelin-induced Apoptosis of A375 Human Melanoma Cells." Journal of Biological Chemistry 273, no. 20 (May 15, 1998): 12584–92. http://dx.doi.org/10.1074/jbc.273.20.12584.
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Klopper, Joshua P., Vibha Sharma, Reid Bissonnette, and Bryan R. Haugen. "Combination PPARγand RXR Agonist Treatment in Melanoma Cells: Functional Importance of S100A2." PPAR Research 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/729876.
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Nuclear hormone receptors, including RXR and PPARγ, represent novel therapeutic targets in melanoma. We have previously shown that the DRO subline of the amelanotic melanoma A375 responds to rexinoid and thiazolidinedione (TZD) treatmentin vitroandin vivo. We performed microarray analysis of A375(DRO) after TZD and combination rexinoid/TZD treatment in which the calcium binding protein S100A2 had increased expression after rexinoid or TZD treatment and a synergistic increase to combination treatment. Increased S100A2 expression is dependent on an intact PPARγreceptor, but it is not sufficient to mediate the antiproliferative effects of rexinoid/TZD treatment. Over expression of S100A2 enhanced the effect of rexinoid and TZD treatment while inhibition of S100A2 expression attenuated the response to rexinoid/TZD treatment, suggesting that S100A2 is necessary for optimal response to RXR and PPARγactivation by respective ligands. In summary, we have identified potential downstream mediators of rexinoid and TZD treatment in a poorly differentiated melanoma and found that alterations in S100A2 expression affect RXR and PPARγsignaling in A375(DRO) cells. These studies provide insight into potential mechanisms of tumor response or resistance to these novel therapies.
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Brito, Cheila, Ana Tomás, Sandra Silva, Maria Rosário Bronze, Ana Teresa Serra, and Marta Pojo. "The Impact of Olive Oil Compounds on the Metabolic Reprogramming of Cutaneous Melanoma Cell Models." Molecules 26, no. 2 (January 8, 2021): 289. http://dx.doi.org/10.3390/molecules26020289.
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Cutaneous melanoma is the deadliest type of skin cancer, characterized by a high molecular and metabolic heterogeneity which contributes to therapy resistance. Despite advances in treatment, more efficient therapies are needed. Olive oil compounds have been described as having anti-cancer properties. Here, we clarified the cytotoxic potential of oleic acid, homovanillyl alcohol, and hydroxytyrosol on melanoma cells. Metabolic viability was determined 48 h post treatment of A375 and MNT1 cells. Metabolic gene expression was assessed by qRT-PCR and Mitogen-Activated Protein Kinase (MAPK) activation by Western blot. Hydroxytyrosol treatment (100 and 200 µM) significantly reduced A375 cell viability (p = 0.0249; p < 0.0001) which, based on the expression analysis performed, is more compatible with a predominant glycolytic profile and c-Jun N-terminal kinase (JNK) activation. By contrast, hydroxytyrosol had no effect on MNT1 cell viability, which demonstrates an enhanced oxidative metabolism and extracellular signal-regulated kinase (ERK) activation. This compound triggered cell detoxification and the use of alternative energy sources in A375 cells, inhibiting JNK and ERK pathways. Despite oleic acid and homovanillyl alcohol demonstrating no effect on melanoma cell viability, they influenced the MNT1 glycolytic rate and A375 detoxification mechanisms, respectively. Both compounds suppressed ERK activation in MNT1 cells. The distinct cell responses to olive oil compounds depend on the metabolic and molecular mechanisms preferentially activated. Hydroxytyrosol may have a cytotoxic potential in melanoma cells with predominant glycolytic metabolism and JNK activation.
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Brito, Cheila, Ana Tomás, Sandra Silva, Maria Rosário Bronze, Ana Teresa Serra, and Marta Pojo. "The Impact of Olive Oil Compounds on the Metabolic Reprogramming of Cutaneous Melanoma Cell Models." Molecules 26, no. 2 (January 8, 2021): 289. http://dx.doi.org/10.3390/molecules26020289.
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Cutaneous melanoma is the deadliest type of skin cancer, characterized by a high molecular and metabolic heterogeneity which contributes to therapy resistance. Despite advances in treatment, more efficient therapies are needed. Olive oil compounds have been described as having anti-cancer properties. Here, we clarified the cytotoxic potential of oleic acid, homovanillyl alcohol, and hydroxytyrosol on melanoma cells. Metabolic viability was determined 48 h post treatment of A375 and MNT1 cells. Metabolic gene expression was assessed by qRT-PCR and Mitogen-Activated Protein Kinase (MAPK) activation by Western blot. Hydroxytyrosol treatment (100 and 200 µM) significantly reduced A375 cell viability (p = 0.0249; p < 0.0001) which, based on the expression analysis performed, is more compatible with a predominant glycolytic profile and c-Jun N-terminal kinase (JNK) activation. By contrast, hydroxytyrosol had no effect on MNT1 cell viability, which demonstrates an enhanced oxidative metabolism and extracellular signal-regulated kinase (ERK) activation. This compound triggered cell detoxification and the use of alternative energy sources in A375 cells, inhibiting JNK and ERK pathways. Despite oleic acid and homovanillyl alcohol demonstrating no effect on melanoma cell viability, they influenced the MNT1 glycolytic rate and A375 detoxification mechanisms, respectively. Both compounds suppressed ERK activation in MNT1 cells. The distinct cell responses to olive oil compounds depend on the metabolic and molecular mechanisms preferentially activated. Hydroxytyrosol may have a cytotoxic potential in melanoma cells with predominant glycolytic metabolism and JNK activation.
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Munshi, Anupama, John F. Kurland, Takashi Nishikawa, Paul J. Chiao, Michael Andreeff, and Raymond E. Meyn. "Inhibition of constitutively activated nuclear factor-κB radiosensitizes human melanoma cells." Molecular Cancer Therapeutics 3, no. 8 (August 1, 2004): 985–92. http://dx.doi.org/10.1158/1535-7163.985.3.8.
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Abstract Melanoma tumors and cultured cell lines are relatively resistant to the cytotoxic effects of ionizing radiation, thereby limiting the use of radiotherapy for the clinical treatment of melanoma. New strategies for sensitizing melanoma cells therefore deserve examination. In an attempt to identify and target signaling pathways that contribute to radioresistance, we investigated the role of nuclear factor-κB (NF-κB), a transcription factor known to inhibit apoptosis induced by a variety of stimuli and promote radioresistance. Two human metastatic melanoma cell lines, A375 and MeWo, were used to examine the radiosensitizing effects of inhibitors of the NF-κB pathway. Nuclear extracts from these cell lines were tested for active NF-κB using the electrophoretic mobility shift assay. Both melanoma cell lines had constitutively activated NF-κB as observed by electrophoretic mobility shift assay. In an attempt to reverse NF-κB activity, cells were treated either with vehicle alone (DMSO) or with a proteasome inhibitor Z-Leu-Leu-Leu-H (MG132; 10 μmol/L for 2 hours prior to irradiation) that inhibited both constitutive and radiation-induced NF-κB activity. The clonogenic cell survival assay showed that pretreatment with MG132 enhanced tumor cell radiosensitivity with the survival factor at 2 Gy being reduced from 48 ± 0.8% and 48 ± 1.6% in vehicle-treated cells to 27.7 ± 0.32% and 34.3 ± 0.7% in MG132-treated MeWo and A375 cells, respectively. To test the role of NF-κB in radioresistance more directly, MeWo cells were stably transfected with a dominant-negative mutant IκBα construct, which led to the inhibition of both constitutive and radiation-induced NF-κB activity. A modest restoration of radiosensitivity was also observed in the stably transfected MeWo cells with survival factor at 2 Gy values being reduced from 47 ± 0.8% in parental MeWo cells to 32.9 ± 0.7% in stable transfectants. Because constitutively activated mitogen-activated protein kinase kinase (MEK) pathway has been shown to lead to activated NF-κB, we wanted to determine the relative contribution of activated MEK in the human melanoma cells. To test this, MeWo and A375 melanoma cells were exposed to the MEK inhibitor PD184352. Treatment with PD184352 partially reversed NF-κB activity but did not impart radiation sensitivity to these cells. Our results indicate that activated NF-κB may be one of the pathways responsible for the radioresistance of melanoma cells and that strategies for inhibiting its influence may be useful in restoring the radioresponse of melanomas.
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Ndlovu, Banele, Maryna De Kock, Jeremy Klaasen, and Farzana Rahiman. "In Vitro Comparison of the Anti-Proliferative Effects of Galenia africana on Human Skin Cell Lines." Scientia Pharmaceutica 89, no. 1 (February 25, 2021): 12. http://dx.doi.org/10.3390/scipharm89010012.
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Malignant melanoma is the major cause of skin cancer-related deaths. Surgery in combination with radiotherapy, immunotherapy or chemotherapy is used to eradicate cancer cells, however, this treatment option is limited by the tolerance of the surrounding healthy tissue. The extracts from Galenia africana have been shown to possess anti-cancer flavonoid compounds and can be a safer and cost-effective alternative treatment. The study aimed to compare the anti-proliferative effects of G. africana on human skin cells (HaCaT) and human malignant melanoma cells (A375). The cells were exposed to various concentrations of the G. africana extract at different times. In vitro assays were employed to determine cell viability and cytotoxicity. Hoechst 33342 staining was performed to observe the nuclear changes, including apoptosis. G. africana significantly reduced the cell viability of the A375 cells in a dose and time-dependent manner, while having no effect on the HaCaT cells. The A375 cells displayed nuclear condensation, brightly stained nuclei and nuclear fragmentation indicative of apoptosis. This suggests a clinical rationale for the use of G. africana as a potential anti-melanoma agent offering efficacy and low toxicity. This study provides new insights for future work on investigating the utilization of G. africana in malignant melanoma treatment.
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Chouchou, Adrien, Cindy Patinote, Pierre Cuq, Pierre-Antoine Bonnet, and Carine Deleuze-Masquéfa. "Imidazo[1,2-a]quinoxalines Derivatives Grafted with Amino Acids: Synthesis and Evaluation on A375 Melanoma Cells." Molecules 23, no. 11 (November 15, 2018): 2987. http://dx.doi.org/10.3390/molecules23112987.
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Imiqualines (imidazoquinoxaline derivatives) are anticancer compounds with high cytotoxic activities on melanoma cell lines. The first generation of imiqualines, with two lead compounds (EAPB0203 and EAPB0503), shows remarkable in vitro (IC50 = 1 570 nM and IC50 = 200 nM, respectively, on the A375 melanoma cell line) and in vivo activity on melanoma xenografts. The second generation derivatives, EAPB02302 and EAPB02303, are more active, with IC50 = 60 nM and IC50 = 10 nM, respectively, on A375 melanoma cell line. The aim of this study was to optimize the bioavailability of imiqualine derivatives, without losing their intrinsic activity. For that, we achieved chemical modulation on the second generation of imiqualines by conjugating amino acids on position 4. A new series of twenty-five compounds was efficiently synthesized by using microwave assistance and tested for its activity on the A375 cell line. In the new series, compounds 11a, 9d and 11b show cytotoxic activities less than second generation compounds, but similar to that of the first generation ones (IC50 = 403 nM, IC50 = 128 nM and IC50 = 584 nM, respectively). The presence of an amino acid leads to significant enhancement of the water solubility for improved drugability.
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Zhao, Ruiting, Yonghong Liu, Sida Liu, Tong Luo, Guang Yuan Zhong, Anqi Liu, Qiang Zeng, and Sherman Xuegang Xin. "Apoptosis-Promoting Effects on A375 Human Melanoma Cells Induced by Exposure to 35.2-GHz Millimeter Wave." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382093413. http://dx.doi.org/10.1177/1533033820934131.
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Malignant tumors pose a major problem in the medical field. Millimeter wave (MMW) exposure have potential apoptosis-promoting effects on several types of tumors. Considering that the penetration depth of millimeter wave is usually several millimeters, we study the apoptosis-promoting effects of millimeter wave exposure on A375 human melanoma tumor cells in vitro, and this topic has not been explored in the previous literature. In this study, we use the A375 human melanoma cell line as an experimental model exposed to 35.2 GHz millimeter wave in vitro to determine any positive effect and further explore the underlying mechanisms. In this study, 2 groups namely, exposed and sham groups, were set. The exposed groups included 4 exposure time periods of 15, 30, 60, and 90 minutes. The cells in the sham group did not receive millimeter wave exposure. After millimeter wave exposure, the A375 cells in the exposed and sham groups were collected for further experimental procedures. The cell viability after exposure was determined using a cell counting kit, and the apoptosis of A375 cells was assessed by Annexin V/propidium iodide. Changes in the expression of apoptosis-related proteins, including cleaved-caspase-3, and -8, were examined by Western blot. We observed that the millimeter wave exposure could inhibit the viability and induce apoptosis in A375 cells, and the expression of cleaved caspase-3 and -8 were upregulated ( P < .05). The results indicated that the millimeter wave at 35.2 GHz exerted apoptosis-promoting effects on the A375 cells via a pathway by activating of caspase-8 and -3.
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Alarifi, Saud, Daoud Ali, Saad Alkahtani, and Rafa S. Almeer. "ROS-Mediated Apoptosis and Genotoxicity Induced by Palladium Nanoparticles in Human Skin Malignant Melanoma Cells." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/8439098.
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The present work was designed to investigate the effect of palladium nanoparticles (PdNPs) on human skin malignant melanoma (A375) cells, for example, induction of apoptosis, cytotoxicity, and DNA damage. Diseases resulting from dermal exposure may have a significant impact on human health. There is a little study that has been reported on the toxic potential of PdNPs on A375. Cytotoxic potential of PdNPs (0, 5, 10, 20, and 40 μg/ml) was measured by tetrazolium bromide (MTT assay) and NRU assay in A375 cells. PdNPs elicited concentration and time-dependent cytotoxicity, and longer exposure period induced more cytotoxicity as measured by MTT and NRU assay. The molecular mechanisms of cytotoxicity through cell cycle arrest and apoptosis were investigated by AO (acridine orange)/EtBr (ethidium bromide) stain and flow cytometry. PdNPs not only inhibit proliferation of A375 cells in a dose- and time-dependent model but also induce apoptosis and cell cycle arrest at G2/M phase (before 12 h) and S phase (after 24 h). The induction of oxidative stress in A375 cells treated with above concentration PdNPs for 24 and 48 h increased ROS level; on the other hand, glutathione level was declined. Apoptosis and DNA damage was significantly increased after treatment of PdNPs. Considering all results, PdNPs showed cytotoxicity and genotoxic effect in A375 cells.
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Shirkavand, Afshan, Ezeddin Mohajerani, Shirin Farivar, Leila Ataie-Fashtami, and Mohammad Hossein Ghazimoradi. "Quantitative Autofluorescence Imaging of A375 Human Melanoma Cell Samples: A Pilot Study." Journal of Lasers in Medical Sciences 12 (February 14, 2021): e4-e4. http://dx.doi.org/10.34172/jlms.2021.04.
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Introduction: Skin cancer is one of the most common types of malignancy worldwide. Human skin naturally contains several endogenous fluorophores, as potential sources can emit inherent fluorescence, called intrinsic autofluorescence (AF). The melanin endogenous fluorophore in the basal cell layer of the epidermis seems to have a strong autofluorescence signal among other ones in the skin. This pilot study aimed to investigate the feasibility of the detection of autofluorescence signals in the A375 human melanoma cell line in the cell culture stage using the FluoVision optical imaging system. Methods: The human skin melanoma cell line (A375) donated as a gift from Switzerland (University Hospital Basel) was cultured. For the imaging of the A375 human melanoma cell sample in this pilot study, the FluoVision optical imaging device (Tajhiz Afarinan Noori Parseh Co) was applied. The proposed clustering image processing code was developed based on the K-mean segmentation method, using MATLAB software (version 16). Results: The quantification of color pixels in the color bar along with the intensity score of the autofluorescence signal ranged between 0 and 70 was written in the image processing code execution and a threshold higher than 40%, proportional to the ratio of autofluorescent cells. The percentage of the signal of A375 autofluorescent melanoma cells in the 3 studied cell samples was calculated as 3.11%±0.6. Conclusion: This imaging method has the advantage of no need for fluorophore labels over the existing fluorescence imaging methods, and it can be regarded as one of the important choices of label-free imaging for this A375 melanoma cell line containing the intrinsic endogenous fluorophore in cell studies.
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Aepler, Julia, Johanna Wodtke, Robert Wodtke, Cathleen Haase-Kohn, Reik Löser, Jens Pietzsch, and Sandra Hauser. "The Role of Transglutaminase 2 in the Radioresistance of Melanoma Cells." Cells 11, no. 8 (April 14, 2022): 1342. http://dx.doi.org/10.3390/cells11081342.
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Transglutaminase 2 (TG2) is a protein expressed in many tissues that exerts numerous, sometimes contradictory, intra- and extracellular functions, under both physiological and pathophysiological conditions. In the context of tumor progression, it has been found to be involved in cell adhesion, DNA repair mechanisms, induction of apoptosis, and mesenchymal transdifferentiation, among others. Here, we hypothesized that TG2 also contributes to the radioresistance of two human melanoma cell lines, A375 and MeWo, which can be seen to differ in their basal TG2 biosynthesis by examining their proliferation and clonal expansion after irradiation. For this purpose, cellular TG2 biosynthesis and TG2 activity were modulated by transfection-induced overexpression or TG2 knock-out and application of TG2-selective inhibitors. Proliferation and clonal expansion of TG2-overexpressing cells was not enhanced over wildtype cells, suggesting that increased TG2 biosynthesis does not further enhance the radioresistance of melanoma cells. Conversely, TG2 knock-out in A375 cells reduced their proliferation, as well as clonal and spheroidal expansion after irradiation, which indicates a contribution of TG2 to the radioresistance of melanoma cells. Since TG1, TG3, and partly also, TG6 biosynthesis was detectable in A375 and MeWo cells, it can be assumed that these other members of the TG family may exert a partially compensatory effect.
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Yu, Sheng-Jia, and Zi-Wen Long. "Effect of SOCS1 silencing on proliferation and apoptosis of melanoma cells: An in vivo and in vitro study." Tumor Biology 39, no. 5 (May 2017): 101042831769431. http://dx.doi.org/10.1177/1010428317694315.
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This study aimed to investigate the effect of SOCS1 silencing on the proliferation and apoptosis of melanoma cells by in vivo and in vitro studies. Immunohistochemical staining was used to detect SOCS1 expression in melanoma tissues and pigmented nevi. Quantitative real-time polymerase chain reaction and western blotting were applied to detect the messenger RNA and protein expressions of SOCS1 in primary human melanocytes and malignant melanoma cell lines (A375, SK-MEL-5, M14, and MV3). Melanoma cells were assigned into mock, negative small interfering RNA, and SOCS1-small interfering RNA groups. The proliferation, cell cycle and apoptosis, and messenger RNA expression of SOCS1 in MV3 and A375 cells were detected using MTT assay, flow cytometry, and quantitative real-time polymerase chain reaction, respectively. The expressions of SOCS1 protein, extracellular signal–regulated kinase, and janus kinase signal transduction and activators of transcription signaling pathways–related proteins were detected using western blotting. After the establishment of subcutaneous xenograft tumor models in nude mice, the latent period, size, volume and growth speed of xenograft tumors in the mock, negative small interfering RNA, and SOCS1-small interfering RNA groups were examined and compared. The results indicated that positive expression rate of SOCS1 was higher in malignant melanoma tissues than in pigmented nevi. MV3 cells had the highest messenger RNA and protein expressions of SOCS1, followed by A357 cells. Compared with the mock and negative small interfering RNA groups, SOCS1-small interfering RNA group showed lower cell viability, elevated cell apoptosis, more cells in G0/G1 phase and less cells in S and G2/M phases, and decreased messenger RNA and protein expressions of SOCS1, p-ERK1/2, p-JAK2, p-STAT1, and p-STAT3. Compared with the mock and negative small interfering RNA groups, the SOCS1-small interfering RNA group showed longer latent period of tumor, smaller tumor size and volume, and smoother tumor growth curve. To conclude, SOCS1 silencing can inhibit proliferation and induce apoptosis of MV3 and A357 melanoma cells in vivo and in vitro by inhibiting extracellular signal–regulated kinase and janus kinase signal transduction and activators of transcription signaling pathways.
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Collard, Marianne, George Chen, Hyeon Jeong Lee, Zhicong Chen, Ji-Xen Cheng, Muzhou Wu, and Rhoda Alani. "Mitochondrial Fatty Acid Oxidation Is Not Vital for Melanoma Cell Proliferation and Migration." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 314. http://dx.doi.org/10.1093/cdn/nzaa044_013.
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Abstract Objectives Melanoma, the 5th most common cancer in the US, is the most aggressive form of skin cancer. Excess adiposity is associated with an increased risk of melanoma in males, and a high-fat diet promotes melanoma tumor growth in mice. Our group found that lipid droplet (LD) content increases with melanoma cell aggressiveness and that fatty acid uptake inhibition reduces cell proliferation and migration; however, the function of these lipids in melanoma is unknown. Since lipids can be used to produce energy by fatty acid oxidation (FAO), we sought to determine whether melanoma cells were using FAO to maintain aggressiveness. Methods Gene expression microarray was used to identify differences in gene expression, which was confirmed by RT-qPCR. WM983A, WM983B, 1205Lu and A375 human melanoma cells were treated with 5 µM Etomoxir and cell proliferation, migration, and respiration were quantified using the Quant-iT™ PicoGreen™ dsDNA Assay Kit, Boyden Chamber transwell migration, and Seahorse XFe96 Flux Analyzer, respectively. Results The most significantly altered genes expressed between four invasive, lipid-rich and four non-invasive, lipid-poor melanoma cells pertained to fatty acid metabolism. Carnitine palmitoyltransferase 1A (CPT1a), the rate limiting enzyme in mitochondrial FAO (mFAO), mRNA was increased in lipid-rich cells compared to the lipid-poor cells (p < 0.05, n = 6–7), indicating that melanoma cells may use LD lipids for mFAO. To determine the importance of mFAO to melanoma cells, we inhibited mFAO with etomoxir, an irreversible CPT1 inhibitor. Treatment of lipid-rich 1205Lu and A375 cells or lipid-poor WM983A and WM983B cells with etomoxir for 4 days had no effect on cell proliferation. Extracellular flux analysis of cells with or without etomoxir showed no difference in ATP production, indicating that melanoma cells do not use mFAO to generate energy under normal conditions. In motile cells, etomoxir reduced lipid-rich A375 cell migration by 8.8% (p = 0.05, n = 2). Conclusions Lipids play a role in melanoma aggressiveness; however, our results indicate that mFAO of lipids is not vital to melanoma cell proliferation or migration. Further studies are required to understand the implication of excess adiposity and circulating lipids in melanoma development and progression. Funding Sources Institutional Department Fund