Journal articles: 'TPA-induced skin cancer'

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Xiu, Dianhui, Min Cheng, Wenlei Zhang, Xibo Ma, and Lin Liu. "Pseudomonas aeruginosa-mannose-sensitive hemagglutinin inhibits chemical-induced skin cancer through suppressing hedgehog signaling." Experimental Biology and Medicine 245, no. 3 (January 5, 2020): 213–20. http://dx.doi.org/10.1177/1535370219897240.

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Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PAM) is an inactivate P. aeruginosa with mannose-sensitive hemagglutinin. Recently, the anticancer properties of PAM against many cancers have been reported across a range of studies. However, the exact mechanism through which PAM prevents skin cancer remains unclear. The aim of this study is to show to what extent PAM could inhibit the dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin cancer. JB6 cells were treated by TPA so as to establish an in vitro model. The effects of PAM on proliferation of the cells were analyzed using cell counting kit-8 assays. Effects on epithelial–mesenchymal transition (EMT) were assayed by real-time PCR and Western blotting. A DMBA/TPA-induced skin cancer mouse model was also established. The results showed that TPA promoted EMT changes through the activation of the hedgehog (Hh) pathway, which was reversed by PAM. Moreover, PAM inhibited the cancer growth and Hh pathway in vivo. These data indicate that PAM may serve as a potential anticancer agent for the treatment of skin cancer. Impact statement Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PAM) restrained the chemical-induced skin cancer cells in vitro and in vivo partly through suppressing the Hh signaling pathway, indicating that PAM may be a promising anticancer agent for treating skin cancer.

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Dao, Vinh, Vincent Hurez, Sri Lakshmi Pandeswara, Kim Cardenas, Lishi Sun, Aijie Liu, Paul Hasty, Z. Dave Sharp, and Tyler Curiel. "Oral rapamycin (eRapa) safely prevents carcinogen-induced dermal carcinogenesis through an interferon-γ-dependent mechanism (TUM7P.931)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 203.13. http://dx.doi.org/10.4049/jimmunol.192.supp.203.13.

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Abstract eRapa extends life in mice and cancer prevention could be a mechanism. Rapamycin inhibits mTOR, which has significant immune effects that are surprisingly unstudied in cancer therapy or prevention. We hypothesize that cancer prevention by eRapa is mediated by improved cancer immune surveillance, which we tested in the well-established DMBA/TPA carcinogen-induced skin cancer model. Mice got eRapa or control chow, and skin tumors were induced with DMBA/TPA over 24 weeks. eRapa reduced benign (p=.001) and malignant (p=.05) tumors in WT mice. T cells and IFN-γ mediate cancer immune surveillance. eRapa reduced skin tumors in βδ KO mice lacking all T cells (p=.04), but not in IFN-γ KO mice (p=.13), consistent with loss of beneficial eRapa-induced, non-T cell IFN-γ. In support, WT or IFN-γ KO T cell transfer into IFN-γ KO mice did not alter eRapa cancer prevention in DMBA/TPA. In WT mice on DMBA/TPA, eRapa increased IFN-γ-producing natural killer cells (p=.01) that could mediate skin cancer immune surveillance, and decreased CD34+CD49fint skin cancer stem cells (p=.01) and CXCR3+ T cells (p<.001) that contribute to cancer in this model. eRapa reduced skin pAKT with divergent mTORC1/2 effects needing more study. eRapa appeared safe (no increased Tregs or reduced protection in infection and autoimmunity models). A widely applicable, safe and tolerable cancer prevention agent would be highly useful. Understanding its immune mechanisms could improve efficacy and widen applications.

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Koul, Ashwani, Mohinder Pal Bansal, Aniqa Aniqa, Harsh Chaudhary, and Neha Arora Chugh. "Lycopene enriched tomato extract suppresses chemically induced skin tumorigenesis in mice." International Journal for Vitamin and Nutrition Research 90, no. 5-6 (October 2020): 493–513. http://dx.doi.org/10.1024/0300-9831/a000597.

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Abstract. The present study revealed the effects of Lycopene enriched tomato extract (LycT) on chemically induced skin cancer in mice. Skin tumors were induced by topical application of 7,12-Dimethylbenz(a)anthracene (DMBA) [500 nmol/100 ul of acetone, twice a week for two weeks] and 12-O-tetradecanoyl phorbol-13-acetate (TPA) [1.7 nmol/100 ul of acetone, twice a week for eighteen weeks] and LycT (5 mg/kg b.w.) was administered orally. Male Balb/c mice were divided into four groups (n = 15 per group): control, DMBA/TPA, LycT and LycT + DMBA/TPA. The chemopreventive response of LycT to skin tumorigenesis was evident by inhibition in tumor incidence, number, size, burden and volume in LycT + DMBA/TPA group when compared to DMBA/TPA group. This was associated with inhibition of cell proliferation in LycT + DMBA/TPA group as observed by the decrease in epidermal morphometric parameters and mRNA and protein expression of proliferating cell nuclear antigen when compared to DMBA/TPA group (p ≤ 0.05). LycT decreased (p ≤ 0.05) the mRNA and protein expression of angiogenic genes (vascular endothelial growth factor, angiopoietin-2, basic fibroblast growth factor) in LycT + DMBA/TPA group, suggesting its anti-angiogenic effects. The increase (p ≤ 0.05) in protein expression of connexin-32 and 43 in LycT + DMBA/TPA group suggests improved inter cellular communication when compared to DMBA/TPA group. Histochemical studies demonstrated that the components of extracellular matrix (fibrous proteins and mucopolysaccharides) were also modulated during skin carcinogenesis and its chemoprevention by LycT. The decrease in cell proliferation parameters and expression of angiogenesis associated genes, modulation of ECM components and increase in expression of connexins suggest that LycT improved multiple dysregulated processes during chemoprevention of skin cancer.

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Cho, Hae-Ra, Yingchun Wang, Xiaohui Bai, Yun-Yan Xiang, Christina Lu, Alexander Post, Ayman Al Habeeb, and Mingyao Liu. "XB130 deficiency enhances carcinogen-induced skin tumorigenesis." Carcinogenesis 40, no. 11 (March 1, 2019): 1363–75. http://dx.doi.org/10.1093/carcin/bgz042.

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AbstractXB130 is an adaptor protein that functions as a mediator of multiple tyrosine kinases important for regulating cell proliferation, survival, migration and invasion. Formerly predicted as an oncogene, alterations of its expression are documented in various human cancers. However, the exact role of XB130 in tumorigenesis is unknown. To address its function in skin tumorigenesis, a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA) study was performed on XB130 knockout (KO), heterozygous (HZ) and wild-type (WT) littermate mice. DMBA/TPA-treated XB130 KO and HZ males developed a significantly higher number of epidermal tumors that were notably larger in size than did WT mice. Interestingly, DMBA/TPA-treated female mice did not show any difference in tumor multiplicity regardless of the genotypes. The skin tumor lesions of XB130 KO males were more progressed with an increased frequency of keratoacanthoma. Deficiency of XB130 dramatically increased epidermal tumor cell proliferation. The responses to DMBA and TPA stimuli were also individually investigated to elucidate the mechanistic role of XB130 at different stages of tumorigenesis. DMBA-treated male XB130 KO mice showed compensatory p53-mediated stress response. TPA-treated XB130 KO males demonstrated more skin ulceration with more severe edema, enhanced cell proliferation, accumulation of infiltrating neutrophils and increased production of pro-inflammatory cytokine genes compared with WT mice. Enhanced activities of nuclear factor-kappa B pathway, increased protein expression of metalloproteinase-9 and ERK1/2 phosphorylation were found in these KO mice. These findings demonstrate that XB130 acts as a tumor suppressor in carcinogen-induced skin tumorigenesis that may be mediated through inhibiting inflammation.

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Arora, Reena, Mohammed Samim, and Chander Parkash. "Evaluation of Anti-inflammatory and Anti-cancer Activity of Calcium Phosphate Encapsulated Resveratrol in Mouse Skin Cancer Model." Biomedical and Pharmacology Journal 14, no. 1 (March 28, 2021): 113–22. http://dx.doi.org/10.13005/bpj/2105.

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Resveratrol, a non-flavonoid phenolic phytochemical present in red grapes and berries, has been reported to have significant health benefits. Resveratrol is known for its chemopreventive and chemotherapeutic effects in multiple cancers as well as cardiovascular and inflammatory diseases. But its higher lipophilicity, poor aqueous solubility and bioavailability remains a challenge for its usage as an effective chemopreventive and chemotherapeutic agent. To overcome this,we have prepared a biocompatible calcium phosphate encapsulated resveratrol (Nanoresveratrol; NRV) and studied its antioxidant, anti-inflammatory and anti-cancer activities in the present study.Nanoresveratrol, unlike resveratrol, readily dispersed in aqueous media and showed a sustained release. Nanoresveratrol (NRV) and resveratrol (RV) showed comparable antioxidant activities. The anti-inflammatory and anticancer activities of nanoresveratrol were studied for its inhibitory effect on 7, 12-dimethylbenz[a]anthracene (DMBA)-induced/12-O-tetradecanoylphorbol-13-acetate (TPA) promoted skin inflammation and tumorigenesis mouse model. Nanoresveratrol showed a significant decrease of TPA-induced skin edema, ODC activity and thymidine incorporation when compared to resveratrol. Nanoresveratrol also inhibited chemical-induced tumorigenesis.Overall, the study results support that nanoresveratrol may represent a potential anti-cancer agent and warrants further investigations for the treatment of skin cancer.

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Rahman, Shakilur, Rizwan Ahmed Ansari, Hasibur Rehman, Suhel Parvez, and Sheikh Raisuddin. "Nordihydroguaiaretic Acid from Creosote Bush (Larrea tridentata) Mitigates 12-O-Tetradecanoylphorbol-13-Acetate-Induced Inflammatory and Oxidative Stress Responses of Tumor Promotion Cascade in Mouse Skin." Evidence-Based Complementary and Alternative Medicine 2011 (2011): 1–10. http://dx.doi.org/10.1093/ecam/nep076.

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Nordihydroguaiaretic acid (NDGA) is a phenolic antioxidant found in the leaves and twigs of the evergreen desert shrub,Larrea tridentata(Sesse and Moc. ex DC) Coville (creosote bush). It has a long history of traditional medicinal use by the Native Americans and Mexicans. The modulatory effects of topically applied NDGA was studied on acute inflammatory and oxidative stress responses in mouse skin induced by stage I tumor promoting agent, 12-O-tetradecanoylphorbol-13-acetate (TPA). Double TPA treatment adversely altered many of the marker responses of stage I skin tumor promotion cascade. Pretreatment of NDGA in TPA-treated mice mitigated cutaneous lipid peroxidation and inhibited production of hydrogen peroxide. NDGA treatment also restored reduced glutathione level and activities of antioxidant enzymes. Elevated activities of myeloperoxidase, xanthine oxidase and skin edema formation in TPA-treated mice were also lowered by NDGA indicating a restrained inflammatory response. Furthermore, results of histological study demonstrated inhibitory effect of NDGA on cellular inflammatory responses. This study provides a direct evidence of antioxidative and anti-inflammatory properties of NDGA against TPA-induced cutaneous inflammation and oxidative stress corroborating its chemopreventive potential against skin cancer.

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Loprinzi, C. L., A. K. Verma, R. K. Boutwell, and P. P. Carbone. "Inhibition of phorbol ester--induced human epidermal ornithine decarboxylase activity by oral compounds: a possible role in human chemoprevention studies." Journal of Clinical Oncology 3, no. 6 (June 1985): 751–57. http://dx.doi.org/10.1200/jco.1985.3.6.751.

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Extensive animal data have suggested that, in some systems, the induction of ornithine decarboxylase (ODC) is an essential, although not sufficient, aspect of tumor promotion and that compounds that inhibit ODC can inhibit tumor formation. Using fasting human volunteers, we report that human epidermal and dermal ODC are consistently induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in a manner similar to that seen in mouse skin. There is a marked intersubject variation in TPA-induced epidermal ODC activity levels. Orally administered compounds significantly inhibited TPA-caused human epidermal ODC induction. These data may be useful in the further development of drugs, doses, and dose schedules for use in human cancer chemoprevention studies.

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Vähätupa, Maria, Saara Aittomäki, Zuzet Martinez Cordova, Ulrike May, Stuart Prince, Hannele Uusitalo-Järvinen, Tero A. Järvinen, and Marko Pesu. "T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development." OncoImmunology 5, no. 12 (October 14, 2016): e1245266. http://dx.doi.org/10.1080/2162402x.2016.1245266.

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Pandey, Chhaya, Rashmi Arnold, and Rahasya Mani Mishra. "Modulation of p21, DAPK1 and COX-2 during the DMBA/TPA-induced mouse skin tumorigenesis and its prevention by phytic acid." Indian Journal of Pharmaceutical and Biological Research 2, no. 04 (December 31, 2014): 61–67. http://dx.doi.org/10.30750/ijpbr.2.4.11.

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Chemoprevention by naturally occurring agents is gaining much attention as a newer dimension in the management of cancer. Many naturally occurring agents have shown cancer chemopreventive potential in a variety of bioassay systems and animal models, having relevance to human disease. Phytic acid or Inositol hexaphosphate (IP6), an antioxidant, is a naturally occurring polyphosphorylated carbohydrate that has shown a strong anticancer activity in several experimental models. We assessed the protective effects of Phytic acid against the 7, 12-dimethylbenz [a] anthracene (DMBA)/ 12-O-tetradecanoylphorbol-13- acetate (TPA) induced mouse skin tumorigenesis at 4 and 16 weeks, the time before and after the tumor development. At molecular level we studied expression and promoter CpG methylation status of p21, DAPK1 and COX-2. Our data suggests exposure of DMBA/TPA methylated the promoter region of p21 and DAPK1 genes in time dependent manner that could be the cause of down regulation of their expression with time, which were reversed by administration of phytic acid. But we did not observe methylation in COX-2 whereas upregulation of COX-2 was observed at protein level in mice treated with DMBA followed by TPA in time dependent manner. Administration of phytic acid prevented theses DMBA/TPA induced molecular changes. Study provides a rationale for cancer chemoprevention by natural occurring compounds like Phytic acid.

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Surien, Omchit, Siti Fathiah Masre, Dayang Fredalina Basri, and Ahmad Rohi Ghazali. "Chemopreventive Effects of Oral Pterostilbene in Multistage Carcinogenesis of Skin Squamous Cell Carcinoma Mouse Model Induced by DMBA/TPA." Biomedicines 10, no. 11 (October 28, 2022): 2743. http://dx.doi.org/10.3390/biomedicines10112743.

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Skin squamous cell carcinoma (SCC) is a type of non-melanoma skin cancer. Pterostilbene is a natural compound proven to exhibit various pharmacological properties, including chemo-preventive effects. This study aimed to explore the chemo-preventive effect of oral pterostilbene during initiation, promotion or continuous on multistage skin SCC mouse models induced by 7,12-Dimethylbenz(a)anthracene (DMBA)/12-O-Tetradecanoylphorbol-13-acetate (TPA). The experimental design consists of five groups of female Institute of Cancer Research (ICR) mice, with two control groups of vehicle and cancer. Three oral pterostilbene groups consisted of orally administered pterostilbene during initiation, promotion, or continuously. Oral pterostilbene significantly reduced the number and volume of tumours. Oral pterostilbene demonstrated less severe skin histology changes compared to the cancer control group, with less pleomorphic in the cells and nuclei, and the basement membrane remained intact. Our results showed fewer invasive tumours in oral PT-treated groups than in cancer groups that displayed mitotic bodies, highly pleomorphic cells and nuclei, and basement membrane invasion. The cell proliferation marker (Ki-67) was reduced in oral pterostilbene-treated groups. Overall, oral pterostilbene is a promising chemo-preventive intervention due to its anti-initiation and anti-promotion on skin carcinogenesis. Thus, the potential molecular mechanisms of oral pterostilbene chemo-prevention agent should be explored.

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Dao, Vinh, Srilakshmi Pandeswara, Yang Liu, Vincent Hurez, Aijie Liu, and Tyler Curiel. "Oral rapamycin (eRapa) requires IFN-γ and promotes γδ T cell cytotoxicity to prevent carcinogen and inflammation-induced dermal cancer (TUM9P.1003)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 210.5. http://dx.doi.org/10.4049/jimmunol.194.supp.210.5.

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Abstract Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, prevents distinct cancers in mice and prolongs life, making it a candidate cancer prevention (and life extension) agent. We hypothesized that eRapa cancer prevention includes immune effects, as mTOR is pivotal in immunity. We tested immune effects in carcinogen (DMBA) and inflammation (TPA)-induced dermal carcinogenesis with eRapa daily at 14 ppm, which protected 100% from skin cancer in wild type (WT) mice. Tumor mTORC1 was not suppressed, supporting eRapa immune effects. γδ T cells and IFN-γ are protective in this model. In δ TCR KO (no γδ T cells) and IFN-γ KO mice, eRapa cancer protection was lost, confirming immune mechanisms. IFN-γ KO mice had significantly reduced CD69+Lamp1+GzB+CXCR3+ epidermal γδ T cells and CXCL10, suggesting IFN-γ is required for epidermal γδ T cell migration (via CXCR3/CXCL10), activation and cytolysis. Bone marrow (BM) chimeras showed eRapa skin cancer protection and maximum γδ T cell epidermal infiltration requires IFN-γ signals in BM (e.g., γδ T cells) and non-BM (e.g., epidermal) cells. Intratumor injections of WT but not Prf1 (perforin) KO γδ T cells regressed DMBA/TPA tumors in δ TCR KO mice on eRapa but not control, showing eRapa boosts anti-tumor γδ T cell cytotoxicity. Our data confirm eRapa cancer prevention through immune mechanisms, challenging the paradigm of mTOR effects solely on cancer cells for prevention, and suggesting novel immune-mediated life extension mechanisms.

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Bhisey, Rajani A., and Satyavati M. Sirsat. "Ultrastructural Analysis of Epidermal Hyperplasia Induced by Multiple 12-0-Tetradecanoyl-Phorbol-13-Acetate (TPA) Treatment of Mouse Skin." Tumori Journal 72, no. 6 (December 1986): 643–50. http://dx.doi.org/10.1177/030089168607200618.

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Stationary epidermal hyperplasia induced by exposure of mouse skin to 1-6 TPA applications was analyzed by electron microscopy and found to be of two types. Intermingled orderly and irregularly stratified hyperplastic regions observed prominently after a single TPA application gave way, on multiple treatment, to epidermal hyperplasia populated by either cuboidal cells with expanded cytoplasm or by highly polar, narrow, tall and pleomorphic cells. Both cell types were poorly differentiated and displayed a paucity of intact desmosomal junctions, resulting in an incohesive tissue structure in which a number of phenotypic variants were expressed. The variants were markedly less mature than the adjacent cells and showed basal cell phenotype, acquisition of secretory activity or a disturbed mitotic process, resulting in the formation of binucleated cells. The observations suggest that the disturbed mitotic process, poor cellular differentiation and induction of metaplasia could be the mode by which an initiated cell may express its tumor phenotype and escape differentiation during the early stage of TPA promotion.

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Li, Hui, Simon Petersen, Alberto Garcia Mariscal, and Cord Brakebusch. "Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation." Cancer Research 79, no. 9 (March 20, 2019): 2167–81. http://dx.doi.org/10.1158/0008-5472.can-18-1253.

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Ko, J.-H., B.-G. Jung, Y.-S. Park, and B.-J. Lee. "Inhibitory effects of interferon-gamma plasmid DNA on DMBA-TPA induced mouse skin carcinogenesis." Cancer Gene Therapy 18, no. 9 (July 29, 2011): 646–54. http://dx.doi.org/10.1038/cgt.2011.36.

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Gebhardt, Christoffer, Astrid Riehl, Moritz Durchdewald, Julia Németh, Gerhard Fürstenberger, Karin Müller-Decker, Alexander Enk, et al. "RAGE signaling sustains inflammation and promotes tumor development." Journal of Experimental Medicine 205, no. 2 (January 21, 2008): 275–85. http://dx.doi.org/10.1084/jem.20070679.

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A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting microenvironment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic inflammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer.

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Li, Wenjuan, Joan Liu, and Yunfeng Zhao. "PKM2 inhibitor shikonin suppresses TPA-induced mitochondrial malfunction and proliferation of skin epidermal JB6 cells." Molecular Carcinogenesis 53, no. 5 (December 19, 2012): 403–12. http://dx.doi.org/10.1002/mc.21988.

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Chang, Soo, Chen, and Shyur. "Essential Oil of Mentha aquatica var. Kenting Water Mint Suppresses Two-Stage Skin Carcinogenesis Accelerated by BRAF Inhibitor Vemurafenib." Molecules 24, no. 12 (June 25, 2019): 2344. http://dx.doi.org/10.3390/molecules24122344.

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The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation. In a two-stage skin carcinogenesis mouse model, the skin papillomas induced by 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) (DT) resemble the lesions in BRAF inhibitor-treated patients. In this study, we investigated the bioactivity of Mentha aquatica var. Kenting Water Mint essential oil (KWM-EO) against PDV cells, mouse keratinocytes bearing HRASQ61L mutation, and its effect on inhibiting papilloma formation in a two-stage skin carcinogenesis mouse model with or without PLX4032 co-treatment. Our results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells. Induction of G2/M cell-cycle arrest and apoptosis in PDV cells was also observed. KWM-EO treatment significantly decreased the formation of cutaneous papilloma further induced by PLX4032 in DT mice (DTP). Immunohistochemistry analyses showed overexpression of keratin14 and COX-2 in DT and DTP skin were profoundly suppressed by KWM-EO treatment. This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and will be worth further exploration for possible application in melanoma patients.

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Szymanski, Pawel T., Safwat A. Ahmed, Sherief Khalifa, Harukuni Tokuda, Eiichiro Ichiishi, Akira Iida, Nobutaka Suzuki, and Hesham Fahmy. "Chemopreventive Effect of Sarcophine-diol on NOR-1-Induced TPA-Promoted Skin Carcinogenesis in Female HOS:HR-1 Mice." Natural Product Communications 8, no. 2 (February 2013): 1934578X1300800. http://dx.doi.org/10.1177/1934578x1300800203.

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The cancer chemopreventive potential of sarcophine-diol in a chemical carcinogen initiation–promotion experimental tumor model in mice was evaluated. Sarcophine-diol, when given orally, afforded significant protection in the mouse skin cancer model initiated by the topical administration of (±)-( E)-4-methyl-2-[( E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) and promoted by 12- O-tetradecanoylphorbol-13-acetate (TPA). These findings, along with our initial reports, suggest that sarcophine-diol is an effective cancer chemopreventive agent, even when administered orally and at a very low dose and thus indicating possible potential human applications in the control of malignancy.

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Ito, Chihiro, Takuya Matsui, Takashi Kobayashi, Harukuni Tokuda, Sivabalan Shanmugam, and Masataka Itoigawa. "Cancer Chemopreventive Activity of Xanthones from Calophyllum elatum." Natural Product Communications 13, no. 4 (April 2018): 1934578X1801300. http://dx.doi.org/10.1177/1934578x1801300417.

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In our continuing search for compounds with antitumor-promoting activity, we screened eight xanthones isolated from Calophyllum elatum Bedd. (Guttiferae) by examining their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12- O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Several compounds tested in this study showed inhibitory activity against EBV, without showing any cytotoxicity. Isogarciniaxanthone E (2) showed more potent activity than any of the other compounds tested. Furthermore, isogarciniaxanthone E (2) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test.

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Yang, Anne Yuqing, Jong Hun Lee, Limin Shu, Chengyue Zhang, Zheng-Yuan Su, Yaoping Lu, Mou-Tuan Huang, et al. "Genome-wide analysis of DNA methylation in UVB- and DMBA/TPA-induced mouse skin cancer models." Life Sciences 113, no. 1-2 (September 2014): 45–54. http://dx.doi.org/10.1016/j.lfs.2014.07.031.

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Konoshima, Takao, and Midori Takasaki. "Cancer-chemopreventive effects of natural sweeteners and related compounds." Pure and Applied Chemistry 74, no. 7 (January 1, 2002): 1309–16. http://dx.doi.org/10.1351/pac200274071309.

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To search for possible cancer-chemopreventive agents from natural resources, several natural sweeteners were screened by the in vitro assay indicated by the inhibitory effects of Epstein-Barr virus early antigen (EBV-EA) induction. Of active compounds that showed the remarkable inhibitory effects on the EBV-EA induction, stevioside, from the leaves of Stevia rebaudiana, and mogroside V, from the fruits of Momordica grosvenori, exhibited significant inhibitory effects on the two-stage mouse skin carcinogenesis in vivo induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effect of stevioside is stronger than that of glycyrrhizin, which had been known as an antitumor-promoter in chemical carcinogenesis. Furthermore, stevioside also inhibited mouse skin carcinogenesis initiated by peroxynitrite. These results suggest that stevioside and mogroside V might be valuable as chemopreventive agents for chemical carcinogenesis.

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Gupta, Krishna P., and N. K. Mehrotra. "Effect of butyric acid on 12-O-tetradecanoylphorbol-13-acetate-(TPA) induced mouse skin ornithine decarboxylase (ODC)." Carcinogenesis 8, no. 11 (1987): 1667–70. http://dx.doi.org/10.1093/carcin/8.11.1667.

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Sati, Jasmine, Biraja Prasad Mohanty, Mohan Lal Garg, and Ashwani Koul. "Pro-Oxidant Role of Silibinin in DMBA/TPA Induced Skin Cancer: 1H NMR Metabolomic and Biochemical Study." PLOS ONE 11, no. 7 (July 14, 2016): e0158955. http://dx.doi.org/10.1371/journal.pone.0158955.

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Wittwer, Jennifer A., Delira Robbins, Fei Wang, Sarah Codarin, Xinggui Shen, Christopher G. Kevil, Ting-Ting Huang, Holly Van Remmen, Arlan Richardson, and Yunfeng Zhao. "Enhancing Mitochondrial Respiration Suppresses Tumor Promoter TPA-Induced PKM2 Expression and Cell Transformation in Skin Epidermal JB6 Cells." Cancer Prevention Research 4, no. 9 (June 14, 2011): 1476–84. http://dx.doi.org/10.1158/1940-6207.capr-11-0028.

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Kim, Myoung Ok, Sung Hyun Kim, Mi Jung Shin, Dong Hoon Yu, Bong Soo Kim, Kyu Tae Chang, Sanggyu Lee, Yong Bok Park, Tae-Hoon Lee, and Zae Young Ryoo. "DMBA/TPA-Induced Tumor Formation Is Aggravated in Human Papillomavirus Type 16 E6/E7 Transgenic Mouse Skin." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 16, no. 7 (July 1, 2006): 325–32. http://dx.doi.org/10.3727/000000006783980964.

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Kowalczyk, Piotr, Jacob J. Junco, Magdalena C. Kowalczyk, Renata Sosnowska, Olga Tolstykh, Zbigniew Walaszek, Margaret Hanausek, and Thomas J. Slaga. "The effects of dissociated glucocorticoids RU24858 and RU24782 on TPA-induced skin tumor promotion biomarkers in SENCAR mice." Molecular Carcinogenesis 53, no. 6 (July 12, 2013): 488–97. http://dx.doi.org/10.1002/mc.22002.

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Su, Zheng-Yuan, Chengyue Zhang, Jong Hun Lee, Limin Shu, Tien-Yuan Wu, Tin Oo Khor, Allan H. Conney, Yao-Ping Lu, and Ah-Ng Tony Kong. "Requirement and Epigenetics Reprogramming of Nrf2 in Suppression of Tumor Promoter TPA-Induced Mouse Skin Cell Transformation by Sulforaphane." Cancer Prevention Research 7, no. 3 (January 17, 2014): 319–29. http://dx.doi.org/10.1158/1940-6207.capr-13-0313-t.

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Agame-Lagunes, B., M. Alegria-Rivadeneyra, A. Alexander-Aguilera, R. Quintana-Castro, C. Torres-Palacios, P. Grube-Pagola, C. Cano-Sarmiento, R. García-Varela, and H. S. García. "Bioactivity of betulinic acid nanoemulsions on skin carcinogenesis in transgenic mice K14E6." Grasas y Aceites 72, no. 4 (December 30, 2021): e433. http://dx.doi.org/10.3989/gya.0553201.

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Alternative therapies for cancer treatment have been developed using bioactive compounds such as betulinic acid (BA). The objective of this study was to investigate the bioactivity of BA in its free form and compare it with its nano-encapsulated form under a skin carcinogenesis protocol in a genetically modified murine model. K14E6 and FVB mice were divided into four groups to be treated with free BA and with betulinic acid nanoemulsion (BANE). Lecithin enriched with medium chain fatty acids (MCFAs) was employed as an emulsifier to prepare the nanoemulsions with a mean droplet size of 40 nm. Skin tumors were induced by exposure to DMBA and TPA directly to the transgenic mice. Tumor development was completely inhibited by BANE and by 70% with free BA. This was validated by histological sections and the gene expression of the Cdk4 and Casp8 genes.

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Liu, Zhaoguo, Pingting Zhu, Yu Tao, Cunsi Shen, Siliang Wang, Lingang Zhao, Hongyan Wu, et al. "Cancer-promoting effect of capsaicin on DMBA/TPA-induced skin tumorigenesis by modulating inflammation, Erk and p38 in mice." Food and Chemical Toxicology 81 (July 2015): 1–8. http://dx.doi.org/10.1016/j.fct.2015.04.002.

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Kim, Sung-Hyun, Myoung-Ok Kim, Peng Gao, Cheng-A. Youm, Hae-ryoung Park, Sang-Ryeul Lee, Kil-Soo Kim, et al. "Overexpression of Extracellular Superoxide Dismutase (EC-SOD) in Mouse Skin Plays a Protective Role in DMBA/TPA-Induced Tumor Formation." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 15, no. 7 (July 1, 2005): 333–41. http://dx.doi.org/10.3727/096504005776449725.

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Singhal, Sharad S., Prakash Kulkarni, Jyotsana Singhal, David Horne, Sanjay Awasthi, and Ravi Salgia. "Abstract 5345: Novel approach to attenuate melanoma initiation and progression." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5345. http://dx.doi.org/10.1158/1538-7445.am2022-5345.

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Abstract Background and Purpose: Melanocytic nevi are benign proliferations of melanocytic cells that are positively correlated with susceptibility to melanoma. Polyaromatic hydrocarbons (PAH) are ubiquitous environmental pollutants that are potent mutagens and carcinogens, and the investigators have taken advantage of these properties to investigate the mechanisms by which chemicals cause cancer of the skin and other organs. In comparison to C57Bl/6 strain, C3H/HeN mice are more susceptible to the development of PAH induced tumors. Therefore, a mouse model of nevus initiation and progression was developed in C3H/HeN mice using a modified chemical carcinogenesis protocol. Experimental Design: In the traditional two-stage skin carcinogenesis model, initiation is accomplished by the application of a subcarcinogenic dose of a carcinogen. Subsequently, tumor development is elicited by repeated treatment with a tumor promoting agent. Nevi develop due to DNA damage initiated by 7, 12-dimethylbenz[a]anthracene (DMBA) followed by chronic promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Results: Dysplastic pigmented skin lesions appeared in ~10 wk with 100% penetrance. Studies reported here demonstrating that inhibition or depletion of RLIP results in apoptosis and cancer regression in an exceptionally broad spectrum on neoplasia have suggested an intriguing possibility that RLIP is an anti-apoptotic mechanism required not only for the survival of cancer cells, but also for their very existence. In support of this assertion results presented here that the well-known carcinogens, DMBA and phorbol esters (PMA or TPA) are ineffective in causing neoplasia in C3H/HeN mice treated with RLIP-targeting agent’s (RLIP antibodies and RLIP antisense). Here we demonstrate that DMBA/PMA-induced skin carcinogenesis in C3H/HeN mouse was suppressed completely by depletion of RLIP by antisense or inhibition by antibodies. In addition, C3H/HeN mice treated with RLIP-targeting agent’s, p53, P38, and JNK activation did not occur in response to carcinogens. These findings demonstrate a fundamental role of RLIP in chemical carcinogenesis. Conclusions: We demonstrate that RLIP expression is significantly greater in cancer cells than in non-malignant cells, and RLIP-targeting agent’s (RLIP antibodies and RLIP antisense) treatment was significantly suppress the generation of melanocytic nevi and their progression to melanoma. (This work was supported in part by the Department of Defense grants W81XWH-16-1-0641 and W81XWH-20-1-0362. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Prakash Kulkarni, Jyotsana Singhal, David Horne, Sanjay Awasthi, Ravi Salgia. Novel approach to attenuate melanoma initiation and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5345.

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Provost, Nicolas, Marielle Moreau, Armelle Leturque, and Carine Nizard. "Ultraviolet A radiation transiently disrupts gap junctional communication in human keratinocytes." American Journal of Physiology-Cell Physiology 284, no. 1 (January 1, 2003): C51—C59. http://dx.doi.org/10.1152/ajpcell.00205.2002.

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Ultraviolet A (UVA) (320–400 nm) radiation is known to cause cutaneous aging and skin cancer. We studied the effect of UVA (365 nm) radiation on the human epidermis by focusing on keratinocyte gap junction-mediated intercellular communication (GJIC). We observed a dose-dependent 10-fold decrease in GJIC induced by UVA in normal human keratinocytes. This decrease in GJIC was associated with time-dependent internalization of connexin43 (Cx43). UVA radiation also damaged the actin cytoskeleton, as shown by microfilament disappearance. Importantly, the decrease in GJIC was transient when keratinocytes were irradiated with 10 J/cm2UVA, with a return to baseline values after 8 h. Concomitantly, Cx43 was relocalized and the actin cytoskeleton was restored. UVA irradiation and 12- O-tetradecanoylphorbol 13-acetate (TPA) treatment activated protein kinase C and reduced GJIC. However, Cx43 localization and phosphorylation were differently regulated by the two treatments. This suggests that at least two different pathways may mediate the observed fall in GJIC. These findings identify keratinocyte GJIC as a new UVA target that might sensitize human skin to photoaging and cancer formation.

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Kinzel, V., G. Fürstenberger, H. Loehrke, and F. Marks. "Three-stage tumorigenesis in mouse skin: DNA synthesis as a prerequisite for the conversion stage induced by TPA prior to initiation." Carcinogenesis 7, no. 5 (1986): 779–82. http://dx.doi.org/10.1093/carcin/7.5.779.

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Kemp, Christopher J., Khoa Vo, and Kay E. Gurley. "Resistance to skin tumorigenesis in DNAPK-deficient SCID mice is not due to immunodeficiency but results from hypersensitivity to TPA-induced apoptosis." Carcinogenesis 20, no. 11 (November 1999): 2051–56. http://dx.doi.org/10.1093/carcin/20.11.2051.

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Xie, Linglin, Yu Jiang, Ping Ouyang, Jie Chen, Hieu Doan, Betty Herndon, Jessica E. Sylvester, et al. "Effects of Dietary Calorie Restriction or Exercise on the PI3K and Ras Signaling Pathways in the Skin of Mice." Journal of Biological Chemistry 282, no. 38 (July 23, 2007): 28025–35. http://dx.doi.org/10.1074/jbc.m604857200.

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Weight control by exercise and dietary calorie restriction (DCR) has been associated with reduced cancer risk, but the underlying mechanisms are not well understood. This study was designed to compare the effects of weight loss by increasing physical activity or decreasing calorie intake on tumor promoter-induced Ras-MAPK and PI3K-Akt pathways. SENCAR mice were randomly assigned to one of the following five groups: ad libitum-fed sedentary control, ad libitum-fed exercise (AL+Exe), exercise but pair-fed at the amount as controls (PF+Exe), 20% DCR, and 20% DCR plus exercise (DCR+Exe). After 10 weeks, body weight and body fat significantly decreased in the groups of DCR, DCR+Exe, and PF+Exe when compared with the controls. AL+Exe did not induce weight loss due to, at least in part, increased food intake. Plasma IGF-1 levels reduced significantly in DCR and DCR+Exe but not PF+Exe. The protein H-Ras and activated Ras-GTP significantly decreased in TPA-induced skin tissues of DCR-fed mice but not exercised mice. PI3K protein, phosphoserine Akt, and p42/p44-MAPK were reduced, however, in both DCR and PF+Exe groups. Immunohistochemistry demonstrated that the significantly reduced H-Ras occurred in subcutaneous fat cells, while the reduced PI3K and PCNA took place only in the epidermis. Plasma leptin decreased in PF+Exe, DCR, and DCR+Exe, while the caspase-3 activity increased in DCR+Exe only. Genomic microarray analysis further indicated that the expression of 34 genes relevant to PI3K and 31 genes to the MAPK pathway were significantly regulated by either DCR or PF+Exe treatments. The reduced PI3K in PF+Exe mice was partially reversed by IGF-1 treatment. The overall results of this study demonstrated that DCR abrogated both Ras and PI3K signaling, which might inhibit TPA-induced proliferation and anti-apoptosis. Selective inhibition of PI3K by PF+Exe but not AL+Exe seems more attributable to the magnitude of the caloric deficit and/or body fat loss than diet versus exercise comparison.

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Zhou, Hong, Qi-xiang Zhao, Jia-dong Yu, Cheng-cheng Yue, Yan Hao, Hua-ping Zheng, Jing Hu, Zhen Wang, and Jiong Li. "Interleukin-38 promotes skin tumorigenesis via regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment in an IL-1Rrp2-dependent manner." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 22.01. http://dx.doi.org/10.4049/jimmunol.206.supp.22.01.

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Abstract As the newest member of the IL-1 family, interleukin-38 (IL-38) has strong associations with chronic inflammatory diseases. However, its roles in tumorigenesis and the underlying mechanism remain poorly understood. Here, we demonstrated that IL-38, which was highly expressed in skin, downregulated in human cutaneous squamous cell carcinomas (CSCC) and 7,12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoyl phorbol-13-acetate (TPA) induced mouse skin tumorigenesis. IL-38 keratinocyte-specific knockout mice (IL-38 cKO) dramatically promoted skin tumor formation and their malignant progression. Mechanistically, IL-38 is dispensable for epidermal mutagenesis. IL-38 keratinocyte-specific deletion reduced proliferative gene expression along with epidermal cell proliferation and hyperplasia. Additionally, keratinocyte-specific deletion of IL-38 was associated with reduced secretion of inflammatory cytokines leading to a decreased infiltration of myeloid cells into the local tumor microenvironment, these inflammation-driven tumorigenesis are essential for carcinogenesis process. Furthermore, we first demonstrated that IL-38 activated the c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) signal transduction pathway to promote proliferation and migration of tumor cells and expression of cancer-related inflammatory cytokines in an IL-1 receptor (IL-1R)-related protein 2 (IL-1Rrp2)-dependent manner. Together, our findings highlight the role of IL-38 in the regulation of epidermal cell hyperplasia and pro-tumorigenic microenvironment through IL-1Rrp2 /JNK and establish a new defined factor IL-38/ IL-1Rrp2 as therapeutic targets in skin cancer.

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Etoh, Tadahiro, Yong P. Kim, Masahiko Hayashi, Michiko Suzawa, Shiming Li, Chi-Tang Ho, and Kanki Komiyama. "Inhibitory effect of a formulated extract from multiple citrus peels on LPS-induced inflammation in RAW 246.7 macrophages." Functional Foods in Health and Disease 3, no. 6 (June 26, 2013): 242. http://dx.doi.org/10.31989/ffhd.v3i6.50.

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Background: Formulated Citrus Peel Extract (GL) made from the peels of six citrus fruits available in Japan, namely navel oranges, citrus hassaku, citrus limon, citrus natsudaidai, citrus miyauchi and satsuma, was initially developed as a cosmetic product to protect skin from UV irradiation. Anecdotal evidences of anti-cancer property of GL have been reported by consumers based on the cases such as topical application for melanoma, and oral ingestion for prostate, lung and liver cancers. Those anecdotal reports stimulated us to investigate anti-tumorigenesis activity of GL. In the previous study, we reported that the topical application of GL inhibited DMBA/TPA-induced skin tumor formation by decreasing inflammatory gene parameters.Objective: In this study, we mainly investigated the effect of GL on translocation of NF-kB together with production of nitric-oxide and TNF-α induced by LPS in RAW 264.7 cells.Results: This investigation showed that GL decreased the release of TNF-α and nitric oxide from macrophage RAW264.7 cells stimulated by LPS in a dose-dependent manner. In addition, GL suppressed the expression of iNOS and nuclear translocation of NF-kB in RAW264.7 cells, inhibited the degradation of IκB-α, and scavenged hydroxyl radicals (DMPO/OH adduct) in vitro.Conclusions: Our findings suggest that GL suppresses the inflammation in vitro, and exerts chemopreventive activity through the inhibition of production of TNF-α and iNOS proteins due to the inhibition of nuclear translocation of NF-kB and oxidative stress. GL appears to be a novel functional natural product capable of preventing inflammation and inflammation-associated tumorigenesis. Keywords: GL, Citrus peel extract, anti-inflammation, Nitric oxide, iNOS, NF-kB, TNF-α

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chen, wanjiao, Vinh A. Dao, Kim Cardenas, Shunhua Lao, Álvaro Padrón, Edward P. Hasty, Zelton Dave Sharp, Vincent Hurez, and Tyler J. Curiel. "Microencapulated rapamycin prevents carcinogen and inflammation driven colon cancer through immune mechanisms." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 73.9. http://dx.doi.org/10.4049/jimmunol.196.supp.73.9.

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Abstract We tested microencapsulated rapamycin (eRapa, ~2.2 mg/kg rapamycin/mouse/day) in carcinogen (azoxymethane, AOM) + inflammatory agent (dextran sodium sulfate, DSS) colon cancer. WT BL6 mice fed eRapa before, and during AOM/DSS had significantly fewer colon tumors and tumor burden than control fed mice (empty microcapsules). eRapa prevented colon cancer in δ TCR KO mice lacking γδ T cells but not in IFN-γ KO mice. In carcinogen (DMBA) + inflammatory agent (TPA) skin cancer, IFN-γ and γδ T cells were both needed for eRapa cancer prevention, showing tumor-specific and common immune requirements for eRapa-mediated cancer prevention. In βδ TCR KO mice lacking all T cells, AOM/DSS induced no cancer or only few tumors, suggesting αβ T cells are required for colon neoplasia and cancer in the AOM/DSS model. Protection from acute colitis in this model usually predicts colon cancer protection. Strikingly, however, eRapa did not prevent acute clinical or histologic colitis induced by DSS, despite cancer protection, suggesting effects on chronic colitis, or induction of cancer-protective but not acute colitis-protective mechanisms. In acute colitis, eRapa significantly decreased spleen and colon weights and CD3+CD4+ T cells, and increased mesenteric lymph node γδ T cells (with decreased Vγ1.1+ and increased Vγ2+ subsets) consistent with altered inflammation and reduced CD4-CXCR3+ and CD4-α4β7 T cells (likely γδ T cells) consistent with altered trafficking but did not affect CCR9+ T cells. In chronic colitis, eRapa significantly increased γδ T cells (with no changes in Vγ1.1+ or Vγ2+ subsets) that could mediate cancer protection. These novel immune effects of rapamycin help define its cancer prevention mechanisms and define novel clinical uses.

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Montero-Montero, Lucía, Jaime Renart, Andrés Ramírez, Carmen Ramos, Mariam Shamhood, Rocío Jarcovsky, Miguel Quintanilla, and Ester Martín-Villar. "Interplay between Podoplanin, CD44s and CD44v in Squamous Carcinoma Cells." Cells 9, no. 10 (September 29, 2020): 2200. http://dx.doi.org/10.3390/cells9102200.

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Podoplanin and CD44 are transmembrane glycoproteins involved in inflammation and cancer. In this paper, we report that podoplanin is coordinately expressed with the CD44 standard (CD44s) and variant (CD44v) isoforms in vivo—in hyperplastic skin after a pro-inflammatory stimulus with 12-O-tetradecanoylphorbol-13-acetate (TPA)—and in vitro—in cell lines representative of different stages of mouse-skin chemical carcinogenesis, as well as in human squamous carcinoma cell (SCC) lines. Moreover, we identify CD44v10 in the mouse-skin carcinogenesis model as the only CD44 variant isoform expressed in highly aggressive spindle carcinoma cell lines together with CD44s and podoplanin. We also characterized CD44v3-10, CD44v6-10 and CD44v8-10 as the major variant isoforms co-expressed with CD44s and podoplanin in human SCC cell lines. Immunofluorescence confocal microscopy experiments show that these CD44v isoforms colocalize with podoplanin at plasma membrane protrusions and cell–cell contacts of SCC cells, as previously reported for CD44s. Furthermore, CD44v isoforms colocalize with podoplanin in chemically induced mouse-skin SCCs in vivo. Co-immunoprecipitation experiments indicate that podoplanin physically binds to CD44v3-10, CD44v6-10 and CD44v8-10 isoforms, as well as to CD44s. Podoplanin–CD44 interaction is mediated by the transmembrane and cytosolic regions and is negatively modulated by glycosylation of the extracellular domain. These results point to a functional interplay of podoplanin with both CD44v and CD44s isoforms in SCCs and give insight into the regulation of the podoplanin–CD44 association.

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Nafz, J., M. Ohnesorge, E. Stockfleth, F. Rösl, and I. Nindl. "Imiquimod treatment of papilloma virus and DMBA /TPA-induced cutaneous skin cancer in Mastomys coucha: an unique animal model system useful for preclinical studies." British Journal of Dermatology 157 (December 7, 2007): 14–17. http://dx.doi.org/10.1111/j.1365-2133.2007.08266.x.

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Wang, Fei, Hongxia Ma, Zhaoguo Liu, Wei Huang, Xiaojing Xu, and Xuemei Zhang. "α-Mangostin inhibits DMBA/TPA-induced skin cancer through inhibiting inflammation and promoting autophagy and apoptosis by regulating PI3K/Akt/mTOR signaling pathway in mice." Biomedicine & Pharmacotherapy 92 (August 2017): 672–80. http://dx.doi.org/10.1016/j.biopha.2017.05.129.

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Rauf, Abdur, Ajmal Khan, Tareq Abu-Izneid, Fahad A. Alhumaydhi, Saud Bawazeer, Muslim Raza, Haroon Khan, Seema Patel, and Ahmed Al-Harrasi. "Novel Anticancer Dimeric Naphthoquinones from Diospyros lotus having Anti- Tumor, Anti-Inflammatory and Multidrug Resistance Reversal Potential: In Vitro, In Vivo and In Silico Evidence." Anti-Cancer Agents in Medicinal Chemistry 21, no. 15 (September 8, 2021): 2089–97. http://dx.doi.org/10.2174/1871520621666210112113127.

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Background: Cancer being a genetically heterogeneous and complex disease and the available therapies are not very effective, rendering them the predominant cause of mortality across the world. The discovery of new anticancer drugs with higher efficacy and milder side effects is a great challenge for health professionals. Objective: The current study focused on the anticancer potential of two known dimeric napthoquiones, diospyrin (1) and 8-hydroxydiospyrin (2) isolated from the roots of Diospyros lotus. Methods: In vitro Epstein-Barr-Virus (EVA) an early antigen activation assay was used to evaluate the antitumor potential of tested compounds followed by a two-stage carcinogenesis assay on mouse skin for anti-carcinogenic effect. Compounds were also assessed for their multidrug resistance reversal potential. The in vitro heatinduced protein denaturation assay was used for the anti-inflammatory effect of the tested compounds. Results: Both compounds evoked marked cytotoxic activity with IC50 of 47.40 and 36.91 ppm, respectively. In Epstein-Barr-Virus (EVA) early antigen activation assay compounds 1 and 2 showed IC50 values of 426 ppm and 412 ppm, respectively. The tested compounds showed 60% survival rate of the lymphoblastoid Raji cells at a concentration of 1000 (mol / ratio 32 pmol TPA). In a two-stage carcinogenesis assay on mouse skin, both compounds significantly delayed the formation of papillomas on mouse skin. Compound 1 showed 50% effect at 14th week, whereas compound 2 exerted the same effect at 13th week, while both provoked 100% effect at 20th week. Both compounds significantly attenuated thermal-induced protein denaturation with EC50 values of 298 and 264 μg/mL, respectively. The dimeric napthoquiones were evaluated for their effects on the reversion of Multidrug-Resistant (MDR) cell lines mediated by P-glycoprotein using rhodamine 123 dye-based exclusion screening test on human mdr1 gene transfected thymic lymphoma L5178 cell line. The compounds 1 and 2 exhibited promising MDR reversal effect in a dose-dependent manner against mouse T-lymphoma cell line. Docking results also showed that both compounds have good docking statistics as compared with standard. Conclusions: Both the compounds demonstrated marked anti-tumor, anti-carcinogenic, and MDR reversal effects with significant attenuation of thermal-induced denaturation of the protein. These compounds may explain the traditional uses of D. lotus which might be effective anticancer agents.

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Rane, Sushil G., Stephen C. Cosenza, Richard V. Mettus, and E. Premkumar Reddy. "Germ Line Transmission of the Cdk4R24C Mutation Facilitates Tumorigenesis and Escape from Cellular Senescence." Molecular and Cellular Biology 22, no. 2 (January 15, 2002): 644–56. http://dx.doi.org/10.1128/mcb.22.2.644-656.2002.

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ABSTRACT Mutations in CDK4 and its key kinase inhibitor p16INK4a have been implicated in the genesis and progression of familial human melanoma. The importance of the CDK4 locus in human cancer first became evident following the identification of a germ line CDK4-Arg24Cys (R24C) mutation, which abolishes the ability of CDK4 to bind to p16INK4a. To determine the role of the Cdk4 R24C germ line mutation in the genesis of other cancer types, we introduced the R24C mutation in the Cdk4 locus of mice by using Cre-loxP-mediated “knock-in” technology. Cdk4 R24C/R24C mouse embryo fibroblasts (MEFs) displayed increased Cdk4 kinase activity resulting in hyperphosphorylation of all three members of the Rb family, pRb, p107, and p130. MEFs derived from Cdk4 R24C/R24C mice displayed decreased doubling times, escape from replicative senescence, and escape sensitivity to contact-induced growth arrest. These MEFs also exhibited a high degree of susceptibility to oncogene-induced transformation, suggesting that the Cdk4 R24C mutation can serve as a primary event in the progression towards a fully transformed phenotype. In agreement with the in vitro data, homozygous Cdk4 R24C/R24C mice developed tumors of various etiology within 8 to 10 months of their life span. The majority of these tumors were found in the pancreas, pituitary, brain, mammary tissue, and skin. In addition, Cdk4 R24C/R24C mice showed extraordinary susceptibility to carcinogens and developed papillomas within the first 8 to 10 weeks following cutaneous application of the carcinogens 9,10-di-methyl-1,2-benz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). This report formally establishes that the activation of Cdk4 is sufficient to promote cancer in many tissues. The observation that a wide variety of tumors develop in mice harboring the Cdk4 R24C mutation offers a genetic proof that Cdk4 activation may constitute a central event in the genesis of many types of cancers in addition to melanoma.

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Li, Yun Rose, Kyle Halliwill, Eve Kandyba, Reyno Delrosario, Quan Tran, Nora Bayani, Di Wu, et al. "Abstract 2198: The impact of carcinogens, obesity, and chronic inflammatory processes on mutational signatures and cancer risk in mouse tumor models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2198. http://dx.doi.org/10.1158/1538-7445.am2022-2198.

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Abstract An estimated 40% of all human cancers are suspected to be a result of modifiable risk factors such as obesity, high fat diet and chronic inflammation. Whole genome sequencing (WGS) of thousands of human tumors have revealed “mutational signatures” that provide a molecular footprint of cancer origins. Whether such signatures exist for modifiable cancer risk factors remains unclear. We studied the impact of lifestyle risk factors using a compendium of 107 mouse tumors that model obesity, high fat diet, wounding, chronic inflammation, or chemotherapy. We used a well-established 2-step skin carcinogenesis model composed of exposure to mutagen DMBA followed by tumor promoter TPA, generating squamous carcinomas that were analysed by WGS for identification of mutational signatures. In addition to recapitulating many COSMIC human signatures, we identified a novel SNV signature induced by a single treatment with DMBA (SBS.DMBA) which explains the majority of all detected mutations. While a single exposure of normal skin to DMBA induces a highly variable number of carcinogen-specific mutations, a very high mutation burden is insufficient for tumorigenesis. SNVs attributable to reactive oxygen species (ROS) are broadly found in about 25% of all mouse tumors, but are most prominent in tumors from mice that are exposed to DMBA in utero, suggesting that the developmental age of mutagen exposure may impact the repair of ROS generated mutations and that the timing of exposure is a poorly understudied component of carcinogenesis. In mouse tumor models of genetic and dietary obesity, the total mutational load and mutational signatures in tumors from obese mice were indistinguishable from those of lean mice despite dramatic differences in tumor latency and progression as well transcriptomic differences in immune activation. We found an enrichment in deleterious Tgfrb2 mutations in tumors from mice with low compared to high body mass index (BMI) (p<0.016). Using a conditionally activated RAS mouse model, we also show that a non-mutagenic inflammatory signal such as a chronic wound can act as the rate-limiting step for full tumor development. Surprisingly these tumors can be evoked even in somatic genomes with very few mutations apart from the initiating Ras driver. Finally, together with the Riva et al study, these chemically induced mouse tumors recapitulate >50% of established human cancer driver genes. DMBA caused 91% of all Hras/Kras mutations, but only a minority of other recurrent driver mutations in genes such as Trp53 and Tert, suggesting that these occur later during the process of carcinogenesis. Taken together, we have analyzed the largest compendium of WGS data from nearly 300 mouse tumors, showing that while exogenous promotional factors do not increase mutation burden or induce novel mutational patterns, they have a major rate-limiting role in determining cancer risk. Citation Format: Yun Rose Li, Kyle Halliwill, Eve Kandyba, Reyno Delrosario, Quan Tran, Nora Bayani, Di Wu, Olga Mirzoeva, Melissa McCreery Reeves, Mishu Islam, Laura Riva, Eric Bergstrom, John Digiovanni, Ludmil Alexandrov, Allan Balmain. The impact of carcinogens, obesity, and chronic inflammatory processes on mutational signatures and cancer risk in mouse tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2198.

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Farombi, Ebenezer O., Babajide O. Ajayi, Isaac A. Adedara, and Solomon E. Owumi. "Abstract A39: 6-Gingerol, a chemopreventive phytochemical as speed breaker in inflammatory and stress signaling cascade triggered by benzo(a)pyrene and dextran sulphate sodium-mediated colorectal cancer in mice." Cancer Prevention Research 13, no. 7_Supplement (July 1, 2020): A39. http://dx.doi.org/10.1158/1940-6215.envcaprev19-a39.

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Abstract Preclinical and clinical investigations have identified unresolved inflammation and oxidative/nitrosative stress as two coconspirators, which play a multifaceted role and serve as driving force in the journey to cancer development. Ulcerative colitis is an inflammatory disease of the colon that predisposes to colorectal cancer, the fourth leading cause of cancer worldwide. Overexpression of proinflammatory mediators, a distinct network of intracellular signaling molecules including upstream kinases and transcription factors, facilitates tumor promotion and CRC progression. Current therapeutic drugs for CRC have severe adverse effects. Several investigations indicate that a plant-based diet rich in a wide variety of fruits and vegetables is effective in preventing or reversing premalignant lesions. Thus, the search for novel chemopreventive agents of physiologic relevance acting on specific and/or multiple molecular and cellular targets holds promise as a rational strategy for the control of health-threatening diseases such as ulcerative colitis and CRC. A bioactive component, 6-gingerol from ginger (Zingiber officinale) has been reported to possess antioxidant and anti-inflammatory activities. Our study demonstrates that 6-gingerol protects against dextran sulfate sodium (DSS)-induced ulcerative colitis in BalBc mice. 6-Gingerol attenuated DSS-mediated increase in immunoexpression of nuclear factor kappa B (NF-κB [p65]), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1 β), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), mitogen-activated kinase (P 38), RANTES, Bcl2, monocyte chemoattractant protein (MCP-1), and β-catenin expression. Similarly, 6-gingerol modulated DSS decrease in adenomatous polyposis coli (APC), DESMIN, Interleukin 10, and levels of antioxidant enzymes. In the two-stage (DMBA initiation and TPA promotion) mouse skin carcinogenesis model, 6-gingerol downregulated the expression of COX-2 and NF-κB. Also, in the benzo(a)pyrene and DSS (BDS) model of colorectal cancer, BDS induced adenocarcinoma and decreased APC, p53 expression, and number of apoptotic cells. In addition, tumor incidence, β-catenin, and cyclin D1 expressions were increased. Treatment with 6-gingerol decreased adenocarcinoma significantly and modulated the expression of these proteins and transcription factors. This anti-inflammatory phytochemical exerted chemopreventive effects by modulating intracellular signaling cascades and proinflammatory mediators and therefore qualifies as therapeutic signature for chemoprevention of inflammation-associated CRC. Citation Format: Ebenezer O. Farombi, Babajide O. Ajayi, Isaac A. Adedara, Solomon E. Owumi. 6-Gingerol, a chemopreventive phytochemical as speed breaker in inflammatory and stress signaling cascade triggered by benzo(a)pyrene and dextran sulphate sodium-mediated colorectal cancer in mice [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A39.

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Na Takuathung, Mingkwan, Kanjana Jaijoy, Noppamas Soonthornchareonnon, and Seewaboon Sireeratawong. "Anti-inflammatory, Antinociceptive, and Antitumorigenesis Activities of Terminalia Bellerica (Gaertn.) Roxb. in Animal Models." Natural Product Communications 17, no. 4 (April 2022): 1934578X2210899. http://dx.doi.org/10.1177/1934578x221089996.

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Previous pharmacological research has demonstrated that Terminalia bellerica (Gaertn.) Roxb. (TB) extract possesses several pharmacological activities. However, there is scant evidence documenting the therapeutic activities of TB extract on inflammation, pain, and cancers. Our study examined the in vivo anti-inflammation, antinociception, and antitumorigenesis effects of TB extract and investigated possible mechanisms for those effects. Anti-inflammation activities of TB extract were evaluated using ethyl phenylpropiolate (EPP)- and arachidonic acid (AA)-induced ear edema models, a cotton pellet-induced granulation formation model, and a carrageenan-induced hind paw edema model. An antinociceptive property of TB extract was assessed using a formalin-induced nociception test. An anticarcinogenesis effect was investigated using a 7,12-dimethylbenz( a) anthracene (DMBA) and 12- O-tetradecanoylphorbol-13-acetate (TPA)-induced tumorigenesis model. In the study, TB extract exhibited significant anti-inflammatory effects against EPP-induced ear edema and carrageenan-induced hind paw edema in rats. However, the TB extract showed insignificant inhibitory activity against AA-induced ear edema and cotton pellet-induced granuloma. A dose-dependent decrease in analgesic activity was observed with TB extract evidenced by decreased licking time in formalin-induced pain in mice in both the early and late phases. TB extract also significantly inhibited DMBA/TPA-induced mouse skin tumorigenesis. In conclusion, TB extract possesses anti-inflammatory, analgesic, and anticarcinogenesis properties which act, at least in part, through inhibitory effects of inflammatory mediator production.

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Choi, Soo Young, Min-Jeong Heo, Chanmi Lee, Yeong Min Choi, In-sook An, Seunghee Bae, Sungkwan An, and Jin Hyuk Jung. "2-deoxy-d-glucose Ameliorates Animal Models of Dermatitis." Biomedicines 8, no. 2 (January 24, 2020): 20. http://dx.doi.org/10.3390/biomedicines8020020.

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Glucose metabolism is a key metabolic pathway that orchestrates cellular homeostasis by generating ATP, nucleotides, and amino acids. Abnormal glucose signaling has been found in many diseases including cancers and inflammatory diseases. According to recent report, glycolysis contributes to pathogenesis of psoriasis and ablation of Glut1 attenuates animal models of psoriasis. While we were screening a molecular target for atopic dermatitis, we found the levels of glucose transporters including Glut1 (SLC2a1) and Glut3 (SLC2a3) are highly expressed in skin biopsies of dermatitis patients from multiple datasets. We demonstrated that administration of 2-deoxy-d-glucose (2DG) ameliorates animal models of 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone induced dermatitis using morphological and histological analysis. These results suggest that inhibition of glucose metabolism ameliorates dermatitis in animal models.

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Cheng, An-Chin, Wan-Ru Jiang, Yu-Hsuan Hsiao, Vladimir Badmaev, Chi-Tang Ho, Roch-Chui Yu, and Min-Hsiung Pan. "Promoting effect of Se-allylselenocysteine on 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis." Journal of Food Bioactives 9 (March 31, 2020). http://dx.doi.org/10.31665/jfb.2020.9221.

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Se-allylselenocysteine (ASC), an analogue of garlic compound, has been shown to inhibit mammary carcinogenesis in vivo and cell growth in vitro. However, the function of ASC on anti-inflammatory effects remains largely unknown. Therefore, we investigated whether ASC has an anti-inflammatory effect on lipopolysaccharide (LPS) -induced inflammation or an anti-tumour effect promoting on DMBA/TPA-induced skin tumorigenesis and tried to elucidate the mechanisms involved. Herein, the results showed that ASC inhibited LPS-induced production of nitric oxide (NO) with a decreased protein level of inducible nitric oxide synthase (iNOS) in RAW 264.7 cells. However, ASC enhanced LPS-induced cyclooxygenase-2 (COX-2) protein levels and mRNA expression. Interestingly, we found for the first time that topical application of ASC on the dorsal skin of DMBA-initiated and TPA-promoted mice significantly accelerated skin tumorigenesis and raised tumour multiplicity as compared to the positive control group (DMBA/TPA). The number of tumours that were 1–3 mm, 3–5 mm, and >5 mm in size per mouse increased in a dose-dependent manner in the ASC pre-treated groups. Pre-treatment with ASC showed a significant increase in the expression of COX-2 compared with the positive control group. In summary, that ASC may modulate the COX-2 protein expression and promoting DMBA/TPA-induced skin cancer in mice.

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Cipolat, Sara, Esther Hoste, Ken Natsuga, Sven R. Quist, and Fiona M. Watt. "Epidermal barrier defects link atopic dermatitis with altered skin cancer susceptibility." eLife 3 (May 6, 2014). http://dx.doi.org/10.7554/elife.01888.

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Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI−/− mice, which lack three barrier proteins—Envoplakin, Periplakin, and Involucrin. EPI−/− mice were highly resistant to developing benign tumours when treated with 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The DMBA response was normal, but EPI−/− skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP). The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells. We conclude that atopy is protective against skin cancer in our experimental model and that the mechanism involves keratinocytes communicating with cells of the immune system via signalling elements that normally protect against environmental assaults.

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De Blasio, Carlo, Nagendra Verma, Marta Moretti, Samantha Cialfi, Azzurra Zonfrilli, Matteo Franchitto, Federica Truglio, et al. "Functional cooperation between ASK1 and p21Waf1/Cip1 in the balance of cell-cycle arrest, cell death and tumorigenesis of stressed keratinocytes." Cell Death Discovery 7, no. 1 (April 12, 2021). http://dx.doi.org/10.1038/s41420-021-00459-3.

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AbstractBoth CDKN1A (p21 Waf1/Cip1) and Apoptosis signal-regulating kinase 1 (ASK1) play important roles in tumorigenesis. The role of p21 Waf1/Cip1 in attenuating ASK1-induced apoptosis by various stress conditions is well established. However, how ASK1 and p21 Waf1/Cip1 functionally interact during tumorigenesis is still unclear. To address this aspect, we crossed ASK1 knockout (ASK1KO) mice with p21Waf1/Cip1 knockout (p21KO) mice to compare single and double-mutant mice. We observed that deletion of p21Waf1/Cip1 leads to increased keratinocyte proliferation but also increased cell death. This is mechanistically linked to the ASK1 axis-induced apoptosis, including p38 and PARP. Indeed, deletion of ASK1 does not alter the proliferation but decreases the apoptosis of p21KO keratinocytes. To analyze as this interaction might affect skin carcinogenesis, we investigated the response of ASK1KO and p21KO mice to DMBA/TPA-induced tumorigenesis. Here we show that while endogenous ASK1 is dispensable for skin homeostasis, ASK1KO mice are resistant to DMBA/TPA-induced tumorigenesis. However, we found that epidermis lacking both p21 and ASK1 reacquires increased sensitivity to DMBA/TPA-induced tumorigenesis. We demonstrate that apoptosis and cell-cycle progression in p21KO keratinocytes are uncoupled in the absence of ASK1. These data support the model that a critical event ensuring the balance between cell death, cell-cycle arrest, and successful divisions in keratinocytes during stress conditions is the p21-dependent ASK1 inactivation.

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Journal articles on the topic 'TPA-induced skin cancer'

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