(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Skin-Neoplasms

Malignant melanoma is a highly aggressive skin cancer, and the overall median survival in patients with metastatic melanoma is only 6-9 months. Although molecular targeted therapies have recently been developed and have improved the overall survival, melanoma patients may show no response and acquisition of resistance to these drugs. Thus, other molecular approaches are essential for the treatment of metastatic melanoma. In the present study, we investigated the effect of cotreatment with dacarbazine and statins on tumor growth, metastasis, and survival rate in mice with metastatic melanomas. We found that cotreatment with dacarbazine and statins significantly inhibited tumor growth and metastasis via suppression of the RhoA/RhoC/LIM domain kinase/serum response factor/c-Fos pathway and enhanced p53, p21, p27, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase 1 expression in vivo. Moreover, the cotreatment significantly improved the survival rate in metastasis-bearing mice. Importantly, treatment with dacarbazine plus 100 mg/kg simvastatin or fluvastatin prevented metastasis-associated death in 4/20 mice that received dacarbazine + simvastatin and in 8/20 mice that received dacarbazine + fluvastatin (survival rates, 20% and 40%, respectively). These results suggested that cotreatment with dacarbazine and statins may thus serve as a new therapeutic approach to control tumor growth and metastasis in melanoma patients.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Dacarbazine; Female; Fluvastatin; Gene Expression Regulation; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung Neoplasms; Melanoma, Experimental; Mice, Inbred C57BL; Signal Transduction; Simvastatin; Skin Neoplasms; Tumor Burden

The relationship between statin use and non-melanoma skin cancer (NMSC) is unclear with conflicting findings in literature. Data from the Women's Health Initiative (WHI) Observational Study and WHI Clinical Trial were used to investigate the prospective relationship between statin use and NMSC in non-Hispanic white (NHW) postmenopausal women.. The WHI study enrolled women aged 50-79 years at 40 US centres. Among 133,541 NHW participants, 118,357 with no cancer history at baseline and complete medication/covariate data comprised the analytic cohort. The association of statin use (baseline, overall as a time-varying variable, duration, type, potency, lipophilicity) and NMSC incidence was determined using random-effects logistic regression models.. Over a mean of 10.5 years of follow-up, we identified 11,555 NMSC cases. Compared with participants with no statin use, use of any statin at baseline was associated with significantly increased NMSC incidence (adjusted odds ratio (ORadj) 1.21; 95% confidence interval (CI): 1.07-1.35)). In particular, lovastatin (OR 1.52; 95% CI: 1.08-2.16), simvastatin (OR 1.38; 95% CI: 1.12-1.69), and lipophilic statins (OR 1.39; 95% CI: 1.18-1.64) were associated with higher NMSC risk. Low and high, but not medium, potency statins were associated with higher NMSC risk. No significant effect modification of the statin-NMSC relationship was found for age, BMI, smoking, solar irradiation, vitamin D use, and skin cancer history.. Use of statins, particularly lipophilic statins, was associated with increased NMSC risk in postmenopausal white women in the WHI cohort. The lack of duration-effect relationship points to possible residual confounding. Additional prospective research should further investigate this relationship.

Topics: Age Factors; Aged; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cohort Studies; Environmental Exposure; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Indoles; Logistic Models; Longitudinal Studies; Lovastatin; Middle Aged; Odds Ratio; Overweight; Prospective Studies; Pyridines; Risk Factors; Simvastatin; Skin Neoplasms; Smoking; Sunlight; Vitamin D; Vitamins; White People