Combination therapy with dacarbazine and statins improved the survival rate in mice with metastatic melanoma

Abstract

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.

Anti-Proliferative Effect of Statins Is Mediated by DNMT1 Inhibition and p21 Expression in OSCC Cells

“…These results suggest that the functions of kinases have been inhibited by p21 upregulation. Similar to our results, statins have been reported to upregulate p21 expression in glioma, hypopharyngeal cancer [ 9 ], anaplastic thyroid cancer [ 10 , 14 ], liver cancer [ 11 ], HeLa cells [ 13 ], colon cancer [ 17 ], oral cancer [ 29 ], and melanoma [ 30 ]. p21 also negatively regulates the cell cycle by binding to proliferating cell nuclear antigen (PCNA) through its carboxyl-terminal domain, thus blocking DNA replication [ 31 ].…”

“…These results indicate that p21 also plays a dominant role in SAS cells. Moreover, studies have shown the pro-apoptotic effect of p21 in different cancers, and its function is mediated by different mechanisms, including caspase-3 activation, p53-dependent activation of p21, modulation pro-apoptotic BAX protein, and Annexin V reactivity [ 19 , 29 , 30 , 31 , 43 , 44 , 45 , 46 ]. Together, statin-induced cell cycle arrest is mediated by modulating the expression of p21 and CDKs in OSCC cells.…”

“…Statins have been reported to inhibit cell proliferation mainly by negative regulation on cell cycle in several cancers. The suppression of cell cycle progression was achieved through the upregulation of cyclin-dependent kinase (CDK) inhibitors, mostly p21 and p27 [ 9 , 10 , 11 , 13 , 14 , 15 , 17 , 29 , 30 ]. These cell cycle-related tumor suppressor genes (TSGs) bind to cyclin-CDKs complexes and inhibit kinase activity, which leads to the cell cycle arrest [ 31 ].…”

Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells

“…Cell migration and invasion assay was performed as previously described [35]. The cells were seeded into the upper chambers in FBS-free RPMI1640 medium after adding rhosin (Merck Millipore) or verteporfin (Cayman Chemical, Ann Arbor, MI, USA).…”

Cinnamaldehyde Enhances Antimelanoma Activity through Covalently Binding ENO1 and Exhibits a Promoting Effect with Dacarbazine

“…However, it produces relative responses in only 15-20% of patients [10]. Studies have shown that cotreatment with DTIC and statins could suppress the growth of tumors and simultaneously improve the survival rate by suppressing the RhoA/RhoC pathway and inducing the expression of cleaved caspase-3, cleaved PARP, p21, p27, and p53 in melanoma [11]. Previous studies have also demonstrated that TMZ can enhance the antitumor activity of FTM, but they have limited effectiveness [12][13][14].…”