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.

• Authors: Masanobu Tsubaki, Tomoya Takeda, Naoya Obata, Keishi Kawashima, Mitsuki Tabata, Motohiro Imano, Takao Satou, Shozo Nishida
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 234 Issue 10 Pg. 17975-17989 (08 2019) ISSN: 1097-4652 [Electronic] United States
• PMID: 30834527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents, Alkylating
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Fluvastatin
• Dacarbazine
• Simvastatin

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dacarbazine (pharmacology)
• Female
• Fluvastatin (pharmacology)
• Gene Expression Regulation
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Lung Neoplasms (drug therapy, genetics, metabolism, secondary)
• Melanoma, Experimental (drug therapy, genetics, metabolism, secondary)
• Mice, Inbred C57BL
• Signal Transduction
• Simvastatin (pharmacology)
• Skin Neoplasms (drug therapy, genetics, metabolism, pathology)
• Tumor Burden (drug effects)