Abstract
BackgroundDespite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries. Chemotherapy plays an important role in melanoma management. Tamoxifen has been used either alone or in- combination with other chemotherapeutic agents to treat melanoma. However, response rate of tamoxifen as a single agent has been comparatively low. In the present study, we investigated whether treatment with methyl-β-cyclodextrin (MCD), a cholesterol depleting agent, increases the efficacy of tamoxifen in melanoma cells.MethodsThis was a two-part study that incorporated in vitro effects of tamoxifen and MCD combination by analyzing cell survival, apoptosis and cell cycle analysis and in vivo antitumor efficacy on tumor isografts in C57BL/6J mice.ResultsMCD potentiated tamoxifen induced anticancer effects by causing cell cycle arrest and induction of apoptosis. Sensitization to tamoxifen was associated with down regulation of antiapoptotic protein Bcl-2, up-regulation of proapoptotic protein Bax, reduced caveolin-1 (Cav-1) and decreased pAkt/pERK levels. Co-administration of tamoxifen and MCD caused significant reduction in tumor volume and tumor weight in mice due to enhancement of drug uptake in the tumor. Supplementation with cholesterol abrogated combined effect of tamoxifen and MCD.ConclusionOur results emphasize a potential synergistic effect of tamoxifen with MCD, and therefore, may provide a unique therapeutic window for improvement in melanoma treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-204) contains supplementary material, which is available to authorized users.
Highlights
Despite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries
Methyl-β-cyclodextrin enhances the susceptibility of A375 and B16F10 cells to tamoxifen Tamoxifen treatment causes a dose-dependent decrease in the survival of A375, B16F10 and B16F1 cells and IC50 was calculated to be 30 μM, 40 μM and 30 μM respectively (Additional file 1: Table S1)
We checked the effect of MCD by treating A375 and B16F10 cells with 2.5 mM of MCD for 1 h or 4 h and no significant change in cell cycle progression, cell survival and Lactate dehydrogenase (LDH) release was observed at 2.5 mM dose of MCD for 4 h
Summary
Despite modern advances in treatment, skin cancer is still one of the most common causes of death in the western countries. We investigated whether treatment with methyl-β-cyclodextrin (MCD), a cholesterol depleting agent, increases the efficacy of tamoxifen in melanoma cells. Chemotherapeutic drugs, radiation and immunotherapy have been widely used to treat melanoma [4,5]. In spite of these options, the median survival rate of melanoma patients is approximately 6 months that increase in the levels of drugs into tumor cells may eventually enhance the therapeutic index. Plasma membrane contains nanometer-sized dynamic microdomains enriched in cholesterol, sphingolipids and gangliosides. These microdomain structures are integral to the regulation of influx or efflux of drugs. We and others have shown that MCD or its modified forms enhance the cytotoxic effect of various chemotherapeutic drugs [21,22,23]
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