Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

Abstract

BackgroundOvarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action.MethodsThe effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches.ResultsWe demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis.ConclusionsThe results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism. Moreover, we also show lovastatin synergizes with doxorubicin, an agent administered for recurrent disease. This synergy occurs by a novel mevalonate-independent mechanism that antagonizes drug resistance, likely by inhibiting P-glycoprotein. These data raise important issues that may impact how statins can best be included in chemotherapy regimens.

The Hedgehog Receptor Patched Functions in Multidrug Transport and Chemotherapy Resistance

“…Martirossyan and colleagues showed that treatment of human ovarian carcinoma cells with lovastatin resulted in more intracellular doxorubicin accumulation and increased the drug efficacy (36). Remarkably, we observed that lovastatin treatment reduced the expression of the Shh target genes Ptc (Fig.…”

“…In this study, we show that the expression of the human Hh receptor Patched (hPtc) in Xenopus oocytes and in the yeast S. cerevisiae increased the efflux of doxorubicin, a chemotherapeutic agent used to treat recurrent cases of cancers (36). This doxorubicin efflux enhancement correlated with a decrease of doxorubicin accumulation in yeasts expressing hPtc, was energy-independent indicating that this effect was not because of ABC transporters, and was dependent of the proton motive force.…”

Synergistic anticancer effects of valproic acid, atorvastatin and pioglitazone in human malignant and murine cells

“…Several studies have demonstrated the pro-apoptotic action of statins, which could relate to the decreased expression of anti-apoptotic proteins such as Bcl-2 (Dimitroulakos et al, 2000), the activation of caspases 3, 7, 8 and 9 (Cafforio et al, 2005), induced apoptosis via the suppression of ERK1/2 and Akt activation (Yanae et al, 2011) and the reactivation JNK, which is a kinase that can act as a tumor suppressor (Meral et al, 2007). Some pre-clinical studies have also shown that statins have a capacity to induce synergistic antitumor effects associated with conventional chemotherapeutics (Gan et al, 2008;Martirosyan et al, 2010;Chen et al, 2013).…”

Anticancer Agents in Combination with Statins

“…P-glycoprotein (P-gp) inhibitory property of statins is useful for its combination treatment with other chemo therapeutic agents [63]. P-gp is a glycosylated membrane associated multi drug resistant protein and responsible for the decreased drug concentration in multi-drug resistant cells [64].…”

“…When doxorubicin is used along with lovastatin in ovarian cancer cells, the statins sensitized the cells to doxorubicin and potentiated its anticancer activity synergistically. By blocking the drug efflux mediated by P-gp, Lovastatin increases the doxorubicin concentration inside the cells [63]. Simvastatin, atorvastatin or lovastatin inhibit the P-gp in high concentration [65,66].…”