Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Abstract

Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphorextracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.Key words prostate cancer; atorvastatin; metformin; apoptosis; combination Prostate cancer is one of the common types of malignant disease in males in the world and is the second leading cause of cancer-related death in the United States. The American Cancer Society estimates for 2016 approximately 180890 new cases will be diagnosed and 26120 men will die of the disease, accounting for about 8.3% of male cancer-related deaths. 1)Androgen deprivation therapy is an effective treatment for advanced prostate cancer. Unfortunately, almost all patients treated with androgen deprivation therapy will progress to castration-resistant prostate cancer (CRPC).2,3) Docetaxel is the most commonly prescribed first-line chemotherapy for CRPC. 4) Although docetaxel provides a modest (2.4-month) increase in median overall survival, many patients with CRPC cannot tolerate this cytotoxic chemotherapy due to advanced age, medical comorbidities, or limited bone marrow reserves. 5)Therefore, the identification of an effective alternative therapy with less toxicity may lead to increased survival and an improved QOL.Metformin is a well-established agent for the treatment of type II diabetes. In addition to its efficacy in lowering glucose levels, recent reports indicate it may have antitumor effects in various cancers, including prostate cancer. 6) Diabetic patients receiving metformin have been shown to have a reduced cancer incidence and a decrease in cancer-specific mortality.7) Further, epidemiologic evidence revealed a decreased incidence of prostate cancer in men taking metformin, 8,9) and both animal and in vitro models demonstrate its activity in prostate cancer cell lines. 10,11) Finall...

Anticancer Activity of Metformin, an Antidiabetic Drug, Against Ovarian Cancer Cells Involves Inhibition of Cysteine-Rich 61 (Cyr61)/Akt/Mammalian Target of Rapamycin (mTOR) Signaling Pathway

“…For, instance metformin in combination with imatinib was found to effective against colorectal cancer [ 13 ]. Similarly, metformin in combination with atorvastatin was found to be effective against prostate cancer [ 14 ]. There have been several reports on the effectiveness of metformin on ovarian cancer cells as well [ 15 – 17 ], but the direct target of this drug in ovarian cancer is yet to be reported.…”

Atorvastatin Enhances Effects of Radiotherapy on Prostate Cancer Cells and Xenograft Tumor Mice Through Triggering Interaction Between Bcl-2 and MSH2

“…The results confirmed that Bcl-2 interacted with MSH2 in both PCa cells and tumor tissues of xenograft tumor mice. These results suggest that the anti-tumor effects of atorvastatin are correlated with DNA repair process of the tumor cells, which have never been reported in the previous studies [ 24 , 25 ]. These findings hint that the drugs might also play the anti-tumor effects on tumor cells through targeting the DNA repair associated molecules.…”

Concomitant attenuation of HMG-CoA reductase expression potentiates the cancer cell growth-inhibitory effect of statins and expands their efficacy in tumor cells with epithelial characteristics

“…[ 49 ]). Indeed, metformin can potentiate the growth inhibitory effect of statins on tumor cell lines and the growth of primary tumors in nude mice [ 50 – 52 ]. Future studies will test potential synergy between statins and metformin (and related compounds) at inhibiting primary tumor growth and metastatic outgrowth in murine tumor models.…”