Synergistic Simvastatin and Metformin Combination Chemotherapy for Osseous Metastatic Castration-Resistant Prostate Cancer

Abstract

Docetaxel (DTX) chemotherapy remains a standard-of-care for metastatic castration-resistant prostate cancer (CRPC). DTX modestly increases survival, yet results in frequent occurrence of side-effects and resistant disease. An alternate chemotherapy with greater efficacy and minimal side-effects is needed. Acquisition of metabolic aberrations promoting increased survival and metastasis in CRPC cells include constitutive activation of Akt, loss of adenosine monophosphate-activated protein kinase (AMPK) activity due to Ser-485/491 phosphorylation, and over-expression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoAR). We report that combination of simvastatin (SIM) and metformin (MET), within pharmacological dose range (500nM to 4µM SIM and 250µM to 2mM MET), significantly and synergistically reduces C4-2B3/B4 CRPC cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. Combination of SIM and MET decreased Akt Ser-473 and Thr-308 phosphorylation and AMPKα Ser-485/491 phosphorylation, increased Thr-172 phosphorylation and AMPKα activity as assessed by increased Ser-79 and Ser-872 phosphorylation of acetyl-CoA carboxylase and HMG-CoAR, respectively; decreased HMG-CoAR activity, and reduced total cellular cholesterol and its synthesis in both cell lines. Studies of C4-2B4 orthotopic NCr-nu/nu mice further demonstrated that combination of SIM and MET (3.5–7.0µg/g body weight SIM and 175–350µg/g body weight MET) daily by oral gavage over 9-week period significantly inhibited primary ventral prostate tumor formation, cachexia, bone metastasis, and biochemical failure more effectively than 24µg/g body weight DTX intraperitoneally-injected every three weeks, 7.0µg/g/day SIM, or 350µg/g/day MET treatment alone, with significantly less toxicity and mortality than DTX, establishing combination SIM and MET as a promising chemotherapeutic alternative for metastatic CRPC.

Ser‐486/491 phosphorylation and inhibition of AMPKα activity is positively associated with Gleason score, metastasis, and castration‐resistance in prostate cancer: A retrospective clinical study

“…Additionally, AMPKα activity, as determined by change in p-Ser-79 ACC, p-Ser-HMG-CoAR, and p-Ser-792 Raptor staining, was diminished in metastatic subject specimens compared to specimens from patients in the non-metastatic group. These clinical observations confirmed our in vitro data, which had compared AMPKα phosphorylation status, protein expression, and activity amongst hormone-dependent and hormone-refractory, metastasis-derived cell lines [14]. Potential biases exist in this work due to the inter-relationship between high Gleason grade and metastasis and between castration-resistance and metastasis: biopsy specimens of those patients who progressed to metastasis were on average of higher Gleason score, and an association between p-Ser-486/491 AMPKα1/α2 staining and both progression to metastasis and higher Gleason score was established; additionally, all CRPC specimens were metastasis specimens.…”

“…We have previously shown that AMPKα activity is significantly inhibited by Ser-486/491 phosphorylation in cell culture and in vivo models of metastatic and castration-resistant prostate cancer [14]. We hypothesize that these findings may translate to clinical specimens and that progression to metastasis and castration-resistance in prostate cancer will be associated with decreased AMPKα activity and increased Ser-486/491 AMPKα1/α2 phosphorylation.…”

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

“…38,39) The combination of metformin and simvastatin was found to decrease the levels of phospho-Akt and phospho-AMPKα1/α2. 40) The inhibitory effect and mechanisms of metformin in combination with atorvastatin have previously not been reported. In the present study, we found the potent effects of metformin in combination with atorvastatin on prostate cancer cells were associated with a strong inhibition of the activation of the transcription factor NF-κB.…”

Individual and joint effects of metformin and statins on mortality among patients with high‐risk prostate cancer

“…[5][6][7][8][9] Recently, pre-clinical data indicated a combination of metformin and statin was better than either drug alone in inhibiting primary tumor growth, metastasis to bone, and biochemical failure; human data on the joint effects of statins and metformin on PCa mortality are limited. 10,11 Because the majority of metformin users also take statins 12,13 some of the favorable outcomes observed among metformin users might be derived from statins.…”