Abstract 3283: Synergistic simvastatin and metformin chemotherapy for metastatic castration-resistant prostate cancer.
Authors: Babcook Melissa A. , Sramkoski R. Michael , Vazquez Edwin J. , Puchowicz Michelle A. , Shukla Sanjeev , Gupta Sanjay 
Published: August 2014

Docetaxel (Dtx), first-line chemotherapy of metastatic castration-resistant prostate cancer (CRPC), provides a modest increase in overall survival, yet results in frequent occurrence of severe side effects and leads to Dtx-resistant disease. Identification of a more effective alternate chemotherapy with fewer side effects would greatly benefit patient quality of life. Metabolic alterations occur in metastatic CRPC cells that may promote survival. 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoAR) is over-expressed and dysregulated, leading to elevated cellular cholesterol levels. In addition, adenosine monophosphate-activated protein kinase (AMPK) activity is significantly decreased by Ser-485/491 phosphorylation, in part due to constitutively-active Akt. Simvastatin (SIM), used to treat hypercholesterolemia (HC), is a potent inhibitor of HMG-CoAR; metformin (MET) is an indirect activator of AMPK prescribed for Type II Diabetes (T2D). T2D and HC are associated with increased risk of advanced prostate cancer (PCa); whereas, SIM or MET treatment is associated with reduced risk of advanced PCa and recurrence following radical prostatectomy or androgen deprivation therapy. Moreover, SIM and MET are significantly less toxic than Dtx. SIM and MET have potential to act synergistically by i) inhibition of HMG-CoAR, ii) activation of AMPK, further inhibiting HMG-CoAR activity by Ser-872 phosphorylation, and iii) inhibition of Akt activity, which is directly upstream of AMPK. Therefore, we hypothesized that combination SIM and MET act synergistically to inhibit metastatic CRPC cell survival. Using C4-2B3 and C4-2B4 cell lines, in vitro models of osseous metastatic CRPC, we determined that (1:500) combination SIM and MET at pharmacologically-relevant concentrations (500nM-4μM and 250μM-2mM, respectively) displays strong synergy per Chou-Talalay calculation and significantly reduces C4-2B3 and B4 viability, without adversely affecting viability of PrEC normal prostate epithelial cells; combination SIM and MET was also shown to significantly inhibit metastatic CRPC cell migration, invasion, and proliferation. Compared to SIM and MET alone, combination treatment led to earlier and more pronounced G1-phase cell cycle arrest in both C4-2B3 and B4. Combination SIM and MET also synergistically increased phospho-Thr-172 and activity of AMPK, and increased phospho-Ser-872 and decreased activity of HMG-CoAR in C4-2B3 and B4 cells in a time-dependent manner. Used individually, SIM and MET show limited promise as CRPC chemotherapeutic agents; however, in combination, they demonstrate more significant, synergistic effects, and may be an effective first-line chemotherapeutic alternative to Dtx for metastatic CRPC.

Citation Format: Melissa A. Babcook, R. Michael Sramkoski, Edwin J. Vazquez, Michelle A. Puchowicz, Sanjeev Shukla, Sanjay Gupta. Synergistic simvastatin and metformin chemotherapy for metastatic castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3283. doi:10.1158/1538-7445.AM2013-3283