Abstract
We investigated the potential of combining the hypoglycemic drug metformin (MET) and the antiepileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET + VPA was assessed in cell lines using RNAi in LNCaP (p53+) and ectopic expression of p53 in PC-3 (p53-). The role of the androgen receptor (AR) was investigated using the AR antagonist enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET + VPA. Knockdown of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53-, AR-) increased apoptosis in response to MET + VPA. In patient-derived prostate tumor explants, MET + VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET + VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling, which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo preclinical studies are required to determine the relative efficacy of MET + VPA as a potential treatment for prostate cancer. Mol Cancer Ther; 16(12); 2689-700. ©2017 AACR.
Highlights
Prostate cancer is the most common cancer in men in the Western world [1, 2]
Reducing circulating hormone levels by androgen deprivation therapy (ADT) is the current standard treatment for metastatic disease, ADT inevitably fails with the emergence of castrateresistant prostate cancer (CRPC), which is a lethal form of the disease
We demonstrate that apoptosis induced by the combination of metformin and valproic acid (VPA) is dependent on the expression of p53 and androgen receptor (AR), suggesting that the combination may be acting through these pathways and could be effective in tumors with functional p53 and AR
Summary
Prostate cancer is the most common cancer in men in the Western world [1, 2]. Despite the curative potential of treatments such as radical prostatectomy and high-dose radiotherapy, 20% to 30% of men will relapse after 5 to 10 years [3, 4]. Reducing circulating hormone levels by androgen deprivation therapy (ADT) is the current standard treatment for metastatic disease, ADT inevitably fails with the emergence of castrateresistant prostate cancer (CRPC), which is a lethal form of the disease. Mutations in p53, androgen receptor (AR), PTEN, and ETS gene fusions are commonly observed in CRPC [5]. There is no durably effective targeted therapy for this stage of the disease. FDA-approved treatments for CRPC consist of abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, radium
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