Prostate cancer (PCa) is the most frequent cancer in men. The evolution from local PCa to
castration-resistant PCa, an end-stage of disease, is often associated with changes in genes such as
p53, androgen receptor, PTEN, and ETS gene fusion products. Evidence is accumulating that repurposing
of metformin (MET) and valproic acid (VPA) either when used alone, or in combination,
with another therapy, could potentially play a role in slowing down PCa progression. This review
provides an overview of the application of MET and VPA, both alone and in combination with other
drugs for PCa treatment, correlates the responses to these drugs with common molecular changes in
PCa, and then describes the potential for combined MET and VPA as a systemic therapy for prostate
cancer, based on potential interacting mechanisms.