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The combination of metformin and valproic acid induces synergistic apoptosis in the presence of p53 and androgen signaling in prostate cancer

Molecular Cancer Therapeutics Aug 24, 2017

Tran LNK, et al. – The authors tried to find out the potential of combining the hypoglycemic drug metformin (MET) and the anti–epileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced anti–tumor responses in prostate cancer. The results of this study displayed that MET+VPA can synergistically kill more prostate cancer cells than either drug alone. Moreover, the response is dependent on the presence of p53 and androgen receptor (AR) signaling which have critical roles in prostate carcinogenesis.

Methods
  • Researchers evaluated the role of p53 in response to MET+VPA in cell lines applying RNA interference in LNCaP (p53+) and ectopic expression of p53 in PC–3 (p53–).
  • They evaluated the role of the androgen receptor applying the AR antagonist, Enzalutamide.

Results
  • The data showed that the combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC–3, with no significant impact in prostate epithelial cells (PrEC).
  • The evidence showed that LNCaP, but not PC–3, illustrated synergistic intrinsic apoptosis in response to MET+VPA.
  • As per the data, knock–down of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR.
  • It was suggested that ectopic expression of p53 in PC–3 (p53–, AR–) increased apoptosis in response to MET+VPA.
  • MET+VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells in patient–derived prostate tumor explants.
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