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.

中文翻译：

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二甲双胍和丙戊酸的组合在p53和雄激素信号存在的情况下诱导前列腺癌中的协同细胞凋亡

我们研究了降血糖药物二甲双胍 (MET) 和抗癫痫药物丙戊酸 (VPA) 联合使用的潜力，这两种药物通过不同的生化途径起作用，以增强前列腺癌的抗肿瘤反应。前列腺癌细胞系（LNCaP 和 PC-3）、正常前列腺上皮细胞 (PrEC) 和患者来源的前列腺肿瘤外植体用 MET 和/或 VPA 处理。评估增殖和细胞凋亡。使用 LNCaP (p53+) 中的 RNAi 和 PC-3 (p53-) 中 p53 的异位表达，在细胞系中评估了 p53 在响应 MET + VPA 中的作用。使用 AR 拮抗剂恩杂鲁胺研究雄激素受体 (AR) 的作用。MET 和 VPA 的组合协同抑制 LNCaP 和 PC-3 的增殖，而对 PrEC 没有显着影响。LNCaP，但不是 PC-3，显示出响应 MET + VPA 的协同内在细胞凋亡。LNCaP (p53+, AR+) 中 p53 的敲低降低了协同凋亡反应，AR 的抑制也是如此。PC-3（p53-，AR-）中 p53 的异位表达增加了响应 MET + VPA 的细胞凋亡。在患者来源的前列腺肿瘤外植体中，MET + VPA 还诱导肿瘤细胞增殖的显着减少和细胞凋亡的增加。总之，我们证明 MET + VPA 可以协同杀死比单独使用任一种药物更多的前列腺癌细胞。该反应取决于 p53 和 AR 信号的存在，它们在前列腺癌发生中起关键作用。需要进一步的体内/体外临床前研究来确定 MET + VPA 作为前列腺癌潜在治疗方法的相对疗效。摩尔癌症治疗; 16(12); 2689-700。