Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 19131, USA.
Cell Death Dis. 2017 Aug 24;8(8):e3007. doi: 10.1038/cddis.2017.417.
Although the newly developed second-generation anti-androgen drug enzalutamide can repress prostate cancer progression significantly, it only extends the survival of prostate cancer patients by 4-6 months mainly due to the occurrence of enzalutamide resistance. Most of the previous studies on AR antagonist resistance have been focused on AR signaling. Therefore, the non-AR pathways on enzalutamide resistance remain largely unknown. By using C4-2, CWR22Rv1 and LNCaP cell lines, as well as mice bearing CWR22Rv1 xenografts treated with either enzalutamide or metformin alone or in combination, we demonstrated that metformin is capable of reversing enzalutamide resistance and restores sensitivity of CWR22Rv1 xenografts to enzalutamide. We showed that metformin alleviated resistance to enzalutamide by inhibiting EMT. Furthermore, based on the effect of metformin on the activation of STAT3 and expression of TGF-β1, we propose that metformin exerts its effects by targeting the TGF-β1/STAT3 axis. These findings suggest that combination of metformin with enzalutamide could be a more efficacious therapeutic strategy for the treatment of castration-resistant prostate cancer.
虽然新开发的第二代抗雄激素药物恩扎鲁胺能显著抑制前列腺癌的进展，但它主要通过延长前列腺癌患者 4-6 个月的生存时间来延长生存时间，这主要是由于恩扎鲁胺耐药的发生。之前关于 AR 拮抗剂耐药性的大多数研究都集中在 AR 信号通路。因此，恩扎鲁胺耐药性的非 AR 通路在很大程度上仍然未知。通过使用 C4-2、CWR22Rv1 和 LNCaP 细胞系，以及单独或联合使用恩扎鲁胺或二甲双胍治疗 CWR22Rv1 异种移植瘤的小鼠，我们证明二甲双胍能够逆转恩扎鲁胺耐药性，并恢复 CWR22Rv1 异种移植瘤对恩扎鲁胺的敏感性。我们表明，二甲双胍通过抑制 EMT 来减轻对恩扎鲁胺的耐药性。此外，基于二甲双胍对 STAT3 激活和 TGF-β1 表达的影响，我们提出二甲双胍通过靶向 TGF-β1/STAT3 轴发挥作用。这些发现表明，二甲双胍与恩扎鲁胺联合使用可能是治疗去势抵抗性前列腺癌的更有效的治疗策略。
