Departments of Urology, Institute of Urology.
Neurology, Stroke Clinical Research Unit, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Anticancer Drugs. 2018 Oct;29(9):871-879. doi: 10.1097/CAD.0000000000000659.
Acquired docetaxel (Doc) resistance in hormone-refractory prostate cancer (HRPC) remains an ongoing clinical challenge, resulting in failed chemotherapy and tumor recurrence. However, the mechanism of Doc-resistance development in prostate cancer cells is still unclear. Here, we observed a subpopulation of prostate cancer cells, in both Doc-resistant cell lines and the tumors of patients with HRPC, which show stem cell markers and greater tumorigenic potential. Those stem-like prostate cancer cells show high expression of ABCB1, which encodes multidrug resistance-related protein P-glycoprotein, leading to the Doc-resistance in prostate cancer. Moreover, we found that Notch signaling pathway activation in Doc-resistant cell lines and tumor tissues of patients with HRPC correlated with tumorigenicity and the development of Doc resistance. Here, we revealed that a combination of Doc and a Notch signaling inhibitor overcomes Doc resistance and increases the survival of mice with Doc-resistant xenografts. Therefore, targeting the Notch signaling pathway may be a promising strategy to overcome the Doc-resistant cancer in the clinic.
在激素难治性前列腺癌（HRPC）中，获得性多西紫杉醇（Doc）耐药仍然是一个持续存在的临床挑战，导致化疗失败和肿瘤复发。然而，前列腺癌细胞中 Doc 耐药发展的机制尚不清楚。在这里，我们观察到前列腺癌细胞的一个亚群，在 Doc 耐药细胞系和 HRPC 患者的肿瘤中，这些细胞表现出干细胞标记物和更强的肿瘤形成能力。这些类干细胞样前列腺癌细胞表现出 ABCB1 的高表达，其编码多药耐药相关蛋白 P-糖蛋白，导致前列腺癌的 Doc 耐药。此外，我们发现 Doc 耐药细胞系和 HRPC 患者肿瘤组织中的 Notch 信号通路激活与致瘤性和 Doc 耐药的发展相关。在这里，我们揭示了 Doc 和 Notch 信号抑制剂的联合使用可以克服 Doc 耐药性，并提高 Doc 耐药异种移植小鼠的存活率。因此，靶向 Notch 信号通路可能是克服临床 Doc 耐药性癌症的一种有前途的策略。
