Magadoux L, Isambert N, Plenchette S, Jeannin J F, Laurens V
EA 7269 Ecole Pratique des Hautes Etudes-University of Burgundy-INSERM U866, Dijon 21079, France.
Int J Oncol. 2014 Sep;45(3):919-28. doi: 10.3892/ijo.2014.2517. Epub 2014 Jun 24.
Drug development for castration resistant prostate cancer (CRPC) is challenging, since this cancer is still associated with high mortality and limited therapeutic options. In 2004, docetaxel became the first-line chemotherapy for CRPC improving survival by a few months and remains the standard of care in CRPC patients. However, existing or developing resistance to docetaxel in patients is the main limitation of its efficacy. The present review presents the molecular mechanisms involved in docetaxel toxicity and in docetaxel resistance in prostate cancer cells. We outlined the endogenous mechanisms of resistance and the role of tumor microenvironment in the resistance of CRPC to docetaxel. This has led us to focus on molecules associated with resistance, such as the molecular chaperones heat shock proteins (HSPs) and clusterin (CLU), and the cytokines interleukin-6 (IL-6) and the divergent member of the tumor growth factor family MIC-1 (macrophage inhibitory cytokine-1 also named GDF-15). We discuss their interest as blood-based markers to monitor docetaxel resistance. Finally, new therapies intended to overcome docetaxel resistance of CRPC targeted on these molecular resistance pathways are present.
去势抵抗性前列腺癌（CRPC）的药物研发具有挑战性，因为这种癌症的死亡率仍然很高，治疗选择有限。2004年，多西他赛成为CRPC的一线化疗药物，可使生存期延长数月，至今仍是CRPC患者的标准治疗方案。然而，患者对多西他赛产生现有或新出现的耐药性是其疗效的主要限制因素。本综述介绍了前列腺癌细胞中多西他赛毒性和耐药性所涉及的分子机制。我们概述了耐药的内源性机制以及肿瘤微环境在CRPC对多西他赛耐药中的作用。这使我们关注与耐药相关的分子，如分子伴侣热休克蛋白（HSPs）和簇集素（CLU），以及细胞因子白细胞介素-6（IL-6）和肿瘤生长因子家族的不同成员巨噬细胞抑制细胞因子-1（MIC-1，也称为GDF-15）。我们讨论了它们作为监测多西他赛耐药性的血液标志物的价值。最后，还介绍了旨在克服CRPC对多西他赛耐药性的针对这些分子耐药途径的新疗法。
