Lima Thiago S, Iglesias-Gato Diego, Souza Luciano D O, Stenvang Jan, Lima Diego S, Røder Martin A, Brasso Klaus, Moreira José M A
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
CAPES Foundation, Ministry of Education of Brazil, Brasília 70040-020, Brazil.
Cancers (Basel). 2021 Mar 14;13(6):1290. doi: 10.3390/cancers13061290.
Docetaxel-a taxane-based chemotherapeutic agent-was the first treatment to demonstrate significant improvements in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, the response to docetaxel is generally short-lived, and relapse eventually occurs due to the development of resistance. To explore the mechanisms of acquired docetaxel resistance in prostate cancer (PCa) and set these in the context of androgen deprivation therapy, we established docetaxel-resistant PCa cell lines, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line. We generated two docetaxel-resistant LNCaPR and C4-2BR sub-lines, with IC50 values 77- and 50-fold higher than those of the LNCaP and C4-2B parental cells, respectively. We performed gene expression analysis of the matched sub-lines and found several alterations that may confer docetaxel resistance. In addition to increased expression of ABCB1, an ATP-binding cassette (ABC) transporter, and a well-known gene associated with development of docetaxel resistance, we identified genes associated with androgen signaling, cell survival, and overexpression of ncRNAs. In conclusion, we identified multiple mechanisms that may be associated with the development of taxane drug resistance in PCa. Actioning these mechanisms could provide a potential approach to re-sensitization of docetaxel-resistant PCa cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with mCRPC.
多西他赛——一种基于紫杉烷的化疗药物——是首个在转移性去势抵抗性前列腺癌（mCRPC）男性患者中显示出总生存期显著改善的治疗方法。然而，对多西他赛的反应通常是短暂的，由于耐药性的发展最终会复发。为了探索前列腺癌（PCa）中获得性多西他赛耐药的机制，并将其置于雄激素剥夺治疗的背景下，我们建立了多西他赛耐药的PCa细胞系，这些细胞系来源于雄激素依赖的LNCaP细胞系以及LNCaP谱系衍生的雄激素非依赖C4-2B亚系。我们生成了两个多西他赛耐药的LNCaPR和C4-2BR亚系，其IC50值分别比LNCaP和C4-2B亲本细胞高77倍和50倍。我们对匹配的亚系进行了基因表达分析，发现了一些可能赋予多西他赛耐药性的改变。除了ATP结合盒（ABC）转运蛋白ABCB1的表达增加外，ABCB1是一个与多西他赛耐药发展相关的知名基因，我们还鉴定了与雄激素信号传导、细胞存活和非编码RNA过表达相关的基因。总之，我们确定了多种可能与PCa中紫杉烷类药物耐药发展相关的机制。针对这些机制可能为使多西他赛耐药的PCa细胞对多西他赛治疗重新敏感提供一种潜在方法，从而进一步增强该药物对mCRPC男性患者的延长生命作用。
