Flynn Vincent, Ramanitharan Anshiya, Moparty Krishnarao, Davis Rodney, Sikka Suresh, Agrawal Krishna C, Abdel-Mageed Asim B
Department of Urology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Int J Oncol. 2003 Aug;23(2):317-23.
Acquirement of multi-drug resistance by tumor cells represents a major obstacle in the management of prostate cancer. Such resistance was demonstrated in the androgen-independent DU-145 cells in response to paclitaxel and the mechanisms by which these cell develops resistance was not understood. The objective of this study was to examine whether abrogation of the constitutively active NF-kappaB in the chemoresistant, androgen independent DU-145 prostate cancer cells will enhance their sensitivity to cytototoxic agents. Inhibition of NF-kappaB by a dominant negative super-repressor IkappaB mutant adenoviral construct enhanced the apoptotic potentials of paclitaxel and rhTNF-alpha in these cells. Using reporter assays and RT-PCR analysis, we demonstrate that paclitaxel-induced cell death was associated with an increase in NF-kappaB activation and MDR-1 gene expression. Abrogation of these effects by the dominant negative IkappaB adenoviral construct suggests that induction and/or constitutive activation of NF-kappaB can block the paclitaxel-induced apoptotic signaling pathways in this cell line, possibly by increasing the expression of anti-apoptotic and MDR-1 gene products, leading to development of chemoresistance in these cells. We conclude that inhibition of NF-kappaB activation may have therapeutic implications for prostate cancer.
肿瘤细胞获得多药耐药性是前列腺癌治疗中的一个主要障碍。在雄激素非依赖性DU - 145细胞中已证实对紫杉醇存在这种耐药性，而这些细胞产生耐药性的机制尚不清楚。本研究的目的是检验在化疗耐药的雄激素非依赖性DU - 145前列腺癌细胞中，消除组成型激活的核因子κB是否会增强它们对细胞毒性药物的敏感性。用显性负性超抑制因子IκB突变腺病毒构建体抑制核因子κB可增强这些细胞中紫杉醇和重组人肿瘤坏死因子α的凋亡潜能。通过报告基因检测和逆转录-聚合酶链反应分析，我们证明紫杉醇诱导的细胞死亡与核因子κB激活增加和多药耐药基因1（MDR - 1）表达增加有关。显性负性IκB腺病毒构建体消除这些效应表明，核因子κB的诱导和/或组成型激活可能通过增加抗凋亡和MDR - 1基因产物的表达来阻断该细胞系中紫杉醇诱导的凋亡信号通路，从而导致这些细胞产生化疗耐药性。我们得出结论，抑制核因子κB激活可能对前列腺癌具有治疗意义。
