■化疗,特别是多西他赛(Doc),作为去势抵抗前列腺癌(CRPC)的主要治疗方法。然而,其疗效受到副作用和化学抗性的阻碍。前列腺癌(PC)中的缺氧与通过血红素氧合酶-1(HO-1)调节对Doc诱导的细胞凋亡的化学抗性相关,血红素代谢的关键酶。这项研究调查了通过HO-1抑制靶向血红素降解途径以增强Doc在PC中的治疗功效。
■利用不同的PC细胞系,我们评估了HO-1抑制单独和Doc对生存力的影响,凋亡,迁移,和上皮间质转化(EMT)标志物,并阐明了潜在的机制。
■HO-1抑制在低氧和常氧条件下显着降低PC细胞的活力,通过相互关联的机制增强Doc诱导的细胞凋亡,包括升高的活性氧(ROS)水平,谷胱甘肽循环中断,信号转导和转录激活因子1(STAT1)通路的调控。STAT1和HO-1之间的相互作用表明其依赖于HO-1激活。此外,观察到细胞迁移和EMT标记(波形蛋白和蜗牛)下调的减少,表明间充质表型的减弱。
■总而言之,HO-1抑制与Doc的组合有望改善PC的治疗结果和推进临床管理。
UNASSIGNED: Chemotherapy, notably docetaxel (Doc), stands as the primary treatment for castration-resistant prostate cancer (CRPC). However, its efficacy is hindered by side effects and chemoresistance. Hypoxia in prostate cancer (PC) correlates with chemoresistance to Doc-induced apoptosis via Heme Oxygenase-1 (HO-1) modulation, a key enzyme in heme metabolism. This study investigated targeting heme degradation pathway via HO-1 inhibition to potentiate the therapeutic efficacy of Doc in PC.
UNASSIGNED: Utilizing diverse PC cell lines, we evaluated HO-1 inhibition alone and with Doc on viability, apoptosis, migration, and epithelial- to- mesenchymal transition (EMT) markers and elucidated the underlying mechanisms.
UNASSIGNED: HO-1 inhibition significantly reduced PC cell viability under hypoxic and normoxic conditions, enhancing Doc-induced apoptosis through interconnected mechanisms, including elevated reactive oxygen species (ROS) levels, glutathione cycle disruption, and modulation of Signal Transducer and Activator of Transcription 1 (STAT1) pathway. The interplay between STAT1 and HO-1 suggests its reliance on HO-1 activation. Additionally, a decrease in cell migration and downregulation of EMT markers (
vimentin and snail) were observed, indicating attenuation of mesenchymal phenotype.
UNASSIGNED: In conclusion, the combination of HO-1 inhibition with Doc holds promise for improving therapeutic outcomes and advancing clinical management in PC.