Spencer Briohny H, McDermott Catherine M, Chess-Williams Russ, Christie David, Anoopkumar-Dukie Shailendra
School of Pharmacy and Pharmacology, Griffith University, Gold Coast Campus, Gold Coast, Queensland, Australia.
Quality Use of Medicines Network, Griffith University, Gold Coast Campus, Gold Coast, Queensland, Australia.
Pharmacology. 2018 Apr 17;102(1-2):10-18. doi: 10.1159/000488713.
BACKGROUND/AIMS: Docetaxel is currently the first-line chemotherapeutic agent available for the treatment of patients with advanced prostate cancer (PCa). While docetaxel has been shown to modestly improve survival times for patients; they also experience significant docetaxel-induced toxicities. If treatment failure occurs, there are currently limited alternatives that show survival benefits for patients and therefore there is an urgent need for adjunct therapies. Some quinazoline-based alpha1-adrenoceptor (ADR) antagonists have previously been shown to have cytotoxic actions in PCa cells, but there is no research into their effects on docetaxel-induced toxicity. Therefore, the aim of this study was to determine if the quinazoline ADR, prazosin influenced the sensitivity of PCa cells to docetaxel in vitro. We hypothesised that prazosin, but not tamsulosin, in combination with docetaxel would possess synergistic cytotoxic actions on PC-3 and LNCaP PCa cells.
PC-3 and -LNCaP cells were pre-treated (1 h) with prazosin (30 µmol/L) or tamsulosin (30 µmol/L), followed by docetaxel (12.5-100 μmol/L) for 24 h. Docetaxel-induced toxicity was measured in terms of changes in cell proliferation, autophagy, apoptosis and the production of reactive oxygen species (ROS).
Prazosin sensitised both cell lines (PC-3 and LNCaP) to docetaxel-induced toxicity. This effect appears to be mediated by autophagy and may also involve apoptosis. These sensitising effects of prazosin appear to be largely independent of ROS production. In contrast, tamsulosin did not affect docetaxel-induced toxicity.
We have shown for the first time that prazosin increases docetaxel-induced toxicity in PC-3 and LNCaP cells. Prazosin may therefore offer a viable treatment option in combination with docetaxel in metastatic PCa.
背景/目的：多西他赛目前是可用于治疗晚期前列腺癌（PCa）患者的一线化疗药物。虽然多西他赛已被证明可适度延长患者的生存时间，但患者也会经历多西他赛引起的显著毒性。如果发生治疗失败，目前对患者有生存益处的替代方案有限，因此迫切需要辅助治疗。一些基于喹唑啉的α1肾上腺素能受体（ADR）拮抗剂此前已被证明在PCa细胞中具有细胞毒性作用，但尚无关于其对多西他赛诱导毒性影响的研究。因此，本研究的目的是确定喹唑啉ADR哌唑嗪是否会在体外影响PCa细胞对多西他赛的敏感性。我们假设哌唑嗪而非坦索罗辛与多西他赛联合使用会对PC-3和LNCaP PCa细胞具有协同细胞毒性作用。
PC-3和LNCaP细胞先用哌唑嗪（30 μmol/L）或坦索罗辛（30 μmol/L）预处理1小时，然后用多西他赛（12.5 - 100 μmol/L）处理24小时。通过细胞增殖、自噬、凋亡和活性氧（ROS）产生的变化来测量多西他赛诱导的毒性。
哌唑嗪使两种细胞系（PC-3和LNCaP）对多西他赛诱导的毒性敏感。这种作用似乎是由自噬介导的，也可能涉及凋亡。哌唑嗪的这些致敏作用似乎在很大程度上与ROS产生无关。相比之下，坦索罗辛不影响多西他赛诱导的毒性。
我们首次表明哌唑嗪会增加多西他赛对PC-3和LNCaP细胞的诱导毒性。因此，哌唑嗪可能是与多西他赛联合用于转移性PCa的可行治疗选择。
