Subeha Mahbuba R, Goyeneche Alicia A, Bustamante Prisca, Lisio Michael A, Burnier Julia V, Telleria Carlos M
Experimental Pathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3A 2B4, Canada.
Cancer Research Program, Research Institute, McGill University Health Centre, Montreal, QC H4A 3JI, Canada.
Cancers (Basel). 2021 Dec 26;14(1):99. doi: 10.3390/cancers14010099.
High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Traditional treatment consists of platinum-based therapy; however, rapid development of platinum resistance contributes to lower life expectancy, warranting newer therapies to supplement the current platinum-based protocol. Repurposing market-available drugs as cancer therapeutics is a cost- and time-effective way to avail new therapies to drug-resistant patients. The anti-HIV agent nelfinavir (NFV) has shown promising toxicity against various cancers; however, its role against HGSOC is unknown. Here, we studied the effect of NFV against HGSOC cells obtained from patients along disease progression and carrying different sensitivities to platinum. NFV triggered, independently of platinum sensitivity, a dose-dependent reduction in the HGSOC cell number and viability, and a parallel increase in hypo-diploid DNA content. Moreover, a dose-dependent reduction in clonogenic survival of cells escaping the acute toxicity was indicative of long-term residual damage. In addition, dose- and time-dependent phosphorylation of H2AX indicated NFV-mediated DNA damage, which was associated with decreased survival and proliferation signals driven by the AKT and ERK pathways. NFV also mediated a dose-dependent increase in endoplasmic reticulum stress-related molecules associated with long-term inhibition of protein synthesis and concurrent cell death; such events were accompanied by a proapoptotic environment, signaled by increased phospho-eIF2α, ATF4, and CHOP, increased Bax/Bcl-2 ratio, and cleaved executer caspase-7. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.
高级别浆液性卵巢癌（HGSOC）是全球女性死亡的一个重要原因。传统治疗方法包括铂类疗法；然而，铂耐药性的迅速发展导致预期寿命降低，因此需要更新的疗法来补充当前基于铂的治疗方案。将市售药物重新用作癌症治疗药物是一种经济且省时的方法，可为耐药患者提供新的治疗手段。抗HIV药物奈非那韦（NFV）已显示出对多种癌症有良好的毒性作用；然而，其对HGSOC的作用尚不清楚。在此，我们研究了NFV对从患者身上获取的处于疾病进展不同阶段且对铂具有不同敏感性的HGSOC细胞的影响。NFV引发了HGSOC细胞数量和活力的剂量依赖性减少，且与铂敏感性无关，同时亚二倍体DNA含量平行增加。此外，逃避急性毒性的细胞克隆形成存活率的剂量依赖性降低表明存在长期的残留损伤。另外，H2AX的剂量和时间依赖性磷酸化表明NFV介导了DNA损伤，这与由AKT和ERK途径驱动的存活和增殖信号减少有关。NFV还介导了与内质网应激相关分子的剂量依赖性增加，这与蛋白质合成的长期抑制和同时发生的细胞死亡有关；这些事件伴随着促凋亡环境，表现为磷酸化eIF2α、ATF4和CHOP增加、Bax/Bcl-2比率增加以及执行性半胱天冬酶-7裂解。最后，我们表明NFV增强了蛋白酶体抑制剂硼替佐米引起的短期细胞周期阻滞和长期毒性。总体而言，我们的体外研究表明，NFV可通过多种机制对不同铂敏感性的HGSOC细胞进行治疗靶向，考虑到其良好的安全性，提示其具有重新利用的潜在益处。
