Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada.
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland.
Int J Mol Sci. 2021 Apr 29;22(9):4699. doi: 10.3390/ijms22094699.
Granulosa cell tumors (GCT) constitute only ~5% of ovarian neoplasms yet have significant consequences, as up to 80% of women with recurrent GCT will die of the disease. This study investigated the effectiveness of procaspase-activating compound 1 (PAC-1), an activator of procaspase-3, in treating adult GCT (AGCT) in combination with selected apoptosis-inducing agents. Sensitivity of the AGCT cell line KGN to these drugs, alone or in combination with PAC-1, was tested using a viability assay. Our results show a wide range in cytotoxic activity among the agents tested. Synergy with PAC-1 was most pronounced, both empirically and by mathematical modelling, when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This combination showed rapid kinetics of apoptosis induction as determined by caspase-3 activity, and strongly synergistic killing of both KGN as well as patient samples of primary and recurrent AGCT. We have demonstrated that the novel combination of two pro-apoptotic agents, TRAIL and PAC-1, significantly amplified the induction of apoptosis in AGCT cells, warranting further investigation of this combination as a potential therapy for AGCT.
颗粒细胞瘤（GCT）仅占卵巢肿瘤的~5%，但后果严重，因为多达 80%的复发性 GCT 女性将死于该疾病。本研究探讨了半胱氨酸天冬氨酸蛋白酶激活剂 1（PAC-1）与选定的凋亡诱导剂联合治疗成人 GCT（AGCT）的疗效。AGCT 细胞系 KGN 对这些药物单独或与 PAC-1 联合使用的敏感性通过活力测定进行了测试。我们的结果显示，在测试的药物中，细胞毒性活性范围很广。与 PAC-1 的协同作用最为明显，无论是通过经验还是通过数学建模，当与肿瘤坏死因子相关凋亡诱导配体（TRAIL）联合使用时。这种组合通过 caspase-3 活性快速诱导凋亡，对 KGN 以及原发性和复发性 AGCT 的患者样本均具有强烈的协同杀伤作用。我们已经证明，两种促凋亡剂 TRAIL 和 PAC-1 的新组合可显著增强 AGCT 细胞凋亡的诱导，这使得该组合作为 AGCT 的潜在治疗方法值得进一步研究。
