Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro.

Powel Crosley,Markku Heikinheimo,Mary M Hitt,Kyle G Potts,Anniina Farkkila,Marjut Pihlajoki,Chloé Burlot,Morgan Craig,Olivia Cardinal,Adrianne L Jenner,Yangxin Fu,Kate Agopsowicz

doi:10.3390/ijms22094699

Abstract

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.

Highlights

We report that procaspase-activating compound 1 (PAC-1)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combination appears to be more effective than PAC-1 combined with chemotherapy drugs carboplatin or gemcitabine, or with embelin, an inhibitor of the X-linked inhibitor of apoptosis protein (XIAP), without increasing sensitivity of normal cells
We developed a mathematical model for the induction of apoptosis in KGN cells by gemcitabine, carboplatin, TRAIL, embelin and PAC-1 (Figure 3A)
Common chemotherapy agents are generally ineffective for fective for Granulosa cell tumors (GCT) [28,29,39] and the lack of effective treatment options contributes to the GCT [28,29,39] and the lack of effective treatment options contributes to the ~80% mortality

Summary

Introduction

Granulosa cell tumor (GCT) is a malignant sex-cord stromal cell form of ovarian cancer that constitutes ~5% of ovarian neoplasms [1]. The majority (89%) of cases are early-stage. GCT [2], yet they present a conundrum: five-year survival is >90%, GCT is known for late recurrence and ~80% of women who relapse will die of the disease [1,3]. Multiple retrospective analyses of case histories have shown that there is no survival advantage between adjuvant chemotherapy, radiotherapy, and observation [6,7]. There are two forms of GCT, adult (AGCT) and juvenile GCT, with 95% of GCTs being AGCT [2]. In 2009, Shah et al, discovered a unique somatic mutation (FOXL2C134W) that was present in 97%

Methods

Results

Conclusion