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Article

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

1
Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
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Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland
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Department of Mathematics and Statistics, Université de Montréal, Montréal, QC H3T 1J4, Canada
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Sainte-Justine University Hospital Research Centre, Montréal, QC H3T 1C5, Canada
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Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland
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Department of Pediatrics, Washington University, St. Louis, MO 63130, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Carmela Ricciardelli
Int. J. Mol. Sci. 2021, 22(9), 4699; https://doi.org/10.3390/ijms22094699
Received: 10 March 2021 / Revised: 24 April 2021 / Accepted: 28 April 2021 / Published: 29 April 2021
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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. View Full-Text
Keywords: caspase-3; GCT; ovarian cancer; PAC-1; mathematical modelling caspase-3; GCT; ovarian cancer; PAC-1; mathematical modelling
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MDPI and ACS Style

Crosley, P.; Farkkila, A.; Jenner, A.L.; Burlot, C.; Cardinal, O.; Potts, K.G.; Agopsowicz, K.; Pihlajoki, M.; Heikinheimo, M.; Craig, M.; Fu, Y.; Hitt, M.M. 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. Int. J. Mol. Sci. 2021, 22, 4699. https://doi.org/10.3390/ijms22094699

AMA Style

Crosley P, Farkkila A, Jenner AL, Burlot C, Cardinal O, Potts KG, Agopsowicz K, Pihlajoki M, Heikinheimo M, Craig M, Fu Y, Hitt MM. 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. International Journal of Molecular Sciences. 2021; 22(9):4699. https://doi.org/10.3390/ijms22094699

Chicago/Turabian Style

Crosley, Powel, Anniina Farkkila, Adrianne L. Jenner, Chloé Burlot, Olivia Cardinal, Kyle G. Potts, Kate Agopsowicz, Marjut Pihlajoki, Markku Heikinheimo, Morgan Craig, Yangxin Fu, and Mary M. Hitt. 2021. "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" International Journal of Molecular Sciences 22, no. 9: 4699. https://doi.org/10.3390/ijms22094699

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