A small molecule SMAC mimic LBW242 potentiates TRAIL- and anticancer drug-mediated cell death of ovarian cancer cells.

PloS One
Eleonora PetrucciUgo Testa

Abstract

Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (SMAC) has been described to sensitize for apoptosis. We have explored the pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays. LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis. LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic ...Continue Reading

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Citations

May 30, 2015·Biometrika·Sihai Dave ZhaoHongzhe Li
Jul 18, 2014·Archivum Immunologiae Et Therapiae Experimentalis·Ammad Ahmad FarooqiHsueh-Wei Chang
Feb 6, 2019·International Journal of Molecular Sciences·Sarah AlexandrouC Elizabeth Caldon
Aug 31, 2017·Archivum Immunologiae Et Therapiae Experimentalis·Ammad Ahmad FarooqiWaleed O Arafat
Feb 21, 2019·Minerva ginecologica·Violante Di Donato, Pierluigi Benedetti Panici
Nov 27, 2019·Cancers·Mudra BinjuYu Yu
Mar 20, 2019·Journal of Gynecologic Oncology·Chiara Di TucciPierluigi Benedetti Panici
May 16, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Simone Fulda
Nov 22, 2013·Molecular Pharmaceutics·Laura GattiPaola Perego

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Methods Mentioned

BETA
flow cytometry
biopsies
protein assay

Software Mentioned

CalcuSyn
Graph Pad
ModFit

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