Examining the In Vitro Efficacy of the IAP Antagonist Birinapant as a Single Agent or in Combination With Dacarbazine to Induce Melanoma Cell Death.

Vesna Vetma, Royal College of Surgeons in Ireland
Jan Rožanc, Royal College of Surgeons in Ireland
Emilie M Charles, Royal College of Surgeons in Ireland
Christian T Hellwig, RO
Leonidas G Alexopoulos, ProtATonce Ltd
Markus Rehm, Royal College of Surgeons in Ireland

Document Type Article

The original article is available at http://www.ingentaconnect.com

Abstract

Antagonists of inhibitors of apoptosis proteins (IAPs), alone or in combination with genotoxic therapeutics, have been shown to efficiently induce cell death in various solid tumors. The IAP antagonist birinapant is currently being tested in phase II clinical trials. We herein aimed to investigate the antitumor efficacy of dacarbazine in vitro, both as a single agent and in combination with birinapant, in melanoma cell lines. Covering clinically relevant drug concentration ranges, we conducted a total of 5,400 measurements in a panel of 12 human melanoma cell lines representing different stages of disease progression. Surprisingly, functionally relevant synergies or response potentiation in combination treatments was not observed, and only one cell line modestly responded to birinapant single treatment (approximately 16% cell death). Although we did not study the underlying resistance mechanisms or more complex in vivo scenarios in which dacarbazine/birinapant response synergies may still possibly manifest, our findings are nevertheless noteworthy because IAP antagonists were demonstrated to strongly enhance responses to DNA-damaging agents in cell lines of other cancer types under comparable experimental conditions in vitro.