Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer

Gunjal Garg, Suwanna Vangveravong, Chenbo Zeng, Lynne Collins, Mary Hornick, Yassar Hashim, David Piwnica-Worms, Matthew A Powell, David G Mutch, Robert H Mach, William G Hawkins, Dirk Spitzer

Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy.