Cancer Therapeutics Insights Redirecting Apoptosis to Aponecrosis Induces Selective Cytotoxicity to Pancreatic Cancer Cells through Increased ROS, Decline in ATP Levels, and VDAC

Pancreatic cancer cell lineswithmutated ras underwent an alternative formof cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (Antabuse; AAA). AAA’smajor effects aremediated through generation of intracellular reactive oxygen species (ROS) and more than 50% decline in intracellular ATP. N-acetyl cysteine and a superoxide dismutase mimetic prevented aponecrosis and restored intracellular ATP levels. DIDS (4,40-diisothiocyanatostilbene-2, 20 disulfonic acid), the panVoltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and short hairpin RNA (shRNA) toVDAC-1 blocked cell death andROS accumulation. In vivo exposure ofAAA led to a 62% reduction in mean tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We concluded that early caspase-independent apoptosiswas shifted toVDAC-mediated "targeted" aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching fromapoptosis to aponecrosis deathpathways, also knownas targetedaponecrosis, couldbeutilized to selectively kill pancreatic cancer cells resistant to apoptosis.Mol Cancer Ther; 12(12); 2792–803. 2013 AACR.