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Research: DINNEN and COLLEAGUES,
Listed in Issue 240
Abstract
DINNEN and COLLEAGUES, (1)Corresponding Author: Robert L. Fine, Experimental Therapeutics Section, Division of Medical Oncology, NYPH-Columbia University Medical Center, 630 West 168th Street, PH-8-STEM, Room 8-406, New York, NY 10032. rlf20@columbia.edu experimented with targeted aponecrosis to selectively kill pancreatic cancer cells resistant to apoptosis.
Background
Pancreatic cancer cell lines with mutated ras underwent an alternative form of cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (Antabuse; AAA).
Methodology
AAA's major effects are mediated through generation of intracellular reactive oxygen species (ROS) and more than 50% decline in intracellular ATP.
Results
N-acetyl cysteine and a superoxide dismutase mimetic prevented aponecrosis and restored intracellular ATP levels. DIDS (4,4'-diisothiocyanatostilbene-2, 2' disulfonic acid), the pan- Voltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and short hairpin RNA (shRNA) to VDAC-1 blocked cell death and ROS accumulation. In vivo exposure of AAA led to a 62% reduction in mean tumour size and eliminated tumours in 30% of nude mice with PANC-1 xenografts.
Conclusion
The authors concluded that early caspase-independent apoptosis was shifted to VDAC-mediated ‘targeted’ aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching from apoptosis to aponecrosis death pathways, also known as targeted aponecrosis, could be utilized to selectively kill pancreatic cancer cells resistant to apoptosis.
References
Dinnen RD(1), Mao Y, Qiu W, Cassai N, Slavkovich VN, Nichols G, Su GH,
Brandt-Rauf P, Fine RL. Redirecting apoptosis to aponecrosis induces selective cytotoxicity to pancreatic cancer cells through increased ROS, decline in ATP levels, and VDAC. Mol Cancer Ther. 12(12):2792-803. Dec 2013. doi: 10.1158/1535-7163.MCT-13-0234. Epub Oct 14 2013.
