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Redirecting apoptosis to aponecrosis induces selective cytotoxicity to pancreatic cancer cells through increased ROS, decline in ATP levels, and VDAC
Journal article   Open access   Peer reviewed

Redirecting apoptosis to aponecrosis induces selective cytotoxicity to pancreatic cancer cells through increased ROS, decline in ATP levels, and VDAC

Richard D Dinnen, Yuehua Mao, Wanglong Qiu, Nicholas Cassai, Vesna N Slavkovich, Gwen Nichols, Gloria H Su, Paul Brandt-Rauf and Robert L Fine
Molecular cancer therapeutics, v 12(12), pp 2792-2803
Dec 2013
DOI: https://doi.org/10.1158/1535-7163.MCT-13-0234
PMID: 24126434
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/1535-7163.mct-13-0234View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Adenosine Triphosphate - metabolism Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacology Apoptosis - drug effects Arsenicals - administration & dosage Arsenicals - pharmacology Ascorbic Acid - administration & dosage Ascorbic Acid - pharmacology Cell Line, Tumor Disease Models, Animal Disulfiram - administration & dosage Disulfiram - pharmacology Dose-Response Relationship, Drug Heterografts Humans Male Mice Necrosis - metabolism Oxides - administration & dosage Oxides - pharmacology Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Reactive Oxygen Species - metabolism Tumor Stem Cell Assay Voltage-Dependent Anion Channels - metabolism
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). AAA's major effects are mediated 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 (4,4'-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 tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We 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.

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Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
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