title: Redirecting apoptosis to aponecrosis induces selective cytotoxicity to pancreatic cancer cells through increased ROS, decline in ATP levels, and VDAC.
abstract: 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.
authors.affiliation: 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.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dinnen
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Mao
authors.forename: Wanglong
authors.initials: W
authors.lastname: Qiu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cassai
authors.forename: Vesna N
authors.initials: VN
authors.lastname: Slavkovich
authors.forename: Gwen
authors.initials: G
authors.lastname: Nichols
authors.forename: Gloria H
authors.initials: GH
authors.lastname: Su
authors.forename: Paul
authors.initials: P
authors.lastname: Brandt-Rauf
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fine
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004221:Disulfiram / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009336:Necrosis / Q000378:metabolism*; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D017382:Reactive Oxygen Species; D050994:Voltage-Dependent Anion Channels; D000255:Adenosine Triphosphate; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide; D004221:Disulfiram