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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

Authors: Dinnen, Richard D; Mao, Yuehua; Qiu, Wanglong; Cassai, Nicholas; Slavkovich, Vesna N; Nichols, Gwen; Su, Gloria H; Brandt-Rauf, Paul; Fine, Robert L

Published In Mol Cancer Ther, (2013 Dec)

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.

PubMed ID: 24126434 Exiting the NIEHS site

MeSH Terms: Adenosine Triphosphate/metabolism*; Animals; Antineoplastic Agents/administration & dosage; Antineoplastic Agents/pharmacology; Apoptosis*/drug effects; Arsenic Trioxide; 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*

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