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Aurintricarboxylic Acid Inhibits Protein Synthesis Independent, Sanguinarine-Induced Apoptosis and Oncosis

Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6, Canada, AMC Cancer Research Center, Denver, CO 80214, USA

Shou-Ching Tang

Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6, Canada

L. Maximilian Buja

University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA

Benjamin F. Trump

AMC Cancer Research Center, Denver, CO 80214, USA

Andrejs Liepins

Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6, Canada

Priya Weerasinghe

Baylor College of Medicine, Department of Medicine, Houston, TX 77030, USA, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6, Canada, AMC Cancer Research Center, Denver, CO 80214, USA

Sanguinarine, a benzophenanthridine alkaloid, has anticancer potential through induction of cell death. We previously demonstrated that sanguinarine treatment at a low concentration (1.5 µg/ml) induced apoptosis in K562 human erythroleukemia cells, and a high concentration (12.5 µg/ml) induced the morphology of blister formation or oncosis-blister cell death (BCD). Treatment of cells at an intermediate sanguinarine concentration (6.25 µg/ml) induced diffuse swelling or oncosis-diffuse cell swelling (DCS). To assess the underlying mechanism of sanguinarine-induced apoptosis and oncosis-BCD in K562 cells, we studied their response to pre-treatment with two chemical compounds: aurintricarboxylic acid (ATA) and cycloheximide (CHX). The pretreatment effects of both chemical compounds on apoptosis and oncosis-BCD were evaluated by measuring multiple parameters using quantitative morphology, electron microscopy, terminal deoxynucleotidyl transferase (TdT) end-labeling and annexin-V-binding. ATA, a DNA endonuclease inhibitor, efficiently prevented DNA nicking and inhibited apoptosis almost completely and oncosis-BCD by about 40%, while CHX, a protein synthesis inhibitor, failed to inhibit both apoptosis and oncosis-BCD. These results demonstrate, first, the importance of endonuclease in sanguinarine-induced apoptosis and to some extent in oncosis-BCD and, second, that this inhibition does not require de novo protein synthesis.

Key Words: Oncosis • apoptosis • necrosis • bimodal cell death • sanguinarine • aurintricarboxylic acid • cycloheximide.

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