OSU-A9, an indole-3-carbinol derivative, induces cytotoxicity in acute myeloid leukemia through reactive oxygen species-mediated apoptosis.

Abstract

Indole-3-carbinol (I3C) is a broadly targeted phytochemical shown to prevent carcinogenesis in animal studies and to suppress the proliferation of cancer cells of human breast, colon, prostate, and endometrium. Here we demonstrate that OSU-A9, an I3C derivative with improved anticancer potency, induces cytotoxicity in acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells were less sensitive to OSU-A9 than leukemia cells. OSU-A9 induces caspase activation, PARP cleavage, and autophagy but not autophagic cell death. Interestingly, pretreatment of AML cell lines and primary AML cells with N-acetylcysteine or glutathione rescues them from apoptosis (and concomitant PARP cleavage) and Akt hypophosphorylation, implicating a key role of reactive oxygen species (ROS) in OSU-A9-related cytotoxicity. Importantly, the anticancer utility of OSU-A9 is extended in vivo as it, administered intraperitoneally, suppresses the growth of THP-1 xenograft tumors in athymic nude mice without obvious toxicity. This study shows that ROS-mediated apoptosis contributes to the anticancer activity of OSU-A9 in AML cell lines and primary AML cells, and thus should be considered in the future assessment of its translational value in AML therapy.

• Authors: Li-Yuan Bai, Jing-Ru Weng, Chang-Fang Chiu, Chia-Yung Wu, Su-Peng Yeh, Aaron M Sargeant, Po-Han Lin, Yu-Min Liao
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 86 Issue 10 Pg. 1430-40 (Nov 15 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 24041743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• (1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl)-methanol
• Antineoplastic Agents
• Cyclin A
• Cyclin B1
• Indoles
• Reactive Oxygen Species
• Proto-Oncogene Proteins c-akt
• Caspase 3
• Methanol

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cyclin A (metabolism)
• Cyclin B1 (metabolism)
• Down-Regulation
• Enzyme Activation
• Humans
• Indoles (pharmacology, therapeutic use)
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Methanol (analogs & derivatives, pharmacology, therapeutic use)
• Mice
• Mice, Nude
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays