Journal
BIOCHEMICAL PHARMACOLOGY
Volume 86, Issue 10, Pages 1430-1440Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.09.002
Keywords
OSU-A9; Indole-3-carbinol; Acute myeloid leukemia; Reactive oxygen species; Glutathione
Categories
Funding
- Taiwan Department of Health, China Medical University Hospital Cancer Research of Excellence [DOH102-TD-C-111-005]
- National Science Council [NSC 101-2314-B-039-021-MY2, NSC 101-2320-B-039-029-MY2]
- China Medical University Hospital [DMR-99-304, DMR-101-008]
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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. (C) 2013 Elsevier Inc. All rights reserved.
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