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.
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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)
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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
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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
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