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OSU-A9, an indole-3-carbinol derivative, induces cytotoxicity in acute myeloid leukemia through reactive oxygen species-mediated apoptosis.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2013 Nov 15; Vol. 86 (10), pp. 1430-40. Date of Electronic Publication: 2013 Sep 13. - Publication Year :
- 2013
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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.<br /> (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Autophagy drug effects
Caspase 3 metabolism
Cell Line, Tumor
Cyclin A metabolism
Cyclin B1 metabolism
Down-Regulation
Enzyme Activation
Humans
Indoles therapeutic use
Leukemia, Myeloid, Acute drug therapy
Leukemia, Myeloid, Acute metabolism
Methanol pharmacology
Methanol therapeutic use
Mice
Mice, Nude
Phosphorylation
Proto-Oncogene Proteins c-akt metabolism
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Apoptosis drug effects
Indoles pharmacology
Leukemia, Myeloid, Acute pathology
Methanol analogs & derivatives
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 86
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 24041743
- Full Text :
- https://doi.org/10.1016/j.bcp.2013.09.002