Journal article
Identification of 6-Benzylthioinosine as a Myeloid Leukemia Differentiation–Inducing Compound
Cancer research (Chicago, Ill.), Vol.68(11), pp.4369-4376
06/01/2008
DOI: 10.1158/0008-5472.CAN-07-6559
PMCID: PMC3896053
PMID: 18519698
Abstract
As the pathophysiology of acute myelogenous leukemia (AML) involves a block of myeloid maturation, a desirable therapeutic strategy is to induce leukemic cell maturation to increase the efficacy and to avoid the side effects of traditional chemotherapeutics. Through a compound library screen, 6-benzylthioinosine (6BT) was identified as a promising differentiation-inducing agent. 6BT induces monocytic differentiation of myeloid leukemia cell lines such as HL-60 and OCI-AML3, as well as primary patient samples as evidenced by morphology, immunophenotyping, and nitroblue tetrazolium reduction. Not only can 6BT induce differentiation but a subset of AML cell lines such as MV4-11 and HNT34 instead undergo 6BT-mediated cell death. Despite inducing cell death in some leukemic cells, 6BT exhibits extremely low toxicity on several nonmalignant cells such as fibroblasts, normal bone marrow, and endothelial cells. This toxicity profile may relate to the function of 6BT as an inhibitor of the nucleoside transporter, ent1, which is thought to prevent it from entering many cell types. In contrast, 6BT likely enters at least some leukemic cell lines as shown by its requirement for phosphorylation for its differentiation activity. 6BT is also able to synergize with currently used myeloid differentiation agents such as ATRA and decitabine. Early studies indicate that the mechanism of action of this compound may involve ATP depletion that leads to growth inhibition and subsequent differentiation. Besides
in vitro
activity, 6BT also shows the ability to impair HL-60 and MV4-11 tumor growth in nude mice. 6BT is a promising new monocytic differentiation agent with apparent leukemic cell–specific activity.
Details
- Title: Subtitle
- Identification of 6-Benzylthioinosine as a Myeloid Leukemia Differentiation–Inducing Compound
- Creators
- David N Wald - Case Western Reserve UniversityHanna M Vermaat - Case Western Reserve UniversityShaolei Zang - Shandong UniversityAndrew Lavik - Case Western Reserve UniversityZizhen Kang - Case Western Reserve UniversityGil Peleg - Case Western Reserve UniversityStanton L Gerson - Case Western Reserve UniversityKevin D Bunting - Case Western Reserve UniversityMunna L Agarwal - Case Western Reserve UniversityBryan L Roth - University of North Carolina at Chapel HillWilliam Tse - Case Western Reserve University
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.68(11), pp.4369-4376
- DOI
- 10.1158/0008-5472.CAN-07-6559
- PMID
- 18519698
- PMCID
- PMC3896053
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- K12 CA076917 || CA / National Cancer Institute : NCI P30 CA043703 || CA / National Cancer Institute : NCI
- Language
- English
- Date published
- 06/01/2008
- Academic Unit
- Pathology; Iowa Neuroscience Institute
- Record Identifier
- 9984201122502771
Metrics
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