Imatinib-induced apoptosis: a possible link to topoisomerase enzyme inhibition.

Abstract

WHAT IS KNOWN AND OBJECTIVE:

Imatinib is a specific BCR/ABL inhibitor, commonly used for the treatment of chronic myeloid leukaemia (CML), a hematological malignancy resulting from a chromosomal translocation that generates the BCR/ABL fusion protein. Recent studies showed that the imatinib has cytotoxic and apoptotic effects on many BCR/ABL-negative cancers. Numerous compounds with cytotoxic potential exert their functions by interfering with the DNA topoisomerase. In this study, we examined the effects of imatinib on tumour cell-killing in relation to DNA topoisomerase enzyme inhibition.

METHODS:

We determined the cytotoxicity by cell proliferation assay (XTT; tetrazolium hydroxide), using the human K562 CML cells, and loss of mitochondrial membrane potential by monitoring the changes in caspase-3 enzyme activity. Type I and II topoisomerase activities were measured by supercoiled plasmid relaxation and minicircle DNA decatenation assays respectively.

RESULTS AND DISCUSSION:

Imatinib-induced apoptosis and inhibited cell proliferation in a dose-dependent manner. We also found that the imatinib was effective in both type I and type II topoisomerase reactions to a varying degree between 94% and 7% for the concentration range of 1 mm-0.02 mm in a dose-dependent manner.

WHAT IS NEW AND CONCLUSION:

Our results suggest that the inhibition of topoisomerases may be a significant factor in imatinib-induced apoptosis in CML.

• Authors: Y Baran, S Zencir, Z Cakir, E Ozturk, Z Topcu
• Journal: Journal of clinical pharmacy and therapeutics (J Clin Pharm Ther) Vol. 36 Issue 6 Pg. 673-9 (Dec 2011) ISSN: 1365-2710 [Electronic] England
• PMID: 21105880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 Blackwell Publishing Ltd.

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Caspase 3
• DNA Topoisomerases, Type I
• DNA Topoisomerases, Type II

Topics

• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects)
• Benzamides
• Caspase 3 (drug effects, metabolism)
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type I (drug effects, metabolism)
• DNA Topoisomerases, Type II (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Humans
• Imatinib Mesylate
• K562 Cells
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology)
• Membrane Potential, Mitochondrial (drug effects)
• Piperazines (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)