Propyl-2-(8-(3,4-difluorobenzyl)-29,59-dioxo-8- azaspiro[bicyclo[3.2.1] octane-3,49-imidazolidine]-19-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest

Kavitha, C. V. and Nambiar, M. and Narayanaswamy, P. B. and Thomas, E. and Rathore, U. and Ananda Kumar, C. S. and Choudhary, B. and Rangappa, K. S. and Raghavan, S. C. (2013) Propyl-2-(8-(3,4-difluorobenzyl)-29,59-dioxo-8- azaspiro[bicyclo[3.2.1] octane-3,49-imidazolidine]-19-yl) acetate induces apoptosis in human leukemia cells through mitochondrial pathway following cell cycle arrest. PLoS ONE, 8 (7). ISSN 1932-6203

Text (Full Text) Che_2013_ Rangappa.PDF - Published Version Download (1MB)

Abstract

Background:Due to the functional defects in apoptosis signaling molecules or deficient activation of apoptosis pathways, leukemia has become an aggressive disease with poor prognosis. Although the majority of leukemia patients initially respond to chemotherapy, relapse is still the leading cause of death. Hence targeting apoptosis pathway would be a promising strategy for the improved treatment of leukemia. Hydantoin derivatives possess a wide range of important biological and pharmacological properties including anticancer properties. Here we investigated the antileukemic activity and mechanism of action of one of the potent azaspiro hydantoin derivative, (ASHD).Materials and Methods:To investigate the antileukemic efficacy of ASHD, we have used MTT assay, cell cycle analysis by FACS, tritiated thymidine incorporation assay, Annexin V staining, JC1 staining and western blot analysis.Results:Results showed that ASHD was approximately 3-fold more potent than the parent compounds in inducing cytotoxicity. Tritiated thymidine assay in conjunction with cell cycle analysis suggests that ASHD inhibited the growth of leukemic cells. The limited effect of ASHD on cell viability of normal cells indicated that it may be specifically directed to cancer cells. Translocation of phosphatidyl serine, activation of caspase 3, caspase 9, PARP, alteration in the ratio of BCL2/BAD protein expression as well as the loss of mitochondrial membrane potential suggests activation of the intrinsic pathway of apoptosis.Conclusion:These results could facilitate the future development of novel hydantoin derivatives as chemotherapeutic agents for leukemia.

Item Type:	Article
Uncontrolled Keywords:	article, human, controlled study, drug efficacy, unclassified drug, Dose-Response Relationship, Drug, antineoplastic activity, cytotoxicity, drug potency, Humans, Cell Survival, Western blotting, Cell Membrane, Models, Time Factors, cell proliferation, Cell Proliferation, human cell, protein expression, Biological, Antitumor, Drug Screening Assays, apoptosis, Apoptosis, Leukemia, signal transduction, Signal Transduction, G2 phase cell cycle checkpoint, Mitochondrial, cell viability, Mitochondria, leukemia cell, caspase 9, Inhibitory Concentration 50, protein bcl 2, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, caspase 3, Spiro Compounds, K562 Cells, Membrane Potential, mitochondrial membrane potential, Imidazoles, enzyme activation, phosphatidylserine, fluorescence activated cell sorting, protein BAD, hydantoin derivative, Caspase Inhibitors, 4 difluorobenzyl) 2', 4' imidazolidine] 1' yl]acetic acid, 5' dioxo 8 azaspirobicyclo3.2.1]octane 3, antileukemic activity, Biological Transport, cell cycle arrest, Cell Cycle Checkpoints, cell cycle progression, DNA Breaks, DNA Repair Enzymes, Hydantoins, Phosphatidylserines, propyl 2 8 (3, S phase cell cycle checkpoint
Subjects:	C Chemical Science > Chemistry
Divisions:	Department of > Chemistry
Depositing User:	Arshiya Kousar Library Assistant
Date Deposited:	11 Oct 2019 05:41
Last Modified:	11 Oct 2019 05:41
URI:	http://eprints.uni-mysore.ac.in/id/eprint/8824

Actions (login required)

View Item