Kavitha, C. V. and Mridula Nambiar and Ananda Kumar, C. S. and Choudhary, Bibha and Muniyappa, K. and Rangappa, K. S. and Sathees Raghavan, C. (2009) Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells. Biochemical Pharmacology, 77 (3). pp. 348-363. ISSN 1873-2968
Full text not available from this repository. (Request a copy)Abstract
Hydantoin derivatives possess a variety of biochemical and pharmacological properties and consequently are used to treat many human diseases. However, there are only few studies focusing on their potential as cancer therapeutic agents. In the present study, we have examined anticancer properties of two novel spirohydantoin compounds, 8-(3,4-difluorobenzyl)-1'-(pent-4-enyl)-8-azaspirobicyclo3.2.1] octane-3,4'-imidazolidine]-2',5'-dione (DFH) and 8-(3,4-dichlorobenzyl)-1'-(pent-4-enyl)-8-azaspirobicyclo3.2.1]oct ane-3,4'-imidazolidine]-2',5'-dione (DCH). Both the compounds exhibited dose- and time-dependent cytotoxic effect on human leukemic cell lines, K562, Reh, CEM and 8ES. Incorporation of tritiated thymidine (H-3) thymidine) in conjunction with cell cycle analysis suggested that DFH and DCH inhibited the growth of leukemic cells. Downregulation of PCNA and p-histone H3 further confirm that the growth inhibition could be at the level of DNA replication. Flow cytometric analysis indicated the accumulation of cells at subG1 phase suggesting induction of apoptosis, which was further confirmed and quantified both by fluorescence-activated cell sorting (FACS) and confocal microscopy following annexin V-FITC/propidium iodide (PI) staining. Mechanistically, our data support the induction of apoptosis by activation of the mitochondrial pathway. Results supporting such a model include, elevated levels of p53, and BAD, decreased level of BCL2, activation and cleavage of caspase 9, activation of procaspase 3, poly (ADP-ribosyl) polymerase (PARP) cleavage, downregulation of Ku70, Ku80 and DNA fragmentation. Based on these results we discuss the mechanism of apoptosis induced by DFH and its implications in leukemia therapy. (C) 2008 Elsevier Inc. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Chemotherapy; Double-strand break; Cytotoxicity; Cell death; Anticancer drugs; Flow cytometry; DNA damage |
| Subjects: | C Chemical Science > Chemistry |
| Divisions: | Department of > Chemistry |
| Depositing User: | Users 19 not found. |
| Date Deposited: | 28 Aug 2019 07:53 |
| Last Modified: | 28 Aug 2019 07:53 |
| URI: | http://eprints.uni-mysore.ac.in/id/eprint/7234 |
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