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Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice

Hegde, Mahesh and Karki, Subhas S and Thomas, Elizabeth and Kumar, Sujeet and Panjamurthy, Kuppusamy and Ranganatha, Somasagara R and Rangappa, Kanchugarakoppal S and Choudhary, Bibha and Raghavan, Sathees C (2012) Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice. In: PLos One, 7 (9).

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Official URL: http://dx.doi.org/10.1371/journal.pone.0043632

Abstract

Background: Levamisole, an imidazo(2,1-b) thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4'-fluorophenyl)-5-thiocyanato-imidazo2,1-b]1,3,4]thi adiazole). Materials and Methods: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. Results: We have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 mu M). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. Conclusion: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.

Item Type: Journal Article
Additional Information: Copyright for this article is belongs to the authors
Department/Centre: Division of Biological Sciences > Biochemistry
Depositing User: Id for Latest eprints
Date Deposited: 03 Dec 2012 09:10
Last Modified: 03 Dec 2012 09:10
URI: http://eprints.iisc.ernet.in/id/eprint/45198

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