A novel inhibitor of BCL2, Disarib abrogates tumor growth while sparing platelets, by activating intrinsic pathway of apoptosis

Vartak, Supriya V and Hegde, Mahesh and Iyer, Divyaanka and Gaikwad, Snehal and Gopalakrishnan, Vidya and Srivastava, Mrinal and Karki, Subhas S and Choudhary, Bibha and Ray, Pritha and Santhoshkumar, T R and Raghavan, Sathees C (2016) A novel inhibitor of BCL2, Disarib abrogates tumor growth while sparing platelets, by activating intrinsic pathway of apoptosis. In: BIOCHEMICAL PHARMACOLOGY, 122 . pp. 10-22.

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Abstract

Antiapoptotic protein BCL2, serves as an excellent target for anticancer therapy owing to its increased level in cancers. Previously, we have described characterization of a novel BCL2 inhibitor, Disarib, which showed selective cytotoxicity in BCL2 `high' cancer cells and CLL patient cells. Here, we have investigated the mechanism of Disarib-induced cytotoxicity, and compared its efficacy with a well-established BCL2 inhibitor, ABT199. We show that Disarib administration caused tumor regression in mouse allograft and xenograft models, exhibited platelet sparing property and did not exhibit significant side effects. Importantly, comparison between Disarib and ABT199, revealed higher efficacy for Disarib in mouse tumor model and cancer cell lines. Disarib induced cell death by activating intrinsic apoptotic pathway. Interestingly, Disarib showed synergism with paclitaxel, suggesting its potential for combination therapy. Thus, we provide mechanistic insights into the cell death pathways induced by Disarib, report that Disarib exhibited better effect than currently used ABT199 and demonstrate its combinatorial potential with paclitaxel. (C) 2016 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Publication:	BIOCHEMICAL PHARMACOLOGY
Additional Information:	Copy right for this article belongs to the PERGAMON-ELSEVIER SCIENCE LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	21 Jan 2017 08:47
Last Modified:	21 Jan 2017 08:47
URI:	http://eprints.iisc.ac.in/id/eprint/55959

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