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A novel inhibitor of BCL2, Disarib abrogates tumor growth while sparing platelets, by activating intrinsic pathway of apoptosis.
Vartak, Supriya V; Hegde, Mahesh; Iyer, Divyaanka; Gaikwad, Snehal; Gopalakrishnan, Vidya; Srivastava, Mrinal; Karki, Subhas S; Choudhary, Bibha; Ray, Pritha; Santhoshkumar, T R; Raghavan, Sathees C.
Afiliación
  • Vartak SV; Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
  • Hegde M; Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
  • Iyer D; Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
  • Gaikwad S; Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410 210, India.
  • Gopalakrishnan V; Institute of Bioinformatics and Applied Biotechnology, Electronics City, Bangalore 560 100, India; Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
  • Srivastava M; Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
  • Karki SS; Department of Pharmaceutical Chemistry, KLE University's College of Pharmacy, Bangalore 560 010, India.
  • Choudhary B; Institute of Bioinformatics and Applied Biotechnology, Electronics City, Bangalore 560 100, India.
  • Ray P; Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410 210, India.
  • Santhoshkumar TR; Rajiv Gandhi Centre for Biotechnology, Trivandrum 695 014, India.
  • Raghavan SC; Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India. Electronic address: sathees@biochem.iisc.ernet.in.
Biochem Pharmacol ; 122: 10-22, 2016 Dec 15.
Article en En | MEDLINE | ID: mdl-27693384
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiadiazoles / Proteínas Proto-Oncogénicas c-bcl-2 / Indoles / Neoplasias / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Año: 2016 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiadiazoles / Proteínas Proto-Oncogénicas c-bcl-2 / Indoles / Neoplasias / Antineoplásicos Límite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Año: 2016 Tipo del documento: Article País de afiliación: India Pais de publicación: Reino Unido