A novel inhibitor of BCL2, Disarib abrogates tumor growth while sparing platelets, by activating intrinsic pathway of apoptosis.
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.
Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
Supriya V
SV
Vartak
Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
Mahesh
M
Hegde
Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
Divyaanka
D
Iyer
Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410 210, India.
Snehal
S
Gaikwad
Institute of Bioinformatics and Applied Biotechnology, Electronics City, Bangalore 560 100, India; Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
Vidya
V
Gopalakrishnan
Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
Mrinal
M
Srivastava
Department of Pharmaceutical Chemistry, KLE University's College of Pharmacy, Bangalore 560 010, India.
Subhas S
SS
Karki
Institute of Bioinformatics and Applied Biotechnology, Electronics City, Bangalore 560 100, India.
Bibha
B
Choudhary
Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410 210, India.
Pritha
P
Ray
Rajiv Gandhi Centre for Biotechnology, Trivandrum 695 014, India.
T R
TR
Santhoshkumar
Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India. Electronic address: sathees@biochem.iisc.ernet.in.
Sathees C
SC
Raghavan
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013830:Thiadiazoles; C000618298:disarib; C052617:Bcl2 protein, mouse
Apoptosis; Cancer therapeutics; Cell death; Chemotherapy; Small molecule inhibitor