| Apoptosis induction in human leukemic cells by a novel protein Bengalin, isolated from Indian black scorpion venom: through mitochondrial pathway and inhibition of heat shock proteins. | |
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MedLine Citation:
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PMID: 19913524 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Scorpion venom possesses protein toxins having numerous biological activities, some of which are potentially anticancerous. Previously we had reported antiproliferative activity of the venom of Indian black scorpion, Heterometrus bengalensis Koch. Here we have isolated and purified a novel protein named Bengalin (72kDa) from the venom, responsible for antiproliferative and apoptogenic activities against human leukemic cells U937 (histiocytic lymphoma) and K562 (chronic myelogenous leukemia). N-terminal sequence of first 20 amino acids of Bengalin was G-P-L-T-I-L-H-I-N-D-V-H-A-A/R-F-E-Q/G-F/G-N-T. Bengalin induced cell growth inhibition at IC(50) values of 3.7 and 4.1 microg/ml for U937 and K562 cells respectively did not significantly affect normal human lymphocytes. Inhibition of U937 and K562 cell proliferation occurred by apoptosis as evidenced from damaged nuclei, cell cycle arrest at sub G1 phase, increase of early apoptotic cells, augmentation of DNA fragmentation and also a reduction of telomerase activity. Further insights revealed that Bax:Bcl2 ratio was elevated after Bengalin treatment. Moreover Bengalin elicited loss of mitochondrial membrane potential (MMP) which commenced cytochrome c release in cytosol, decreased heat shock protein (HSP) 70 and 90 expression, activated caspase-9, caspase-3 and induced poly(ADP-ribose) polymerase (PARP) cleavage. We have also determined that HSP70 and 90 inhibitions correlated with Bengalin induced antiproliferation, caspase-3 upregulation, apoptogenesis and increased DNA fragmentation. These results hypothesize that Bengalin might provide a putative molecular mechanism for their anticancer effect on human leukemic cells which might be mediated by mitochondrial death cascade. Inhibition of HSPs might also play a crucial role in induction of apoptosis. |
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Authors:
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Shubho Das Gupta; Antony Gomes; Anindita Debnath; Archita Saha; Aparna Gomes |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-11-12 |
Journal Detail:
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Title: Chemico-biological interactions Volume: 183 ISSN: 1872-7786 ISO Abbreviation: Chem. Biol. Interact. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-01-27 Completed Date: 2010-02-25 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0227276 Medline TA: Chem Biol Interact Country: Ireland |
Other Details:
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Languages: eng Pagination: 293-303 Citation Subset: IM |
Copyright Information:
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2009 Elsevier Ireland Ltd. All rights reserved. |
Affiliation:
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Drug Development Division, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata-700032, India. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Antineoplastic Agents / isolation & purification, toxicity* Apoptosis* Caspase 3 / metabolism Caspase 9 / metabolism Cytochromes c / metabolism G1 Phase HSP70 Heat-Shock Proteins / metabolism HSP90 Heat-Shock Proteins / metabolism Heat-Shock Proteins / antagonists & inhibitors*, metabolism Humans India K562 Cells Leukemia / drug therapy Membrane Potential, Mitochondrial / drug effects Mitochondria / drug effects, metabolism* Molecular Sequence Data Poly(ADP-ribose) Polymerases / metabolism Proto-Oncogene Proteins c-bcl-2 / metabolism Scorpion Venoms / chemistry* U937 Cells bcl-2-Associated X Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/HSP70 Heat-Shock Proteins; 0/HSP90 Heat-Shock Proteins; 0/Heat-Shock Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Scorpion Venoms; 0/bcl-2-Associated X Protein; 9007-43-6/Cytochromes c; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9 |
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