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Apoptotic effects of mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways.
Biochem Pharmacol. 2010 Feb 01; 79(3):361-72.BP

Abstract

Apo-1 (Fas/CD95), a cell surface receptor, triggers apoptosis after binding to its physiological ligand, Apo-1L (FasL/CD95L). This study reports that mahanine, purified from the leaves of Murraya koenigii, has a dose- and time-dependent anti-proliferative activity in acute lymphoid (MOLT-3) and chronic myeloid (K562) leukemic cell lines and in the primary cells of leukemic and myeloid patients, with minimal effect on normal immune cells including CD34(+) cells. Leukemic cells underwent phosphatidylserine externalization and DNA fragmentation, indicating mahanine-induced apoptosis. An increase in reactive oxygen species suggests that the mahanine-induced apoptosis was mediated by oxidative stress. A significant drop in the Bcl2/Bax ratio, the loss of mitochondrial transmembrane potential as well as cytochrome c release from the mitochondria to the cytosol suggested involvement of the mitochondrial pathway of apoptosis. Cytochrome c release was followed by the activation of caspase-9, caspase-3 and caspase-7, and cleavage of PARP in both MOLT-3 and K562 cells. In MOLT-3 cells, formation of the Fas-FasL-FADD-caspase-8 heterotetramer occurred, leading to the cleavage of Bid to its truncated form, which consequently resulted in formation of the mitochondrial transmembrane pore. The incubation of MOLT-3 cells with mahanine in the presence of caspase-8 inhibitor or FasL-neutralizing NOK-2 antibody resulted in the decrease of mahanine-induced cell death. Mahanine was also a potent inhibitor of K562 xenograft growth, which was evident in an athymic nude mice model. In summary, these results provide evidence for involvement of the death receptor-mediated extrinsic pathway of apoptosis in the mahanine-induced anticancer activity in MOLT-3 cells, but not in K562 cells, which are deficient in Fas/FasL.

Authors+Show Affiliations

Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, A Unit of Council of Scientific and Industrial Research, 4, Raja S.C. Mullick Road, Kolkata 700032, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19751707

Citation

Bhattacharya, Kaushik, et al. "Apoptotic Effects of Mahanine On Human Leukemic Cells Are Mediated Through Crosstalk Between Apo-1/Fas Signaling and the Bid Protein and Via Mitochondrial Pathways." Biochemical Pharmacology, vol. 79, no. 3, 2010, pp. 361-72.
Bhattacharya K, Samanta SK, Tripathi R, et al. Apoptotic effects of mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways. Biochem Pharmacol. 2010;79(3):361-72.
Bhattacharya, K., Samanta, S. K., Tripathi, R., Mallick, A., Chandra, S., Pal, B. C., Shaha, C., & Mandal, C. (2010). Apoptotic effects of mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways. Biochemical Pharmacology, 79(3), 361-72. https://doi.org/10.1016/j.bcp.2009.09.007
Bhattacharya K, et al. Apoptotic Effects of Mahanine On Human Leukemic Cells Are Mediated Through Crosstalk Between Apo-1/Fas Signaling and the Bid Protein and Via Mitochondrial Pathways. Biochem Pharmacol. 2010 Feb 1;79(3):361-72. PubMed PMID: 19751707.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apoptotic effects of mahanine on human leukemic cells are mediated through crosstalk between Apo-1/Fas signaling and the Bid protein and via mitochondrial pathways. AU - Bhattacharya,Kaushik, AU - Samanta,Suman K, AU - Tripathi,Rakshamani, AU - Mallick,Asish, AU - Chandra,Sarmila, AU - Pal,Bikas C, AU - Shaha,Chandrima, AU - Mandal,Chitra, Y1 - 2009/09/12/ PY - 2009/07/21/received PY - 2009/08/25/revised PY - 2009/09/02/accepted PY - 2009/9/16/entrez PY - 2009/9/16/pubmed PY - 2009/12/23/medline SP - 361 EP - 72 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 79 IS - 3 N2 - Apo-1 (Fas/CD95), a cell surface receptor, triggers apoptosis after binding to its physiological ligand, Apo-1L (FasL/CD95L). This study reports that mahanine, purified from the leaves of Murraya koenigii, has a dose- and time-dependent anti-proliferative activity in acute lymphoid (MOLT-3) and chronic myeloid (K562) leukemic cell lines and in the primary cells of leukemic and myeloid patients, with minimal effect on normal immune cells including CD34(+) cells. Leukemic cells underwent phosphatidylserine externalization and DNA fragmentation, indicating mahanine-induced apoptosis. An increase in reactive oxygen species suggests that the mahanine-induced apoptosis was mediated by oxidative stress. A significant drop in the Bcl2/Bax ratio, the loss of mitochondrial transmembrane potential as well as cytochrome c release from the mitochondria to the cytosol suggested involvement of the mitochondrial pathway of apoptosis. Cytochrome c release was followed by the activation of caspase-9, caspase-3 and caspase-7, and cleavage of PARP in both MOLT-3 and K562 cells. In MOLT-3 cells, formation of the Fas-FasL-FADD-caspase-8 heterotetramer occurred, leading to the cleavage of Bid to its truncated form, which consequently resulted in formation of the mitochondrial transmembrane pore. The incubation of MOLT-3 cells with mahanine in the presence of caspase-8 inhibitor or FasL-neutralizing NOK-2 antibody resulted in the decrease of mahanine-induced cell death. Mahanine was also a potent inhibitor of K562 xenograft growth, which was evident in an athymic nude mice model. In summary, these results provide evidence for involvement of the death receptor-mediated extrinsic pathway of apoptosis in the mahanine-induced anticancer activity in MOLT-3 cells, but not in K562 cells, which are deficient in Fas/FasL. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/19751707/Apoptotic_effects_of_mahanine_on_human_leukemic_cells_are_mediated_through_crosstalk_between_Apo_1/Fas_signaling_and_the_Bid_protein_and_via_mitochondrial_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(09)00740-0 DB - PRIME DP - Unbound Medicine ER -