Withaferin A induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade |
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Authors: | Chandan Mandal Avijit Dutta Asish Mallick Sarmila Chandra Laxminarain Misra Rajender S Sangwan Chitra Mandal |
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Institution: | (1) Department of Infectious diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata, 700 032, India;(2) Present address: Division of Infectious Disease, Department of Medicine, Chang Gung University School of Medicine and Hospital, 5 Fu-Shin St. Kuei-Shen, Taoyuan, Taiwan;(3) Kothari Medical Center, 8/3, Alipore Road, Kolkata, 700027, India;(4) Central Institute of Medicinal and Aromatic Plants P.O. C.I.M.A.P, Lucknow, 226015, India |
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Abstract: | Withaferin A (WA) is present abundantly in Withania somnifera, a well-known Indian medicinal plant. Here we demonstrate how WA exhibits a strong growth-inhibitory effect on several human
leukemic cell lines and on primary cells from patients with lymphoblastic and myeloid leukemia in a dose-dependent manner,
showing no toxicity on normal human lymphocytes and primitive hematopoietic progenitor cells. WA-mediated decrease in cell viability was observed through apoptosis as demonstrated by externalization of phosphatidylserine,
a time-dependent increase in Bax/Bcl-2 ratio; loss of mitochondrial transmembrane potential, cytochrome c release, caspases 9 and 3 activation; and accumulation of cells in sub-G0 region based on DNA fragmentation. A search for
the downstream pathway further reveals that WA-induced apoptosis was mediated by an increase in phosphorylated p38MAPK expression,
which further activated downstream signaling by phosphorylating ATF-2 and HSP27 in leukemic cells. The RNA interference of
p38MAPK protected these cells from WA-induced apoptosis. The RNAi knockdown of p38MAPK inhibited active phosphorylation of
p38MAPK, Bax expression, activation of caspase 3 and increase in Annexin V positivity. Altogether, these findings suggest
that p38MAPK in leukemic cells promotes WA-induced apoptosis. WA caused increased levels of Bax in response to MAPK signaling,
which resulted in the initiation of mitochondrial death cascade, and therefore it holds promise as a new, alternative, inexpensive
chemotherapeutic agent for the treatment of patients with leukemia of both lymphoid and myeloid origin.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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