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
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
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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| Creator |
Mandal, Chandan
Dutta, Avijit Mallick, Asish Chandra, Sarmila Misra, Laxminarain Sangwan, Rajender S Mandal, Chitra |
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| Subject |
Infectious Diseases and Immunology
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| Description |
Withaferin A (WA) is present abundantly in
Withania somnifera, a well-known Indian medicinal plant.
Here we demonstrate how WA exhibits a strong growthinhibitory
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.
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| Date |
2008
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/143/1/APOPTOSIS%2C13(12)%2C1450%2D1464%2C2008[13].pdf
Mandal, Chandan and Dutta, Avijit and Mallick, Asish and Chandra, Sarmila and Misra, Laxminarain and Sangwan, Rajender S and Mandal, Chitra (2008) 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. Apoptosis, 13 (12). pp. 1450-1464. |
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| Relation |
http://dx.doi.org/10.1007/s10495-008-0271-0
http://www.eprints.iicb.res.in/143/ |
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