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2016 ; 107
(9
): 1302-14
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Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by
inhibiting cell cycle progression
#MMPMID27311589
Okamoto S
; Tsujioka T
; Suemori S
; Kida J
; Kondo T
; Tohyama Y
; Tohyama K
Cancer Sci
2016[Sep]; 107
(9
): 1302-14
PMID27311589
show ga
Treatment outcomes for acute myeloid leukemia and myelodysplastic syndromes (MDS)
remain unsatisfactory despite progress in various types of chemotherapy and
hematopoietic stem cell transplantation. Therefore, there is a need for the
development of new treatment options. We investigated the growth-suppressive
effects of withaferin A (WA), a natural plant steroidal lactone, on
myelodysplasia and leukemia cell lines. WA exhibited growth-suppressive effects
on the cell lines, MDS-L, HL-60, THP-1, Jurkat and Ramos, and induction of cell
cycle arrest at G2/M phase at relatively low doses. Evaluation by annexin V/PI
also confirmed the induction of partial apoptosis. Gene expression profiling and
subsequent gene set enrichment analysis revealed increased expression of heme
oxygenase-1 (HMOX1). HMOX1 is known to induce autophagy during anticancer
chemotherapy and is considered to be involved in the treatment resistance. Our
study indicated increased HMOX1 protein levels and simultaneous increases in the
autophagy-related protein LC3A/B in MDS-L cells treated with WA, suggesting
increased autophagy. Combined use of WA with chloroquine, an autophagy inhibitor,
enhanced early apoptosis and growth suppression. Together with the knowledge that
WA had no apparent suppressive effect on the growth of human normal bone marrow
CD34-positive cells in the short-term culture, this drug may have a potential for
a novel therapeutic approach to the treatment of leukemia or MDS.