Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression.
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.
Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan.
Shuichiro
S
Okamoto
Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan.
Takayuki
T
Tsujioka
Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan.
Shin-Ichiro
S
Suemori
Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan.
Jun-Ichiro
J
Kida
Division of Hematology, Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan.
Toshinori
T
Kondo
Division of Biochemistry, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan.
Yumi
Y
Tohyama
Department of Laboratory Medicine, Kawasaki Medical School, Okayama, Japan. ktohyama@med.kawasaki-m.ac.jp.
Kaoru
K
Tohyama
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D054358:Withanolides; D051547:Heme Oxygenase-1; C009684:withaferin A
Acute myeloid leukemia; gene set enrichment analysis; heme oxygenase-1; myelodysplastic syndromes; withaferin A