Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression.
Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression.
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DOI：
10.1111/cas.12988
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发表时间：
2016-09
期刊：
影响因子：
5.7
通讯作者：
Tohyama K
中科院分区：
文献类型：
--
作者：
Okamoto S;Tsujioka T;Suemori S;Kida J;Kondo T;Tohyama Y;Tohyama K
尽管各种类型的化疗和造血干细胞移植取得了进展，但急性髓细胞白血病和骨髓增生异常综合征（MDS）的治疗结果仍不令人满意。因此，需要开发新的治疗方案。我们研究了醉茄素A（WA）（一种天然植物甾体内酯）对骨髓增生异常和白血病细胞系的生长抑制作用。WA对细胞系MDS-L、HL-60、THP-1、Jurkat和拉莫斯表现出生长抑制作用，并在相对低的剂量下诱导细胞周期停滞在G2/M期。通过膜联蛋白V/PI的评估也证实了部分凋亡的诱导。基因表达谱分析和随后的基因集富集分析显示血红素加氧酶-1（HMOX 1）的表达增加。已知HMOX 1在抗癌化疗期间诱导自噬，并被认为与治疗耐药性有关。我们的研究表明，在用WA处理的MDS‐L细胞中，HMOX 1蛋白水平增加，同时自噬相关蛋白LC 3A/B增加，表明自噬增加。WA与自噬抑制剂氯喹联合使用，增强了早期凋亡和生长抑制。结合WA对短期培养的人正常骨髓CD 34阳性细胞的生长没有明显抑制作用的知识，这种药物可能具有治疗白血病或MDS的新治疗方法的潜力。
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.
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影响因子：
5.7
作者：
Hyoda T;Tsujioka T;Nakahara T;Suemori S;Okamoto S;Kataoka M;Tohyama K
通讯作者：
Tohyama K
影响因子：
5.1
作者：
Roy RV;Suman S;Das TP;Luevano JE;Damodaran C
通讯作者：
Damodaran C
影响因子：
3.4
作者：
Grogan, Patrick T.;Sarkaria, Jann N.;Timmermann, Barbara N.;Cohen, Mark S.
通讯作者：
Cohen, Mark S.
影响因子：
2.9
作者：
Stan, Silvia D.;Zeng, Yan;Singh, Shivendra V.
通讯作者：
Singh, Shivendra V.
影响因子：
7.2
作者：
Oh, Jung Hwa;Lee, Tae-Jin;Kwon, Taeg Kyu
通讯作者：
Kwon, Taeg Kyu