Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia

被引:30
作者
Huang, Jingcao [1 ,2 ,3 ]
Lyu, Hui [1 ]
Wang, Jianxiang [2 ,3 ]
Liu, Bolin [1 ]
机构
[1] Univ Colorado, Dept Pathol, Sch Med, Aurora, CO USA
[2] Chinese Acad Med Sci, State Key Lab Expt Hematol, Inst Hematol & Blood Dis Hosp, Tianjin, Peoples R China
[3] Peking Union Med Coll, Tianjin, Peoples R China
基金
中国国家自然科学基金;
关键词
Survivin; Targeted therapy; YM155; Chemotherapy; Acute myeloid leukemia; SEPANTRONIUM BROMIDE YM155; BREAST-CANCER CELLS; SMALL-MOLECULE SUPPRESSOR; DNA-DAMAGE RESPONSE; PHASE-II; ANTITUMOR-ACTIVITY; APOPTOSIS PROTEIN; LUNG-CANCER; COMBINATION; EXPRESSION;
D O I
10.1016/j.canlet.2015.05.033
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Overexpression of survivin is observed in various hematological malignancies, including acute myeloid leukemia (AML). Studies show that elevated expression of survivin correlates with a worse clinic outcome in AML patients. It remains unclear whether inhibition of survivin may alter the efficacy of chemotherapy against AML. Here, we evaluate the effects of specific knockdown of survivin on AML cells' sensitivity to chemotherapy, and investigate the therapeutic potential of the transcription inhibitor of survivin YM155 either alone or in combination with chemotherapeutic agents. We found Kasumi-1 and HL-60 cells had relatively higher expression levels of survivin among all AML cell lines tested. Specific knockdown of survivin in Kasumi-1 and HL-60 cells resulted in: inhibition of cell proliferation; cell cycle G2/M arrest; induction of DNA damage response and apoptosis. Downregulation of survivin enhanced etoposide- or doxorubicin-induced anti-proliferative/anti-survival activity in AML cells. The small molecule inhibitor YM155 reduced survivin ma dose- and time-dependent manner and trigged apoptosis in Kasumi-1 and HL-60 cells. The combinatorial effects of YM155 and chemotherapeutics were either synergetic or antagonistic, depending upon the drugs used for combination and the type of AML cells being treated. Collectively, our data demonstrate that survivin plays an important role in the maintenance and proliferation of AML cells. While specific knockdown of survivin enhances chemosensitivity, the combinations of YM155 and chemotherapeutic agents exhibit synergetic or antagonistic effects on AML cells. Our findings provide a rationale for further assessment of survivin-targeted therapy in the treatment of patients with AML. 2015 The Authors. Published by Elsevier Ireland Ltd.
引用
收藏
页码:160 / 172
页数:13
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