Senolysis of gemcitabine-induced senescent human pancreatic cancer cells

被引:1
作者
Hoque, Mohammad Mahbubul [1 ]
Iida, Yuichi [1 ]
Kotani, Hitoshi [1 ]
Harada, Mamoru [1 ]
机构
[1] Shimane Univ, Dept Immunol, Fac Med, Izumo, Shimane 6938501, Japan
关键词
Bcl-xL; gemcitabine; pancreatic cancer; senescence; senolysis; THERAPY; INHIBITION;
D O I
10.1002/cnr2.2075
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
IntroductionGemcitabine (GEM) is often used to treat pancreatic cancer. Many anti-cancer drugs induce cancer cell death, but some cells survive after cell cycle arrest. Such a response to DNA damage is termed cellular senescence. Certain drugs, including the Bcl-2-family inhibitor ABT-263, kill senescent cells; this is termed senolysis. In this study, we examined the therapeutic benefits of ABT-263 in GEM-induced senescence of human pancreatic cancer cells.Methods and ResultsOf four pancreatic cancer cell lines (PANC-1, AsPC-1, CFPAC-1, and PANC10.05), GEM induced senescent features in PANC-1 and AsPC-1 cells, including increases in the cell sizes and expression levels of mRNAs encoding interleukin (IL)-6/IL-8 and induction of beta-galactosidase. Successive treatment with GEM and ABT-263 triggered apoptosis in PANC-1 and AsPC-1 cells and suppressed colony formation significantly. Senolysis of GEM-induced senescent pancreatic cancer cells by ABT-263 was triggered by a Bcl-xL inhibitor, but not by a Bcl-2 inhibitor, suggesting a central role for Bcl-xL in senolysis. In a xenograft mouse model, combined treatment with GEM and ABT-737 (an ABT-263 analog exhibiting the same specificity) suppressed in vivo growth of AsPC-1 significantly.ConclusionTogether, our results indicate that sequential treatment with GEM and senolytic drugs effectively kill human pancreatic cancer cells.
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页数:11
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