PI3K/mTOR 双重抑制剂 NVP-BEZ235 降低 Mcl-1 表达，并使卵巢癌细胞对 Bcl-xL 靶向策略敏感，前提是诱导 Bim 表达。
PI3K/mTOR dual inhibitor NVP-BEZ235 decreases Mcl-1 expression and sensitizes ovarian carcinoma cells to Bcl-xL-targeting strategies, provided that Bim expression is induced.
机构信息
Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France.
Normandy University, France; UNICAEN, "Biology and Innovative Therapeutics of Locally Aggressive Cancers" Unit (EA 4656), Caen, France; François Baclesse Comprehensive Cancer Centre, Caen, France; (d)On secondment from ISPB, Faculte de Pharmacie, Universite Lyon 1, Lyon, France.
出版信息
Cancer Lett. 2014 Jun 28;348(1-2):38-49. doi: 10.1016/j.canlet.2014.03.001. Epub 2014 Mar 18.
We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Here we assessed the anticancer potential of combining ABT-737-induced inhibition of Bcl-xL with Mcl-1 inhibition via PI3K/Akt/mTOR pathway disruption using NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation without inducing apoptosis. It strongly repressed Mcl-1 expression and induced Puma expression in both cell lines tested while differentially modulating Bim between the two. Interestingly, NVP-BEZ235 efficiently sensitized ovarian carcinoma cells to ABT-737, provided that Bim expression was induced. Moreover, inhibiting the ERK1/2 pathway restored Bim expression and sensitized low Bim-expressing cancer cells to the BEZ235/ABT-737 treatment.
我们之前曾表明 Bcl-xL 和 Mcl-1 协同保护铂耐药卵巢癌细胞免于凋亡。在这里，我们评估了联合使用 ABT-737 抑制 Bcl-xL 与通过 PI3K/Akt/mTOR 通路抑制 Mcl-1（使用 NVP-BEZ235）的抗癌潜力。NVP-BEZ235 抑制细胞增殖而不诱导细胞凋亡。它强烈抑制两种细胞系中的 Mcl-1 表达并诱导 Puma 表达，同时在两者之间差异调节 Bim。有趣的是，NVP-BEZ235 有效地使卵巢癌细胞对 ABT-737 敏感，只要诱导 Bim 表达。此外，抑制 ERK1/2 通路恢复了 Bim 表达，并使低表达 Bim 的癌细胞对 BEZ235/ABT-737 治疗敏感。
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