Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib
Benchmarking effects of mTOR, PI3K, and dual PI3K/mTOR inhibitors in hepatocellular and renal cell carcinoma models developing resistance to sunitinib and sorafenib
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DOI：
10.1007/s00280-013-2129-6
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发表时间：
2013-05-01
影响因子：
3
通讯作者：
Raymond, Eric
中科院分区：
文献类型：
--
作者：
Serova, Maria;de Gramont, Armand;Raymond, Eric
评估第一代雷帕霉素类似物（依维莫司、替西莫司和雷帕霉素）和第二代抑制mTOR激酶（AZD-8055）、PI3K （BKM-120）或两者（BEZ-235和GDC-0980）在肝细胞癌（HCC）和肾癌（RCC）细胞中对索拉非尼或舒尼替尼获得性耐药的疗效。在人肝癌SK-HEP1、RCC 786-0、索拉非尼（SK-Sora）或舒尼替尼耐药（786-Suni）细胞中，评估雷帕霉素类似物（1-20 μ M）和第二代药物（0.03-20.0 μ M）的抗增殖（MTT法）和细胞信号传导（Western blot）作用。在PTEN和Bcl2高表达的SK-HEP1细胞中，雷帕霉素类似物的抗增殖作用较差。然而，SK-Sora细胞比SK-HEP1细胞对雷帕霉素类似物更敏感（a parts per thousand yen1 mu M）。在缺乏PTEN和Bcl2表达的786-0细胞中，千分之一μ M雷帕霉素类似物阻断mTORC1信号传导，短暂激活Akt，抑制细胞增殖。786-Suni细胞长期暴露于舒尼替尼后，p27表达增加，对雷帕霉素类似物的敏感性降低，尽管雷帕霉素类似物可以抑制mTORC1功能。第二代药物对亲代细胞、SK-Sora和786-Suni细胞的生长抑制作用比雷帕霉素类似物更强。这些新药的生长抑制浓度也阻断了mTORC1的下游靶点。雷帕霉素类似物抑制mTORC1下游靶点，并在HCC和RCC细胞中产生抗增殖作用。第二代药物似乎也是mTORC1信号传导的有效抑制剂；然而，它们似乎在抑制亲代HCC和RCC细胞的细胞增殖以及对索拉非尼或舒尼替尼产生耐药性的细胞中更有效。
To evaluate first-generation rapamycin analogs (everolimus, temsirolimus, and rapamycin) and second-generation drugs inhibiting mTOR kinase (AZD-8055), PI3K (BKM-120) or both (BEZ-235 and GDC-0980) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) cells characterized for acquired resistance to sorafenib or sunitinib.Anti-proliferative (MTT assay) and cell signaling (Western blot) effects of rapamycin analogs (1-20 mu M) and second-generation drugs (0.03-20.0 mu M) were assessed in human HCC SK-HEP1, RCC 786-0, and sorafenib- (SK-Sora) or sunitinib-resistant (786-Suni) cells.In SK-HEP1 cells displaying high PTEN and Bcl2 expression, rapamycin analogs had poor anti-proliferative effects. However, SK-Sora cells were more sensitive to rapamycin analogs (a parts per thousand yen1 mu M) than SK-HEP1 cells. In 786-0 cells, lacking PTEN and Bcl2 expression, a parts per thousand yen1 mu M rapamycin analogs blocked mTORC1 signaling, transiently activated Akt, and inhibited cell proliferation. Protracted sunitinib exposure in 786-Suni cells yielded an increase in p27 expression and a decreased sensitivity to rapamycin analogs, although mTORC1 function could be inhibited with rapamycin analogs. Second-generation drugs induced more potent growth inhibition than rapamycin analogs at concentrations > 0.03 mu M in parental cells, SK-Sora, and 786-Suni cells. Growth inhibitory concentrations of these new drugs also blocked mTORC1 downstream targets.Rapamycin analogs inhibited mTORC1 downstream targets and yielded anti-proliferative effects in HCC and RCC cells. Second-generation drugs also appeared to be potent inhibitors of mTORC1 signaling; however, they appeared to be far more potent in inhibiting cellular proliferation in parental HCC and RCC cells and in cells developing resistance to sorafenib or sunitinib.