Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma.
Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma.
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DOI：
10.1158/1078-0432.ccr-10-2289
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发表时间：
2011-04-15
期刊：
影响因子：
--
通讯作者：
Dorigo O
中科院分区：
文献类型：
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作者：
Santiskulvong C;Konecny GE;Fekete M;Chen KY;Karam A;Mulholland D;Eng C;Wu H;Song M;Dorigo O
该研究评估了在卵巢癌的临床前模型中使用NVP-BEZ 235作为潜在的新型治疗策略的双重PI 3 K和mTOR抑制的效果。通过免疫印迹证明NVP-BEZ 235对PI 3 K/Akt/mTOR信号传导的抑制。在18个卵巢癌细胞系中评估了对细胞增殖的影响，包括4对同基因顺铂敏感和顺铂耐药细胞系。使用免疫活性转基因鼠卵巢癌模型（LSL-K-rasG 12 D/+PtenloxP/loxP）评价NVP-BEZ 235对已建立的肿瘤生长的体内作用。NVP-BEZ 235降低了所有测定的卵巢癌细胞系中的细胞增殖，并使顺铂耐药细胞对顺铂的细胞毒性作用敏感。具有PI 3 K激活突变或Pten缺失的细胞系比没有这些突变的细胞系对NVP-BEZ 235的作用显著更敏感（p < 0.05）。在p4 E-BP 1的相对水平和NVP-BEZ 235的IC 50之间发现了统计学显著相关性。在具有已建立的腹膜内肿瘤疾病的LSL-K-rasG 12 D/+PtenloxP/loxP小鼠中，口服给予NVP-BEZ 235降低了肿瘤组织中的pAkt、p4 E-BP 1和Ki 67，并且与对照动物相比导致显著更长的存活期（p < 0.05）。NVP-BEZ 235还诱导细胞周期停滞、半胱天冬酶3活性和减少细胞迁移。使用NVP-BEZ 235同时靶向PI 3 K和mTOR有效抑制卵巢癌细胞生长，即使在存在铂抗性的情况下也是如此，并且具有腹腔内卵巢肿瘤疾病的小鼠的存活率很低。我们提出，使用NVP-BEZ 235双重抑制PI 3 K和mTOR可能是卵巢癌患者的有效新治疗方法。
This study evaluates the effect of dual PI3K and mTOR inhibition using NVP-BEZ235 in preclinical models of ovarian cancer as a potential novel therapeutic strategy. Inhibition of PI3K/Akt/mTOR signaling by NVP-BEZ235 was demonstrated by immunoblotting. The effect on cell proliferation was assessed in eighteen ovarian cancer cell lines, including four pairs of syngeneic cisplatin-sensitive and cisplatin-resistant cell lines. The in vivo effects of NVP-BEZ235 on established tumor growth were evaluated using an immunocompetent, transgenic murine ovarian cancer model (LSL-K-rasG12D/+PtenloxP/loxP). NVP-BEZ235 decreased cell proliferation in all ovarian cancer cell lines assayed and sensitized cisplatin-resistant cells to the cytotoxic effects of cisplatin. Cell lines with PI3K activating mutations or Pten deletions were significantly more sensitive to the effect of NVP-BEZ235 than cell lines without these mutations (p < 0.05). A statistically significant correlation was found between relative levels of p4E-BP1 and the IC50 for NVP-BEZ235. In LSL-K-rasG12D/+PtenloxP/loxP mice with established intraperitoneal tumor disease, oral administration of NVP-BEZ235 decreased pAkt, p4E-BP1 and Ki67 in tumor tissue, and resulted in significantly longer survival compared to control animals (p < 0.05). NVP-BEZ235 also induced cell cycle arrest, caspase 3 activity, and reduced cell migration. Targeting PI3K and mTOR simultaneously using NVP-BEZ235 effectively inhibits ovarian cancer cell growth even in the presence of platinum resistance and prolongs survival of mice with intra-abdominal ovarian tumor disease. We propose that dual PI3K and mTOR inhibition using NVP-BEZ235 may be an effective novel therapeutic approach in patients with ovarian cancer.