Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells.
Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells.
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DOI：
10.1038/s41598-017-08649-9
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发表时间：
2017-08-14
影响因子：
4.6
通讯作者：
Richardson A
中科院分区：
文献类型：
--
作者：
Abdullah MI;Abed MN;Richardson A
只有40%的晚期卵巢癌患者的生存时间超过5年。我们之前已经证明，匹伐他汀可以诱导小鼠卵巢癌移植瘤的消退。为了评估法尼基二磷酸合成酶抑制剂或香叶醇转移酶I抑制剂是否增强卵巢癌细胞对匹伐他汀的反应，我们在一组卵巢癌细胞中评估了匹伐他汀与唑来膦酸、利塞膦酸和GGTI-2133的组合。匹伐他汀(IC50 = 0.6-14 μM)、唑来膦酸(IC50 = 21-57 μM)、利塞膦酸(IC50 >； 100 μM)或GGTI2133(IC50 >； 25 μM)均能抑制卵巢癌细胞的生长。在11个细胞株中，10个细胞株中的10个细胞株在细胞生长试验中显示出相加或协同作用，在台盼蓝排斥试验、细胞ATP或caspase 3/7、8和9试验中，匹伐他汀与唑来膦酸的联合作用也显示出相加或协同作用。匹伐他汀可降低GGT-IIβ水平和几种小GTP酶的膜定位，而唑来膦酸可增强这一作用。GGT-Iβ和GGT-IIβ的siRNA联合使用，但单独使用时不能显著增加细胞对匹伐他汀的敏感性。这些数据表明，已经在临床上使用的药物唑来膦酸与匹伐他汀联合治疗卵巢癌可能是有效的。
Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50 = 0.6–14 μM), zoledronic acid (IC50 = 21–57 μM), risedronate (IC50 > 100 μM) or GGTI-2133 (IC50 > 25 μM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer.
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DOI：
10.1158/1078-0432.ccr-14-3368
发表时间：
2015-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kobayashi Y;Kashima H;Wu RC;Jung JG;Kuan JC;Gu J;Xuan J;Sokoll L;Visvanathan K;Shih IeM;Wang TL
通讯作者：
Wang TL
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
3.5
作者：
Budman, DR;Calabro, A
通讯作者：
Calabro, A
影响因子：
2
作者：
Elsayed, Mahitab;Kobayashi, Daisuke;Shimazoe, Takao
通讯作者：
Shimazoe, Takao
DOI：
10.1007/978-1-61779-080-5_34
发表时间：
2011-01-01
期刊：
CANCER CELL CULTURE: METHODS AND PROTOCOLS, SECOND EDITION
影响因子：
--
作者：
Bijnsdorp, Irene V.;Giovannetti, Elisa;Peters, Godefridus J.
通讯作者：
Peters, Godefridus J.