Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia
Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia
复制标题
DOI：
10.1111/jphp.12934
复制
发表时间：
2018-08-01
影响因子：
3.3
通讯作者：
Nishiguchi, Kohshi
中科院分区：
文献类型：
--
作者：
Minegaki, Tetsuya;Koiki, Saya;Nishiguchi, Kohshi
目的肿瘤缺氧是癌症治疗的主要障碍，导致预后不良。因此，开发在缺氧中有效的癌症治疗是必要的。含氮双膦酸盐（N-BPs），用于治疗骨疾病，在常氧条件下对几种癌细胞具有细胞毒性。因此，我们研究了N-BPs在癌细胞中的细胞毒性在hypoxia.MethodsWe研究了N-BPs，他汀类药物和抗癌药物在人类癌细胞在低氧条件下（1%O-2）的细胞毒性。通过实时逆转录聚合酶链反应和Western blotting.Key findingsIn缺氧，5-氟尿嘧啶和顺铂的细胞生长抑制在缺氧中的甲羟戊酸途径中的酶的表达水平进行了测量相比，在常氧，但细胞生长抑制N-BP和通过唑来膦酸诱导的凋亡是在缺氧中高于常氧。此外，香叶基香叶醇完全抑制唑来膦酸盐的生长抑制作用。此外，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的mRNA和蛋白水平在缺氧中显着降低。此外，辛伐他汀增强zoledronate.ConclusionsThe N-BPs的细胞毒性，而不是5-氟尿嘧啶和顺铂的生长抑制作用，是增强缺氧，通过HMG-CoA还原酶功能的损失。N-BPs在常氧和低氧条件下均能有效抗癌。
ObjectivesTumour hypoxia is a major obstacle in cancer therapy that leads to poor prognosis. Therefore, the development of cancer treatments that are effective in hypoxia is necessary. Nitrogen-containing bisphosphonates (N-BPs), which are used to treat bone disease, are cytotoxic to several cancer cells in normoxia. Therefore, we investigated the cytotoxicity of N-BPs in cancer cells in hypoxia.MethodsWe studied the cytotoxicities of N-BPs, statins and anticancer drugs in human cancer cells under hypoxic conditions (1% O-2). The expression levels of enzymes in the mevalonate pathway in hypoxia were measured by real-time reverse transcription polymerase chain reaction and Western blotting.Key findingsIn hypoxia, cell growth inhibition by 5-fluorouracil and cisplatin was not changed as compared to that in normoxia; however, cell growth inhibition by N-BPs and via zoledronate-induced apoptosis was higher in hypoxia than that in normoxia. Furthermore, geranylgeraniol completely inhibited the growth inhibitory effects of zoledronate. Additionally, the mRNA and protein levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase significantly decreased in hypoxia. Moreover, simvastatin potentiated the growth inhibitory effect of zoledronate.ConclusionsThe cytotoxicity of N-BPs, but not 5-fluorouracil and cisplatin, is potentiated in hypoxia, through the loss of HMG-CoA reductase function. N-BPs may be effective against cancer in normoxia and hypoxia.