Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia

作者：Minegaki Tetsuya^*; Koiki Saya; Douke Yutaro; Yamane Chihiro; Suzuki Ai; Mori Misato; Tsujimoto Masayuki; Nishiguchi Kohshi

来源：Journal of Pharmacy and Pharmacology, 2018, 70(8): 1040-1047.

DOI：10.1111/jphp.12934

• bisphosphonate
• hypoxia
• mevalonate pathway

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.

• 出版日期2018-8