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- Title
Augmentation of the cytotoxic effects of nitrogen‐containing bisphosphonates in hypoxia.
- Authors
Minegaki, Tetsuya; Koiki, Saya; Douke, Yutaro; Yamane, Chihiro; Suzuki, Ai; Mori, Misato; Tsujimoto, Masayuki; Nishiguchi, Kohshi
- Abstract
Abstract: Objectives: Tumour 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. Methods: We studied the cytotoxicities of N‐BPs, statins and anticancer drugs in human cancer cells under hypoxic conditions (1% O2). 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 findings: In 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. Conclusions: The 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.
- Subjects
CANCER treatment; PROGNOSIS; HYPOXEMIA; TREATMENT of bone diseases; POLYMERASE chain reaction
- Publication
Journal of Pharmacy & Pharmacology, 2018, Vol 70, Issue 8, p1040
- ISSN
0022-3573
- Publication type
Article
- DOI
10.1111/jphp.12934