Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An in Vitro Study
| Autor: | Daisuke Kobayashi, Naoya Matsunaga, Yuko Yoshizawa, Shigehiro Ohdo, Yuya Tsurudome, Toshio Kubota, Mahitab Elsayed, Takao Shimazoe, Natsuki Watanabe, Tohru Matsuura, Takashi Ogino, Ryusei Murata |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pharmacology RHOA biology Geranylgeranyl pyrophosphate Chemistry Cell growth Farnesyl pyrophosphate Pharmaceutical Science General Medicine Mevalonic acid 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Geranylgeranylation 030220 oncology & carcinogenesis biology.protein medicine Cancer research Mevalonate pathway Fluvastatin medicine.drug |
| Zdroj: | Biological & Pharmaceutical Bulletin. 39:1238-1246 |
| ISSN: | 1347-5215 0918-6158 |
| Popis: | Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay. In this study, we demonstrated a potent synergistic antiproliferative effect of both drugs when used in combination in both cell lines. Moreover, we studied the molecular mechanism behind this synergistic effect, which was inhibited by the addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the effect of ZOL and FLU combination on RhoA and Ras guanosine 5'-triphosphate (GTP)-proteins. The combination induced a marked accumulation in RhoA and unprenylated Ras. GGPP and FPP reversed the increase in the amount of both proteins. These results indicated that the combination treatment impaired RhoA and Ras signaling pathway by the inhibition of geranylgeranylation and/or farnesylation. This study provides a potentially effective approach for the treatment of pancreatic cancer using a combination treatment of ZOL and FLU. |
| Databáze: | OpenAIRE |
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