title: Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An in Vitro Study.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of Pharmaceutical Sciences, Kyushu University.
authors.forename: Mahitab
authors.initials: M
authors.lastname: Elsayed
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Toshio
authors.initials: T
authors.lastname: Kubota
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.forename: Ryusei
authors.initials: R
authors.lastname: Murata
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshizawa
authors.forename: Natsuki
authors.initials: N
authors.lastname: Watanabe
authors.forename: Tohru
authors.initials: T
authors.lastname: Matsuura
authors.forename: Yuya
authors.initials: Y
authors.lastname: Tsurudome
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogino
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.forename: Takao
authors.initials: T
authors.lastname: Shimazoe
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D004164:Diphosphonates; D005229:Fatty Acids, Monounsaturated; D007093:Imidazoles; D007211:Indoles; D011106:Polyisoprenyl Phosphates; C066737:RHOA protein, human; D000077340:Fluvastatin; D000077211:Zoledronic Acid; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid