title: Effects of bisphosphonates on human esophageal squamous cell carcinoma cell survival.
abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers in Japan. Anticancer chemotherapy has been useful for ESCC treatment. However, therapeutic options are limited. Recently, bisphosphonates (BPs), which are osteoporosis drugs, have shown anticancer effects in several cancer cell lines, but the effects against ESCC cell lines are unknown. In this study, we examined the cytotoxic effects of BPs and their mechanisms of cytotoxicity in human ESCC cell lines. A first-generation BP (etidronate), two second-generation BPs (alendronate and pamidronate), and two third-generation BPs (risedronate and zoledronate) were used in this study. All BPs, except etidronate, were cytotoxic, as indicated by increased caspase-3/7 activity and numbers of Annexin-fluorescein isothiocyanate positive cells in ESCC cell lines. From cell cycle analysis, G0/G1-phase arrest was observed upon treatment with second- and third-generation BPs. In addition, Cyclin D1 protein expression levels were decreased by second- and third-generation BP treatment. Although squalene and trans, trans-farnesol minimally affected BP cytotoxicity, treatment with geranylgeraniol inhibited BP cytotoxicity almost completely. We concluded that second- and third-generation BPs are cytotoxic to ESCC cell lines as they induce apoptosis and inhibit the cell cycle through mevalonate pathway inhibition. Therefore, BP treatment may be a beneficial therapy in ESCC patients.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Minegaki
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Morioka
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Takanashi
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Uno
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsujimoto
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishiguchi
mesh_terms: D017302:Annexins / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D053179:Caspase 7 / Q000187:drug effects / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004938:Esophageal Neoplasms / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005204:Farnesol / Q000494:pharmacology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D013185:Squalene / Q000494:pharmacology
chemical_list: D017302:Annexins; D050071:Bone Density Conservation Agents; C530104:CCND1 protein, human; D004164:Diphosphonates; D004224:Diterpenes; D019938:Cyclin D1; D005204:Farnesol; D013185:Squalene; C017338:geranylgeraniol; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7
keywords: bisphosphonate; esophageal cancer; mevalonate pathway