title: Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels.
abstract: We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.
authors.affiliation: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Okamoto
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kawamura
authors.forename: Masato
authors.initials: M
authors.lastname: Shingyoji
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fukamachi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tada
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takiguchi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tatsumi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use*; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D016159:Tumor Suppressor Protein p53; D000077211:Zoledronic Acid; D053148:Caspase 3; D002945:Cisplatin
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