title: Synergistic antitumor effect of ionomycin and cisplatin against renal cell carcinoma in vitro and in vivo.
abstract: Objectives. To characterize the synergistic antitumor effects of the calcium ionophore, ionomycin, and of cisplatin against human renal cell carcinoma cell line, ACHN, both in vitro and in vivo.Methods. The in vitro growth rate of ACHN after exposure to these compounds was measured, using the MTT assay. The apoptotic features in ACHN were evaluated by DNA ladder analysis and flow cytometric analysis. Bcl-2 and Bax expression levels in ACHN after treatment were examined by Western blot. The synergistic antitumor effects of ionomycin and cisplatin against the growth of established ACHN tumors in athymic nude mice were then tested.Results. The in vitro growth rate of ACHN was suppressed more by ionomycin and cisplatin in combination than by either alone. DNA ladder and fragmentation were more obvious when the cells were incubated with ionomycin and cisplatin together than with either reagent alone. Ionomycin treatment increased the expression level of Bax protein, whereas Bcl-2 expression was not influenced. Although an intraperitoneal injection of cisplatin or an intratumoral injection of ionomycin against subcutaneous ACHN tumors somewhat reduced tumorigenicity in nude mice, the effect was significantly enhanced by a combination of these drugs.Conclusions. The synergistic antitumor effects suggest that ionomycin-based therapy could be a novel therapeutic strategy with which to treat advanced renal cell carcinoma.
authors.affiliation: Department of Urology, Kobe University School of Medicine, Kobe, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: I
authors.initials: I
authors.lastname: Hara
authors.forename: H
authors.initials: H
authors.lastname: Miyake
authors.forename: S
authors.initials: S
authors.lastname: Hara
authors.forename: A
authors.initials: A
authors.lastname: Gotoh
authors.forename: S
authors.initials: S
authors.lastname: Arakawa
authors.forename: S
authors.initials: S
authors.lastname: Kamidono
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D015759:Ionomycin / Q000627:therapeutic use*; D007476:Ionophores / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; C494827:Bax protein, mouse; D007476:Ionophores; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D015759:Ionomycin; D002945:Cisplatin