title: Tamoxifen inhibits particulate-associated protein kinase C activity, and sensitises cultured human glioblastoma cells not to etoposide but to gamma-radiation and BCNU.
abstract: We investigated the potential mechanisms of tamoxifen cytotoxicity in the U-373, U-138, and U-87 human glioblastoma cell lines, namely interference with protein kinase C (PKC) activity, the oestrogen receptor, and/or the production of transforming growth factor beta 1 (TGF-beta 1). We further examined the effects of tamoxifen on the cytotoxicity exerted by gamma-radiation, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and etoposide in this cell line panel. Thus, the cells were treated for 4 days with tamoxifen, gamma-radiation, purified recombinant human TGF-beta 1 (rhTGF-beta 1), BCNU, or etoposide, either alone or at certain combinations. Cellular responses were evaluated with the sulphorhodamine B assay, as well as by multiple drug effect analysis, and related to PKC activities in particulate and cellular fractions; cellular oestrogen receptor contents; and the influence of rhTGF-beta 1 on cell growth. Tamoxifen inhibited cell proliferation as well as the phosphorylation capacity of the particulate, but not of the cytosolic fractions dose-dependently, at comparable kinetics, and at IC50 values of approximately 15 microM. At these concentrations, tamoxifen acted synergistically with gamma-radiation (4- to 6-fold) and additively with BCNU (approximately 2-fold), but did not affect etoposide cytotoxicity. The cells were negative to immunostaining for the oestrogen receptor, and rhRGF-beta 1 did not influence their growth up to 100 nm. Our data suggest that tamoxifen can sensitise cultured glioblastoma cells not to etoposide but to gamma-radiation and BCNU, possibly through interference with membrane PKC, supporting its evaluation in experimental protocols for primary malignant gliomas.
authors.affiliation: South-American Office for Anticancer Drug Development (SOAD), Hospital de Clinicas de Porto Alegre, SP, Brazil.
authors.forename: A B
authors.initials: AB
authors.lastname: da Rocha
authors.forename: D R
authors.initials: DR
authors.lastname: Mans
authors.forename: E A
authors.initials: EA
authors.lastname: Bernard
authors.forename: C
authors.initials: C
authors.lastname: Ruschel
authors.forename: A F
authors.initials: AF
authors.lastname: Logullo
authors.forename: L A
authors.initials: LA
authors.lastname: Wetmore
authors.forename: A
authors.initials: A
authors.lastname: Leyva
authors.forename: G
authors.initials: G
authors.lastname: Schwartsmann
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002330:Carmustine / Q000627:therapeutic use*; D002455:Cell Division; D004357:Drug Synergism; D005047:Etoposide / Q000627:therapeutic use*; D005720:Gamma Rays; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D007150:Immunohistochemistry; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D005047:Etoposide; D011493:Protein Kinase C; D002330:Carmustine