title: Valproic acid increases the in vitro effects of nitrosureas on human glioma cell lines.
abstract: Valproic acid (VPA) has been recently investigated for its anticancer properties in different tumors, including malignant gliomas. The aim of the present work was to evaluate the effects of VPA, alone or in combination with other chemotherapeutic drugs, on in vitro growth of human glioma cell lines. A172, U373, U138, U87, and SW1783 were treated with VPA alone or in combination with mitoxantrone, etoposide, or 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU). The effects of treatments on cell growth were assessed with crystal violet staining and analyzed using the combination index (CI). The percentage of apoptotic cells and the DNA content for cell cycle phases detection were also investigated by flow cytometry. Despite a certain variability, glioma cell lines were rather resistant to the drugs tested. Addition of VPA decreased the IC50 of the chemotherapeutic agents in all cell lines tested. This effect was more evident with BCNU. The synergic effect of the association of VPA and BCNU was related to an increased block of cell cycle with accumulation in S-G2/M phases of cell cycle rather than an increased programmed cell death. In our experimental model, VPA showed anticancer properties per se on human glioma cell lines and our data support the hypothesis that, if used in association with conventional chemotherapy, it might improve the effects of single chemotherapeutic agents.
authors.affiliation: Department of Clinical Investigation, Neurological National Institute Carlo Besta, Milan, Italy. eciusani@istituto-besta.it
authors.forename: Emilio
authors.initials: E
authors.lastname: Ciusani
authors.forename: Marco
authors.initials: M
authors.lastname: Balzarotti
authors.forename: Chiara
authors.initials: C
authors.lastname: Calatozzolo
authors.forename: Ugo
authors.initials: U
authors.lastname: de Grazia
authors.forename: Amerigo
authors.initials: A
authors.lastname: Boiardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Salmaggi
authors.forename: Danilo
authors.initials: D
authors.lastname: Croci
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008942:Mitoxantrone / Q000008:administration & dosage; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D014635:Valproic Acid; D005047:Etoposide; D008942:Mitoxantrone; D002330:Carmustine