title: Neutron activation increases activity of ruthenium-based complexes and induces cell death in glioma cells independent of p53 tumor suppressor gene.
abstract: Novel metal complexes have received great attention in the last decades due to their potential anticancer activity. Notably, ruthenium-based complexes have emerged as good alternative to the currently used platinum-based drugs for cancer therapy, providing less toxicity and side effects to patients. Glioblastoma is an aggressive and invasive type of brain tumor and despite of advances is the field of neurooncology there is no effective treatment until now. Therefore, we sought to investigate the potential antiproliferative activity of phosphine-ruthenium-based complexes on human glioblastoma cell lines. Due to its octahedral structure as opposed to the square-planar geometry of platinum(II) compounds, ruthenium(II) complexes exhibit different structure-function relationship probably acting through a different mechanism from that of cisplatin beyond their ability to bind DNA. To better improve the pharmacological activity of metal complexes we hypothesized that neutron activation of ruthenium in the complexes would allow to decrease the effective concentration of the compound needed to kill tumor cells. Herein we report on the effect of unmodified and neutron activated phosphine ruthenium II complexes on glioblastoma cell lines carrying wild-type and mutated p53 tumor suppressor gene. Induction of apoptosis/authophagy as well as generation of reactive oxygen species were determined. The phosphine ruthenium II complexes tested were highly active against glioblastoma cell lines inducing cell death both through apoptosis and autophagy in a p53 independent fashion. Neutron activation of ruthenium compounds rendered them more active than their original counterparts suggesting a new strategy to improve the antitumor activity of these compounds.
authors.affiliation: Laboratório de Genética Humana e Biologia Molecular, Unidade Acadêmica de Ciências da Saúde, Regional Jataí, Universidade Federal de Goiás, cidade Universitária-Campus Jatobá, BR 364, Km 195, n. 3800, Jataí, CEP 75801020, Brazil.
authors.forename: Aline Monezi
authors.initials: AM
authors.lastname: Montel
authors.affiliation: Centro Nacional de Desenvolvimento da Tecnologia Nuclear, CDTN, Belo Horizonte, MG, Brazil.
authors.forename: Raquel Gouvêa
authors.initials: RG
authors.lastname: Dos Santos
authors.affiliation: Centro Nacional de Desenvolvimento da Tecnologia Nuclear, CDTN, Belo Horizonte, MG, Brazil.
authors.forename: Pryscila Rodrigues
authors.initials: PR
authors.lastname: da Costa
authors.affiliation: Laboratório de Genética Molecular e Citogenética, Instituto de Ciências Biológicas, Universidade Federal de Goiás - UFG, Goiânia, GO, Brazil.
authors.forename: Elisângela de Paula
authors.initials: EP
authors.lastname: Silveira-Lacerda
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, Brazil.
authors.forename: Alzir Azevedo
authors.initials: AA
authors.lastname: Batista
authors.affiliation: Laboratório de Genética Humana e Biologia Molecular, Unidade Acadêmica de Ciências da Saúde, Regional Jataí, Universidade Federal de Goiás, cidade Universitária-Campus Jatobá, BR 364, Km 195, n. 3800, Jataí, CEP 75801020, Brazil. wagbrpt@hotmail.com.
authors.forename: Wagner Gouvêa
authors.initials: WG
authors.lastname: Dos Santos
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000528:radiation effects; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000494:pharmacology* / Q000528:radiation effects; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009502:Neutrons; D010720:Phosphines / Q000494:pharmacology* / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D017975:Ruthenium Compounds / Q000494:pharmacology* / Q000528:radiation effects; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D010720:Phosphines; D017382:Reactive Oxygen Species; D017975:Ruthenium Compounds; D016159:Tumor Suppressor Protein p53
keywords: Brain tumor; Glioblastoma; Metal complex; Radiotherapy; Ruthenium(II)