title: Inhibition of nuclear factor-κB by dehydroxymethylepoxyquinomicin induces schedule-dependent chemosensitivity to anticancer drugs and enhances chemoinduced apoptosis in osteosarcoma cells.
abstract: Osteosarcoma (OS) is the most common primary malignant bone tumor, usually developing in children and adolescents, and is highly invasive and metastatic, potentially developing chemoresistance. Thus, novel effective treatment regimens are urgently needed. This study was the first to investigate the anticancer effects of dehydroxymethylepoxyquinomicin (DHMEQ), a highly specific nuclear factor-κB (NF-κB) inhibitor, on the OS cell lines HOS and MG-63. We demonstrate that NF-κB blockade by DHMEQ inhibits proliferation, decreases the mitotic index, and triggers apoptosis of OS cells. We examined the effects of combination treatment with DHMEQ and cisplatin, doxorubicin, or methotrexate, drugs commonly used in OS treatment. Using the median effect method of Chou and Talalay, we evaluated the combination indices for simultaneous and sequential treatment schedules. In all cases, combination with a chemotherapeutic drug produced a synergistic effect, even at low single-agent cytotoxic levels. When cells were treated with DHMEQ and cisplatin, a more synergistic effect was obtained using simultaneous treatment. For the doxorubicin and methotrexate combination, a more synergistic effect was achieved with sequential treatment using DHMEQ before chemotherapy. These synergistic effects were accompanied by enhancement of chemoinduced apoptosis. Interestingly, the highest apoptotic effect was reached with sequential exposure in both cell lines, independent of the chemotherapeutic agent used. Likewise, DHMEQ decreased cell invasion and migration, crucial steps for tumor progression. Our data suggest that combining DHMEQ with chemotherapeutic drugs might be useful for planning new therapeutic strategies for OS treatment, mainly in resistant and metastatic cases.
authors.affiliation: Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil. amcgen@gmail.com
authors.forename: Angel Mauricio
authors.initials: AM
authors.lastname: Castro-Gamero
authors.forename: Kleiton Silva
authors.initials: KS
authors.lastname: Borges
authors.forename: Vanessa
authors.initials: V
authors.lastname: da Silva Silveira
authors.forename: Regia Caroline Peixoto
authors.initials: RC
authors.lastname: Lira
authors.forename: Rosane
authors.initials: R
authors.lastname: de Paula Gomes Queiroz
authors.forename: Fabiana Cardoso Pereira
authors.initials: FC
authors.lastname: Valera
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Scrideli
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: Tone
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003512:Cyclohexanones / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D008940:Mitotic Index; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate