title: In vitro antitumor effect of sodium butyrate and zoledronic acid combined with traditional chemotherapeutic drugs: a paradigm of synergistic molecular targeting in the treatment of Ewing sarcoma.
abstract: Histone deacetylase inhibitors and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, particularly when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been systematically evaluated in Ewing sarcoma. The in vitro effects on cellular proliferation, viability and survival were investigated in two Ewing sarcoma cell lines, SK-ES-1 and RD-ES. The cell lines were treated with sodium butyrate, a histone deacetylase inhibitor and zoledronic acid, a bisphosphonate, alone, together or in combination with chemotherapeutic drugs recommended for clinical treatment of Ewing sarcoma. The data demonstrated that the combination of sodium butyrate and zoledronic acid had a synergistic cytotoxic effect at 72 h following treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between sodium butyrate or zoledronic acid and the traditional antineoplastic drugs (doxorubicin, etoposide and vincristine) demonstrated a synergistic cytotoxic effect at 72 h in SK-ES-1 and RD-ES cells, except for the combinations of sodium butyrate with vincristine and of zoledronic acid with doxorubicin, which showed only an additive effect in RD-ES cell lines as compared to each agent alone. These acute effects observed in both Ewing sarcoma cell lines were confirmed by the clonogenic assay. The present data suggest that combining histone deacetylase inhibitors and bisphosphonates with traditional chemotherapeutic drugs is a promising therapeutic strategy for the treatment of Ewing sarcoma, and provides a basis for further studies in this field.
authors: Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Michel Pinheiro
authors: MP
authors: Dos Santos
authors: Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Caroline Brunetto
authors: CB
authors: de Farias
authors: Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Rafael
authors: R
authors: Roesler
authors: Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Algemir Lunardi
authors: AL
authors: Brunetto
authors: Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Ana Lucia
authors: AL
authors: Abujamra
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D020148:Butyric Acid / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000494:pharmacology; D000077211:Zoledronic Acid
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006633:Histamine Antagonists; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles; D020148:Butyric Acid; D014750:Vincristine; D005047:Etoposide; D000077211:Zoledronic Acid; D004317:Doxorubicin