title: Targeted polytherapy in small cell sarcoma and its association with doxorubicin.
abstract: A paradigm shift has occurred in the last decade from chemotherapy to targeted therapy for the management of many patients with advanced sarcoma. This work identifies a combination of targeted agents and doxorubicin that are effective against small cell sarcoma cell lines. Three small cell sarcoma cell lines were studied: RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma). Each cell line was exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (HSP90 inhibitor), abacavir (anti-telomerase) or sorafenib (tyrosine kinase inhibitor) alone, combined with one another, or combined with doxorubicin. Cell viability, cell cycle analysis and apoptosis were assessed by MTS assay, propidium iodide-Annexin V staining, and caspase 3/7 activity, respectively. The Chou and Talalay combination index (CI) was used to determine whether the effects were additive (CI = 1), synergistic (CI < 1) or antagonistic (CI > 1). In monotherapy, targeted agents achieved 30-90% reductions in viability, with the exception of abacavir. Dual-targeted combination therapies with vorinostat, sorafenib and 17-DMAG demonstrated synergy. Abacavir was antagonistic with every other drug and was not further studied. Both vorinostat and 17-DMAG synergized with doxorubicin, achieving 60% cell killing compared to 12% with doxorubicin alone. No synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17-DMAG and doxorubicin did not show synergy, but increased the subG1 population at 24H, from 30% to 70% compared to monotherapies with an increase in apoptosis. This work provides evidence of synergy of combinations of vorinostat, 17-DMAG and sorafenib in small cell sarcoma. In addition to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations.
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA; Medical Oncology Department, Saint-Antoine Hospital, Public Assistance of Paris Hospitals, Pierre and Marie Curie University, Paris VI, Paris, France.
authors.forename: S N
authors.initials: SN
authors.lastname: Dumont
authors.affiliation: University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Dumont
authors.affiliation: University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Reynoso
authors.affiliation: Claude Bernard Lyon I University, Centre Léon Bérard, Lyon, France.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Blay
authors.affiliation: University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA. Electronic address: sarahndumont@yahoo.fr.
authors.forename: J C
authors.initials: JC
authors.lastname: Trent
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D018228:Sarcoma, Small Cell / Q000188:drug therapy / Q000378:metabolism*; D000077157:Sorafenib; D000077337:Vorinostat
chemical_list: D016227:Benzoquinones; D006877:Hydroxamic Acids; D047029:Lactams, Macrocyclic; D010671:Phenylurea Compounds; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D009536:Niacinamide; D000077337:Vorinostat; D004317:Doxorubicin; D000077157:Sorafenib
keywords: Cell line; Combination; Doxorubicin; Small cell sarcoma; Targeted therapy