Targeted polytherapy in small cell sarcoma and its association with doxorubicin

Mol Oncol. 2014 Dec;8(8):1458-68. doi: 10.1016/j.molonc.2014.05.016. Epub 2014 Jun 10.

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.

Keywords: Cell line; Combination; Doxorubicin; Small cell sarcoma; Targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Benzoquinones / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Doxorubicin / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Lactams, Macrocyclic / pharmacology
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology
  • Sarcoma, Small Cell / drug therapy
  • Sarcoma, Small Cell / metabolism*
  • Sorafenib
  • Vorinostat

Substances

  • Benzoquinones
  • Hydroxamic Acids
  • Lactams, Macrocyclic
  • Phenylurea Compounds
  • 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
  • Niacinamide
  • Vorinostat
  • Doxorubicin
  • Sorafenib