Targeted polytherapy in small cell sarcoma and its association with doxorubicin

S. N. Dumont, D. Yang, A. G. Dumont, David Reynoso, J. Y. Blay, J. C. Trent

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1458-1468
Number of pages11
JournalMolecular Oncology
Volume8
Issue number8
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

Fingerprint

Small Cell Sarcoma
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Doxorubicin
Cell Line
Sarcoma
A 204
Apoptosis
Caspase 7
Ewing's Sarcoma
Histone Deacetylase Inhibitors
Rhabdomyosarcoma
Propidium
Annexin A5
Telomerase
Caspase 3
Protein-Tyrosine Kinases
Cell Survival
Cell Cycle
Therapeutics
vorinostat

Keywords

  • Cell line
  • Combination
  • Doxorubicin
  • Small cell sarcoma
  • Targeted therapy

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Targeted polytherapy in small cell sarcoma and its association with doxorubicin. / Dumont, S. N.; Yang, D.; Dumont, A. G.; Reynoso, David; Blay, J. Y.; Trent, J. C.

In: Molecular Oncology, Vol. 8, No. 8, 01.12.2014, p. 1458-1468.

Research output: Contribution to journalArticle

Dumont, S. N. ; Yang, D. ; Dumont, A. G. ; Reynoso, David ; Blay, J. Y. ; Trent, J. C. / Targeted polytherapy in small cell sarcoma and its association with doxorubicin. In: Molecular Oncology. 2014 ; Vol. 8, No. 8. pp. 1458-1468.
@article{1d3bc1515d1e4713b4a9ea44bd305cf3,
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.",
keywords = "Cell line, Combination, Doxorubicin, Small cell sarcoma, Targeted therapy",
author = "Dumont, {S. N.} and D. Yang and Dumont, {A. G.} and David Reynoso and Blay, {J. Y.} and Trent, {J. C.}",
year = "2014",
month = "12",
day = "1",
doi = "10.1016/j.molonc.2014.05.016",
language = "English (US)",
volume = "8",
pages = "1458--1468",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",
number = "8",

}

TY - JOUR

T1 - Targeted polytherapy in small cell sarcoma and its association with doxorubicin

AU - Dumont, S. N.

AU - Yang, D.

AU - Dumont, A. G.

AU - Reynoso, David

AU - Blay, J. Y.

AU - Trent, J. C.

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

KW - Cell line

KW - Combination

KW - Doxorubicin

KW - Small cell sarcoma

KW - Targeted therapy

UR - http://www.scopus.com/inward/record.url?scp=84911967880&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911967880&partnerID=8YFLogxK

U2 - 10.1016/j.molonc.2014.05.016

DO - 10.1016/j.molonc.2014.05.016

M3 - Article

VL - 8

SP - 1458

EP - 1468

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 8

ER -