Identification and validation of compounds selectively killing resistant cancer: Delineating cell line-specific effects from P-Glycoprotein-induced toxicity

András Furedi, Szilard Toth, Kornelia Szebenyi, Veronika F S Pape, Dóora Tüurk, Nora Kucsma, Lászlóo Cervenak, Jóozsef Tovari, G. Szakács

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgpdependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1<<enty>sup-/-/enty>sup>;;p53<<enty>sup-/-/enty>sup>; spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer.

Original languageEnglish
Pages (from-to)45-56
Number of pages12
JournalMolecular Cancer Therapeutics
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

Fingerprint

P-Glycoprotein
Oxyquinoline
Cell Line
Neoplasms
National Cancer Institute (U.S.)
Poisons
Pharmaceutical Preparations
Doxorubicin
Breast Neoplasms
Technology
Phenotype
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Identification and validation of compounds selectively killing resistant cancer : Delineating cell line-specific effects from P-Glycoprotein-induced toxicity. / Furedi, András; Toth, Szilard; Szebenyi, Kornelia; Pape, Veronika F S; Tüurk, Dóora; Kucsma, Nora; Cervenak, Lászlóo; Tovari, Jóozsef; Szakács, G.

In: Molecular Cancer Therapeutics, Vol. 16, No. 1, 01.01.2017, p. 45-56.

Research output: Contribution to journalArticle

Furedi, András ; Toth, Szilard ; Szebenyi, Kornelia ; Pape, Veronika F S ; Tüurk, Dóora ; Kucsma, Nora ; Cervenak, Lászlóo ; Tovari, Jóozsef ; Szakács, G. / Identification and validation of compounds selectively killing resistant cancer : Delineating cell line-specific effects from P-Glycoprotein-induced toxicity. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 1. pp. 45-56.
@article{d58d6053e66a4eec876d395cd71756b8,
title = "Identification and validation of compounds selectively killing resistant cancer: Delineating cell line-specific effects from P-Glycoprotein-induced toxicity",
abstract = "Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgpdependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1<sup-/-/enty>sup>;;p53<sup-/-/enty>sup>; spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer.",
author = "Andr{\'a}s Furedi and Szilard Toth and Kornelia Szebenyi and Pape, {Veronika F S} and D{\'o}ora T{\"u}urk and Nora Kucsma and L{\'a}szl{\'o}o Cervenak and J{\'o}ozsef Tovari and G. Szak{\'a}cs",
year = "2017",
month = "1",
day = "1",
doi = "10.1158/1535-7163.MCT-16-0333-T",
language = "English",
volume = "16",
pages = "45--56",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Identification and validation of compounds selectively killing resistant cancer

T2 - Delineating cell line-specific effects from P-Glycoprotein-induced toxicity

AU - Furedi, András

AU - Toth, Szilard

AU - Szebenyi, Kornelia

AU - Pape, Veronika F S

AU - Tüurk, Dóora

AU - Kucsma, Nora

AU - Cervenak, Lászlóo

AU - Tovari, Jóozsef

AU - Szakács, G.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgpdependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1<sup-/-/enty>sup>;;p53<sup-/-/enty>sup>; spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer.

AB - Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgpdependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1<sup-/-/enty>sup>;;p53<sup-/-/enty>sup>; spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer.

UR - http://www.scopus.com/inward/record.url?scp=85009968380&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009968380&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-16-0333-T

DO - 10.1158/1535-7163.MCT-16-0333-T

M3 - Article

C2 - 27760838

AN - SCOPUS:85009968380

VL - 16

SP - 45

EP - 56

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 1

ER -