The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1

R. Abdul-Ghani, V. Serra, B. Györffy, K. Jürchott, A. Solf, M. Dietel, R. Schäfer

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Multidrug resistance may be achieved by the activation of membrane transporters, detoxification, alterations in DNA repair or failure in apoptotic pathways. Recent data have suggested an involvement of mitogenic signalling pathways mediated by Ras and phosphoinositol-3-kinase (PI3K/Akt) in controlling multidrug resistance. Since these pathways are important targets for therapeutic interference, we sought to investigate whether blocking effectors kinases by specific inhibitors would result in a sensitization toward cytotoxic drugs. We found that cotreatment of drug-resistant HT29RDB colon cancer cells with the topoisomerase inhibitor doxorubicin and the PI3K-inhibitor LY294002 resulted in massive apoptosis, while cotreatment with the Mek inhibitors PD98059 or U0126 had no effect. This suggested that the PI3K-pathways controls cell survival and drug resistance in these cells. Besides blocking Akt phosphorylation, the PI3K-inibitor increased the intracellular doxorubicin concentration threefold. LY294002 inhibits drug export in a competitive manner as revealed by measuring drug efflux in the presence and the absence of inhibitor. The efficacy of drug efflux inhibition by LY294002 was similar to that achieved by the MRP1 inhibitors MK571 and genistein. We conclude that the PI3K inhibitor LY294002 may have therapeutic potential when combined with doxorubicin in the treatment of MRP1-mediated drug resistance.

Original languageEnglish
Pages (from-to)1743-1752
Number of pages10
JournalOncogene
Volume25
Issue number12
DOIs
Publication statusPublished - Mar 16 2006

Fingerprint

2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Phosphatidylinositol 3-Kinases
Colon
Carcinoma
Doxorubicin
Pharmaceutical Preparations
Multiple Drug Resistance
Drug Resistance
Phosphotransferases
Topoisomerase Inhibitors
Membrane Transport Proteins
Genistein
DNA Repair
Colonic Neoplasms
Cell Survival
Phosphorylation
Apoptosis
Therapeutics

Keywords

  • Colon cancer
  • Doxorubicin
  • LY294002
  • Multi-drug resistance-associated protein MRP1
  • Phosphoinositol 3-kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Abdul-Ghani, R., Serra, V., Györffy, B., Jürchott, K., Solf, A., Dietel, M., & Schäfer, R. (2006). The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1. Oncogene, 25(12), 1743-1752. https://doi.org/10.1038/sj.onc.1209201

The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1. / Abdul-Ghani, R.; Serra, V.; Györffy, B.; Jürchott, K.; Solf, A.; Dietel, M.; Schäfer, R.

In: Oncogene, Vol. 25, No. 12, 16.03.2006, p. 1743-1752.

Research output: Contribution to journalArticle

Abdul-Ghani, R, Serra, V, Györffy, B, Jürchott, K, Solf, A, Dietel, M & Schäfer, R 2006, 'The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1', Oncogene, vol. 25, no. 12, pp. 1743-1752. https://doi.org/10.1038/sj.onc.1209201
Abdul-Ghani, R. ; Serra, V. ; Györffy, B. ; Jürchott, K. ; Solf, A. ; Dietel, M. ; Schäfer, R. / The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1. In: Oncogene. 2006 ; Vol. 25, No. 12. pp. 1743-1752.
@article{d1a0f73672fc44359918d0d5b4ea2c73,
title = "The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1",
abstract = "Multidrug resistance may be achieved by the activation of membrane transporters, detoxification, alterations in DNA repair or failure in apoptotic pathways. Recent data have suggested an involvement of mitogenic signalling pathways mediated by Ras and phosphoinositol-3-kinase (PI3K/Akt) in controlling multidrug resistance. Since these pathways are important targets for therapeutic interference, we sought to investigate whether blocking effectors kinases by specific inhibitors would result in a sensitization toward cytotoxic drugs. We found that cotreatment of drug-resistant HT29RDB colon cancer cells with the topoisomerase inhibitor doxorubicin and the PI3K-inhibitor LY294002 resulted in massive apoptosis, while cotreatment with the Mek inhibitors PD98059 or U0126 had no effect. This suggested that the PI3K-pathways controls cell survival and drug resistance in these cells. Besides blocking Akt phosphorylation, the PI3K-inibitor increased the intracellular doxorubicin concentration threefold. LY294002 inhibits drug export in a competitive manner as revealed by measuring drug efflux in the presence and the absence of inhibitor. The efficacy of drug efflux inhibition by LY294002 was similar to that achieved by the MRP1 inhibitors MK571 and genistein. We conclude that the PI3K inhibitor LY294002 may have therapeutic potential when combined with doxorubicin in the treatment of MRP1-mediated drug resistance.",
keywords = "Colon cancer, Doxorubicin, LY294002, Multi-drug resistance-associated protein MRP1, Phosphoinositol 3-kinase",
author = "R. Abdul-Ghani and V. Serra and B. Gy{\"o}rffy and K. J{\"u}rchott and A. Solf and M. Dietel and R. Sch{\"a}fer",
year = "2006",
month = "3",
day = "16",
doi = "10.1038/sj.onc.1209201",
language = "English",
volume = "25",
pages = "1743--1752",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1

AU - Abdul-Ghani, R.

AU - Serra, V.

AU - Györffy, B.

AU - Jürchott, K.

AU - Solf, A.

AU - Dietel, M.

AU - Schäfer, R.

PY - 2006/3/16

Y1 - 2006/3/16

N2 - Multidrug resistance may be achieved by the activation of membrane transporters, detoxification, alterations in DNA repair or failure in apoptotic pathways. Recent data have suggested an involvement of mitogenic signalling pathways mediated by Ras and phosphoinositol-3-kinase (PI3K/Akt) in controlling multidrug resistance. Since these pathways are important targets for therapeutic interference, we sought to investigate whether blocking effectors kinases by specific inhibitors would result in a sensitization toward cytotoxic drugs. We found that cotreatment of drug-resistant HT29RDB colon cancer cells with the topoisomerase inhibitor doxorubicin and the PI3K-inhibitor LY294002 resulted in massive apoptosis, while cotreatment with the Mek inhibitors PD98059 or U0126 had no effect. This suggested that the PI3K-pathways controls cell survival and drug resistance in these cells. Besides blocking Akt phosphorylation, the PI3K-inibitor increased the intracellular doxorubicin concentration threefold. LY294002 inhibits drug export in a competitive manner as revealed by measuring drug efflux in the presence and the absence of inhibitor. The efficacy of drug efflux inhibition by LY294002 was similar to that achieved by the MRP1 inhibitors MK571 and genistein. We conclude that the PI3K inhibitor LY294002 may have therapeutic potential when combined with doxorubicin in the treatment of MRP1-mediated drug resistance.

AB - Multidrug resistance may be achieved by the activation of membrane transporters, detoxification, alterations in DNA repair or failure in apoptotic pathways. Recent data have suggested an involvement of mitogenic signalling pathways mediated by Ras and phosphoinositol-3-kinase (PI3K/Akt) in controlling multidrug resistance. Since these pathways are important targets for therapeutic interference, we sought to investigate whether blocking effectors kinases by specific inhibitors would result in a sensitization toward cytotoxic drugs. We found that cotreatment of drug-resistant HT29RDB colon cancer cells with the topoisomerase inhibitor doxorubicin and the PI3K-inhibitor LY294002 resulted in massive apoptosis, while cotreatment with the Mek inhibitors PD98059 or U0126 had no effect. This suggested that the PI3K-pathways controls cell survival and drug resistance in these cells. Besides blocking Akt phosphorylation, the PI3K-inibitor increased the intracellular doxorubicin concentration threefold. LY294002 inhibits drug export in a competitive manner as revealed by measuring drug efflux in the presence and the absence of inhibitor. The efficacy of drug efflux inhibition by LY294002 was similar to that achieved by the MRP1 inhibitors MK571 and genistein. We conclude that the PI3K inhibitor LY294002 may have therapeutic potential when combined with doxorubicin in the treatment of MRP1-mediated drug resistance.

KW - Colon cancer

KW - Doxorubicin

KW - LY294002

KW - Multi-drug resistance-associated protein MRP1

KW - Phosphoinositol 3-kinase

UR - http://www.scopus.com/inward/record.url?scp=33645038097&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645038097&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1209201

DO - 10.1038/sj.onc.1209201

M3 - Article

C2 - 16288223

AN - SCOPUS:33645038097

VL - 25

SP - 1743

EP - 1752

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 12

ER -