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

Oncogene volume 25, pages 1743–1752 (2006)Cite this article

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.

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Acknowledgements

This work was supported by the Marie Curie fellowship (HPMD-CT-2000-00001).We thank Alexandra Stege and Conny Gieseler for technical help.

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Author notes

  1. R Abdul-Ghani and V Serra: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Tumor Pathology, Institute of Pathology, Charité, Universitätsmedizin Berlin, Schumannstr, Berlin, Germany

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

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  1. R Abdul-Ghani
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  2. V Serra
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Correspondence to R Schäfer.

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Abdul-Ghani, R., Serra, V., Györffy, B. et al. The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1. Oncogene 25, 1743–1752 (2006). https://doi.org/10.1038/sj.onc.1209201

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