Tyrosine kinase inhibitors influence ABCG2 expression in EGFR-positive MDCK BCRP cells via the PI3K/Akt signaling pathway

ChemMedChem. 2012 Apr;7(4):650-62. doi: 10.1002/cmdc.201100543. Epub 2012 Feb 22.

Abstract

Multidrug resistance observed in cancer chemotherapy is commonly attributed to overexpression of efflux transporter proteins. These proteins act as ATP-dependent drug efflux pumps, actively extruding chemotherapeutic agents from cells and causing a decrease in intracellular drug accumulation. Besides the well-recognized role of P-glycoprotein (P-gp, ABCB1), the breast cancer resistance protein (BCRP, ABCG2) is becoming increasingly accepted as playing an important role in multidrug resistance. In contrast to P-glycoprotein, only a few inhibitors of ABCG2 are known. According to the literature, tyrosine kinase inhibitors (TKIs) can be considered to be broad-spectrum inhibitors, interacting with ABCB1, ABCC1 and ABCG2. Here, we investigated seven different TKIs, gefitinib, erlotinib, AG1478, PD158780, PD153035, nilotinib and imatinib, for their potential to restore ABCG2 sensitivity to cells. Furthermore, we analyzed the alteration of ABCG2 expression caused by TKIs and demonstrated that EGFR inhibitors such as gefitinib and PD158780 reduced both total and surface expression of ABCG2 in EGRF-positive MDCK BCRP cells by interaction with the PI3K/Akt signaling pathway. The reduced ABCG2 content led to an increased effect of XR9577, a well-known ABCG2 modulator, lowering the concentration required for half maximal inhibition. On the other hand, BCR-ABL inhibitors had no influence on ABCG2 expression and modulator activity. Interestingly, a combination of an EGFR inhibitor with the PI3K/Akt inhibitor LY294002 led to a significant reduction of ABCG2 expression at low concentrations of the drugs. Based on our results, we assume that EGFR exerts a post-transcriptional enhancing effect on ABCG2 expression via the PI3K/Akt signaling pathway, which can be attenuated by EGFR inhibitors. Blocking the key signaling pathway regulating ABCG2 expression with EGFR inhibitors, combined with the inhibition of ABCG2 with potent modulators might be a promising approach to circumvent MDR in cancer cells.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Humanized
  • Benzamides
  • Benzimidazoles / pharmacology
  • Cell Line
  • Cetuximab
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple / drug effects
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride
  • Gefitinib
  • Humans
  • Imatinib Mesylate
  • Morpholines / pharmacology
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology
  • Signal Transduction / drug effects
  • Tyrphostins / pharmacology

Substances

  • 6-(methylamino)pyrido(3,4-d)pyrimidine
  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Benzamides
  • Benzimidazoles
  • Chromones
  • Morpholines
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • Tyrphostins
  • RTKI cpd
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Imatinib Mesylate
  • Erlotinib Hydrochloride
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • bisbenzimide ethoxide trihydrochloride
  • Cetuximab
  • Gefitinib
  • 4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline
  • multidrug resistance-associated protein 1