Lapatinib and erlotinib are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance

• Published in: Biochemical pharmacology Vol. 79; no. 2; pp. 154 - 161
• Main Authors: Kuang, Ye-Hong, Shen, Tong, Chen, Xiang, Sodani, Kamlesh, Hopper-Borge, Elizabeth, Tiwari, Amit K., Lee, Jeferson W.K.K., Fu, Li-Wu, Chen, Zhe-Sheng
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.01.2010; Elsevier
• Subjects: ABC transporters; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Cell Line; Drug Resistance, Multiple; EGFR; Erlotinib; Erlotinib Hydrochloride; Humans; Lapatinib; Medical sciences; MRP7/ABCC10; Multidrug resistance; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Pharmacology. Drug treatments; Quinazolines - pharmacology; Tyrosine kinase inhibitor; ABC; MRP7 (ABCC10); Tyrosine kinase inhibitor; Multidrug resistance; MRP7/ABCC10; EGFR; TKI; HER; Erlotinib; P-gp (ABCB1); MDR; ABC transporters; Lapatinib; ABCG2; Antineoplastic agent; Treatment resistance; Enzyme; Quinazoline derivatives; Transferases; Enzyme inhibitor; Epidermal growth factor receptor; Multiple resistance; Reversibility; Protein-tyrosine kinase; ABC transporter
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2009.08.021

In recent years, a number of TKIs (tyrosine kinase inhibitors) targeting epidermal growth factor receptor (EGFR) family have been synthesized and some have been approved for clinical treatment of cancer by the FDA. We recently reported a new pharmacological action of the 4-anilinoquinazoline derived EGFR TKIs, such as lapatinib (Tykerb®) and erlotinib (Tarceva®), which significantly affect the drug resistance patterns in cells expressing the multidrug resistance (MDR) phenotype. Previously, we showed that lapatinib and erlotinib could inhibit the drug efflux function of P-glycoprotein (P-gp, ABCB1) and ABCG2 transporters. In this study, we determined if these TKIs have the potential to reverse MDR due to the presence of the multidrug resistance protein 7 (MRP7, ABCC10). Our results showed that lapatinib and erlotinib dose-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to several established MRP7 substrates, specifically docetaxel, paclitaxel, vinblastine and vinorelbine, whereas there was no or a less effect on the control vector transfected HEK293 cells. [3H]-paclitaxel accumulation and efflux studies demonstrated that lapatinib and erlotinib increased the intracellular accumulation of [3H]-paclitaxel and inhibited the efflux of [3H]-paclitaxel from MRP7-transfected cells but not in the control cell line. Lapatinib is a more potent inhibitor of MRP7 than erlotinib. In addition, the Western blot analysis revealed that both lapatinib and erlotinib did not significantly affect MRP7 expression. We conclude that the EGFR TKIs, lapatinib and erlotinib reverse MRP7-mediated MDR through inhibition of the drug efflux function, suggesting that an EGFR TKI based combinational therapy may be applicable for chemotherapeutic practice clinically.