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

Abstract

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 lesser 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.

Lapatinib Antagonizes Multidrug Resistance-Associated Protein 1-Mediated Multidrug Resistance by Inhibiting Its Transport Function

“…Our previous findings showed lapatinib could inhibit the function of ABCB1, ABCG2 and MRP10 (26,27). To demonstrate the interaction of lapatinib and other MDR proteins, the cell lines C-A120, HEK293/ MRP2 and NIH3T3/MRP4-2 as well as SW1573/ 2R120 were used in our research.…”

“…Lapatinib is an orally active dual TKI that has been used in combination with capecitabine or letrozole for the treatments of patients with advanced breast cancer (25). We previously reported that lapatinib inhibited the function of ABCB1, ABCG2 and MRP10 (26,27). In this study, we explored the effect of lapatinib on the efficacy of conventional chemotherapeutic agents in MRP1-, MRP2-, MRP4-and LRP-overexpressing cancer cells in vitro and in vivo.…”

Interaction of innovative small molecule drugs used for cancer therapy with drug transporters

“…Modulation of P-glycoprotein-mediated drug resistance by erlotinib appears to be substrate dependent (Shi et al, 2007;Noguchi et al, 2009). In addition, Kuang et al reported that erlotinib potently reverses MRP7-mediated multidrug resistance (Kuang et al, 2010). Thomas et al (2009) reported population pharmacokinetics in erlotinib-treated patients with head and neck squamous cell carcinoma.…”

“…ABCG2-transfected cells exhibited lower intracellular accumulation of erlotinib than cells lacking ABCG2, indicating that erlotinib is a substrate of Gnoth et al, 2010), K562 cells (Haouala et al, 2010), LLC-PK1 cells (Hu et al, 2009;Gnoth et al, 2010), MDCKII cells (Lagas et al, 2010) Abcb1a/1b(-/-) mice (Hu et al, 2009;Gnoth et al, 2010), Abcb1a/1b(-/-) Abcg2(-/-) mice (Lagas et al, 2010;Asakawa et al, 2011) MRP2 (ABCC2) LLC-PK1 cells (Shibayama et al, 2011) BCRP (ABCG2) MDCKII cells (Lagas et al, 2010;Agarwal et al, 2011) Abcg2(-/-) mice (Lagas et al, 2010;Agarwal et al, 2011), Abcb1a/1b(-/-) Abcg2(-/-) mice (Lagas et al, 2010;Agarwal et al, 2011;Asakawa et al, 2011) Sunitinib P-glycoprotein (ABCB1) K562 cells (Haouala et al, 2010), LLC-PK1 cells (Hu et al, 2009), MDCKII cells Abcb1a/1b(-/-) mice (Hu et al, 2009;Tang et al, 2011), (Minematsu and Giacomini, 2011) MATE2-K (SLC47A2) Metformin (IC50 = 3.45 mM) HEK293 cells (Minematsu and Giacomini, 2011) P-glycoprotein (ABCB1) Vincristine (IC50 = 2 mM) K562 cells (Noguchi et al, 2009) MRP7 (ABCC10) Paclitaxel HEK293 cells (Kuang et al, 2010) BCRP (ABCG2) E 217bG, methotrexate, mitoxantrone HEK293 (Shi et al, 2007), K562 cells (Noguchi et al, 2009) Gefitinib OCT1 (SLC22A1) MPP + HEK293 cells (Galetti et al, 2010) OCT2 (SLC22A2) MPP + HEK293 cells (Galetti et al, 2010) MATE2-K (SLC47A2) Metformin (IC50 = 0.194 mM) HEK293 cells (Minematsu and Giacomini, 2011) P-glycoprotein (ABCB1) Calcein-AM, docetaxel, doxorubicin, paclitaxel, rhodamine-123, topotecan CL1 cells (Yang et al, 2005), LL...…”

“…CL1 cells (Yang et al, 2005), HL60 cells (Ozvegy-Laczka et al, 2004), K562 cells (Yanase et al, 2004), MCF7 cells (Yang et al, 2005), PC-6 cells , Saos2 cells (Leggas et al, 2006) Imatinib OCT1 (SLC22A1) Metformin (IC50 = 1.47 mM) HEK293 cells (Minematsu and Giacomini, 2011) MATE1 (SLC47A1) Metformin (IC50 = 0.048 mM) HEK293 cells (Minematsu and Giacomini, 2011) MATE2-K (SLC47A2) Metformin (IC50 = 0.478 mM) HEK293 cells (Minematsu and Giacomini, 2011) P-glycoprotein (ABCB1) Calcein-AM (Ki = 18.3 mM) LLC-PK1 cells (Hamada et al, 2003) MRP7 (ABCC10) Paclitaxel HEK293 cells (Shen et al, 2009) BCRP (ABCG2) Mitoxantrone, SN-38, topotecan HEK293 cells (Burger et al, 2004), MCF7 cells (Burger et al, 2004), Saos2 cells (Houghton et al, 2004) Lapatinib OATP1B1 (SLCO21A6) E217bG CHO cells (Polli et al, 2008;Fachinformation, 2010) P-glycoprotein (ABCB1) Topotecan CHO cells (Molina et al, 2008) MRP7 (ABCC10) Paclitaxel HEK293 cells (Kuang et al, 2010) BCRP (ABCG2) E 217bG, methotrexate, SN-38, topotecan HEK293 cells (Dai et al, 2008), H1975 cells (Perry et al, 2010), H358 cells (Perry et al, 2010), MDA-MB-231 cells (Molina et al, 2008;Perry et al, 2010), Susa S/R cells (Perry et al, 2010) Nilotinib OCT1 (SLC22A1) Metformin CML cells (Davies et al, 2009), HEK293 cells (Minematsu and Giacomini, 2011) OCT3 (SLC22A3) Metformin (IC50 = 0.35 mM) HEK293 cells (Minematsu and Giacomini, 2011) P-glycoprotein (ABCB1) Calcein-AM, dasatinib, rhodamine CML cells (Davies et al, 2009;Hiwase et al, 2010), HEK293 cells (Dohse et al, 2010), K562 cells (Hegedus et al, 2009) MRP7 (ABCC10) Paclitaxel HEK293 cells (Shen et al, 2009) BCRP (ABCG2) E 217bG, Hoechst 33342, methotrexate (Ki = 0.69 mM), pheophorb...…”