Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences

Abstract

Although multidrug resistance (MDR) proteins are known to play a role in drug resistance and modification pharmacodynamic characteristics of certain conventional chemotherapeutics, information about their interactions with tyrosine kinase inhibitors (TKIs) remains fragmentary and somewhat controversial. The chronic administration of TKIs in many clinical situations strongly suggests that any possible interactions with MDR transporters should be studied as a function of time. For example, short periods of exposure to TKIs could provide insights into the nature of the binding to MDR-related proteins, either as substrates or as inhibitors, whereas prolonged exposure to TKIs could provide insights into cellular responses to binding/inhibition of MDR-related proteins. In this report, we provide evidence that suggests that both Gefitinib and Vandetanib may act as transported substrates for Breast Cancer Resistance Protein (BCRP, ABCG2). Conversely, the interaction of Gefitinib and Vandetanib with P-glycoprotein (PgP, MDR1) appeared to be as inhibitors alone. Consistent with this, short periods of exposure (≤24 h) to either Gefitinib or Vandetanib increased the effectiveness of SN-38, the active metabolite of CPT-11. Conversely, prolonged exposure (5 days) decreased SN-38 effectiveness, and was associated with BCRP up-regulation and reduced cell accumulation in S-phase, possibly though reduced intracellular accumulation of SN-38. This report underlines the needs for more detailed characterisation new biologically targeted anticancer drugs, in particular analysing periods of both short and prolonged drug exposure reflecting potentially distinct situations in the clinic in order to optimise future development in combination with established chemotherapeutic approaches.

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

“…In recent years, TKIs have been identified as inhibitors of several ATP-binding cassette (ABC) efflux transporters that are commonly upregulated in cancer cells including P-glycoprotein (multidrug resistance protein 1), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP) 1 [10][11][12][13][14][15][16][17][18]. ABC efflux transporters consist of a large family of membrane-spanning proteins involved in the active extrusion of substrates such as endogenous molecules, drugs, and drug metabolites from the cell through hydrolysis of ATP [19][20][21].…”

Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans

“…Interestingly, the cell line exhibiting a lower level of drug efflux (BCRP genetic variant) tends to exhibit a lower accumulation of the kinase inhibitor when compared with the cell line expressing the wild-type transporter [50]. Transport of gefitinib by BCRP was also recently reported by Azzariti et al [51] using Caco-2 cells. Overall, these in vitro experiments tend to suggest that gefitinib is transported by BCRP.…”

“…CYP1A2, CYP2C9 and CYP2C19 were not involved in the biotransformation, in vitro [18]. N-demethylation of imatinib was also found to be catalyzed by CYP2C8 in human liver microsomes and cDNA-expressed systems [18,19] Conflicting [18,19] Conflicting [18,19] No [18,19] Yes [19] No [18,19] No [18,19] Gefitinib Yes [22,23] Yes [22,23] Yes [22,23] Yes [23,24] No [22,23] No [22] No [22] N o [ 51] Conflicting [48][49][50][51] Erlotinib Yes [23,25] N o [23,25] Yes [23] Yes [23,25] No [25] No [25] Yes [52] No (MRP2) [52] Yes [50] Lapatinib Yes [53] No (MRP2) [53] Yes [53] Sorafenib Yes [pi]…”

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

“…TKIs such as the BCR-ABL kinase inhibitors (imatinib, nilotinib and dasatinib), EGFRs kinase inhibitors (gefitinib, erlotinib, lapatinib) and others, show substrate-like properties at lower concentration and inhibitor-like properties at higher concentration via competitive inhibition of the transporters function [208] . In addition to the concentrationdependent type of interaction, it has been proposed that exposure time to TKIs also plays a role [209] . Short exposure (≤ 24 h) to either gefitinib or vandetanib demonstrated a synergic interaction with SN-38, whereas prolonged exposure (5 days) showed a strong antagonism between gefitinib or vandetanib and SN-38.…”

“…Gefitinib enhanced the oral bioavailability of irinotecan and topotecan, and increased their apparent bioavailability and decreased systemic clearance in mice [215,216] . Therefore, studies are needed that investigate the exact type of interactions between TKIs and cytotoxic drugs [95,208,209] .…”