ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein

Abstract

P-glycoprotein (P-gp) pumps multiple types of drugs out of the cell, using energy generated from ATP, and confers multidrug resistance (MDR) on cancer cells. ZD6474 is an orally active, selective inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. This study was designed to examine whether ZD6474 reverses P-gp-mediated MDR in cancer cells. Here, we show that clinically achievable levels of ZD6474 reverse P-gp-mediated MDR of the P-gp-overexpressing cell lines derived from breast cancer, MCF-7/adriamycin (ADR), and human oral epidermoid carcinoma, KBV200 to ADR, docetaxel, and vinorelbine. This ability to reverse the P-gp-mediated resistance is comparable to that of another frequently used reversal agent known as verapamil. ZD6474 itself moderately inhibits the proliferation of both MCF-7 and MCF-7/ADR cells with almost equal activity, but its inhibitory effect is not altered by co-incubation with verapamil, suggesting that ZD6474 may not be a substrate of P-gp. In addition, ZD6474 increases the intracellular accumulation of the P-gp substrate, rhodamine-123, and ADR, by enhancing the uptake and/or decreasing the efflux of these compounds in resistant cells. Further studies show that ZD6474 stimulates ATPase activity in a dose-dependent manner, which is required for the proper function of P-gp. In contrast, ZD6474 does not inhibit the expression level of P-gp. Our results suggest that ZD6474 is capable of reversing MDR in cancer cells by directly inhibiting the function of P-gp, a finding that may have clinical implications for ZD6474.

Synthesis of heterocycle-modified betulinic acid derivatives as antitumor agents

“…Considering that amides are more stable than esters in metabolism, these synthetic amides derivatives are more promising candidates for antitumor agents than these esters derivatives. Adriamycin (ADR) and docetaxel (DOC) are selected as positive controls and they are both resisted by MCF-7/ADR significantly [25,26] and the results are consistent with this.…”

Interactions of Multitargeted Kinase Inhibitors and Nucleoside Drugs: Achilles Heel of Combination Therapy?

“…Earlier reports indicated interaction of TKIs with ATPbinding domains of ATP-binding cassette (ABC) transportermediated multidrug resistance (MDR) proteins in cancer cells (43)(44)(45). Inhibition of P-glycoprotein (P-gp) activity (46) resulted in enhanced cytotoxic effects of multiple anticancer drugs by increasing accumulation of P-gp and ATP-binding cassette subfamily G member 2 (ABCG2) substrates (47,48). Earlier studies showed inhibition of hENT1-mediated activity in K562 cells by p38 MAPK inhibitors (29), and our current and previous results (32) indicate that another group of potential target proteins are hNTs.…”

Euphorbia factor L1 reverses ABCB1‐mediated multidrug resistance involving interaction with ABCB1 independent of ABCB1 downregualtion

“…As described before, MDR reversal agents against ABCB1 could be divided into three classes. Compounds belonging to the second class such as vandetanib and verapamil increasing the ATPase activity of ABCB1 in a dosedependent manner could inhibit the efflux of ABCB1 [Hamada and Tsuruo, 1988;Mi and Lou, 2007]. Herein, EFL1 stimulated the ATPase activity, increased intracellular accumulation of anticancer drugs and inhibited drug efflux of ABCB1.…”

“…Lapatinib was demonstrated to reverse ABCB1-mediated MDR and can increase the ATPase activities of the transporters at low concentrations [Dai et al, 2008]. It has been reported that vandetanib and verapamil can increase the ATPase activity of ABCB1 in a dose-dependent manner [Hamada and Tsuruo, 1988;Mi and Lou, 2007].…”