Human ABCC4 peptide

Intracellular cyclic nucleotides are eliminated by phosphodiesterases (PDEs) and by ATP Binding cassette transporters such as ABCC4 and ABCC5. PDE5 and ABCC5 have similar affinity for cGMP whereas ABCC5 has much higher affinity for cGMP compared with cAMP. Since the substrate (cGMP) is identical for these two eliminatory processes it is conceivable that various PDE inhibitors also modulate ABCC5-transport. Cyclic GMP is also transported by ABBC4 but the affinity is much lower with a K-m 50-100 times higher than for that of ABBCC5. The present study aimed to determine K-i-values for specific or relative specific PDE5 inhibitors (vardenafil, tadalafil, zaprinast and dipyridamole) and the non-specific PDE inhibitors (IBMX, caffeine and theophylline) for ABCC5 andABCC4 transport. The transport of [H-3]-cGMP (2 mu M) was concentration-dependently inhibited with the following K-i-values: vardenafil (0.62 mu M), tadalatil (14.1 mu M), zaprinast (0.68 mu M) and dipyridamole (1.2 mu M), IBMX (10 mu M), caffeine (48 mu M) and theophylline (69 mu M). The K-i-values for the inhibition of the [H-3]-cAMP (2 mu M) transport were: vardenatil (3.4 mu M), tadalafil (194 mu M), zaprinast (2.8 mu M), clipyridamole (5.5 mu M), [BMX (16 mu M), caffeine (41 mu M) and theophylline (85 mu M). The specificity for ABCC5 we defined as ratio between K-i-values for inhibition at [H-3] -cAMP and [H-3]-cAMP transport. Tadalafil showed the highest specificity (K-i-ratio: 0.073) and caffeine the lowest (K-i-ratio: 1.2). (C) 2014 The Authors. Published by Elsevier B.V.

The effectiveness of chemotherapeutic treatment is usually limited by the overexpression of adenosine triphosphate binding cassette (ABC) transporters, which mediate multidrug resistance (MDR) by acting as efflux pumps to remove chemotherapeutic agents from MDR cancer cells. Thus, the inhibition of ABC transporters may represent a promising strategy to reverse MDR. This study was to characterize the actions of FG020326, a newly synthesized triaryl-substituted imidazole derivative, to reverse MDR in vitro and in vivo. FG020326 significantly potentiated the cytotoxicity of paclitaxel, doxorubicin, and vincristine in the ABCB1 (P-glycoprotein, P-gp) overexpressing cells KBv200 and MCF-7/adr, but not in the ABCB1 negative parental cell lines KB and MCF-7. However, FG020326 did not alter the cytotoxicity of the aforementioned drugs in ABCC1 (MRP1), ABCC4 (MRP4), ABCG2 (BCRP) and LRP overexpressing cell lines, KB-CV60, NIH3T3/MRP4-2, S1-MI-80 and SW1573/2R120, respectively. FG020326, following p.o. administration, was present in concentrations sufficient for reversal of MDR in mice. The co-administration of FG020326 with paclitaxel or vincristine significantly enhanced the antitumor activity of these drugs without significantly increasing toxicity in the mice bearing the KBv200 cell xenografts. In addition, FG020326, at concentrations that reversed MDR, did not significantly affect the activity of CYP3A4 or alter the pharmacokinetic profile of paclitaxel after co-administration with paclitaxel. FG020326 produced a significant concentration-dependent displacement of [H-3]azidopine and inhibition of efflux of drug from cells. Furthermore, FG020326 was co-localized with ABCB1 in cell membranes. Hence, FG020326 is characterized as a third generation MDR modulator that holds great promise for the treatment of cancer patients with ABCB1-mediated MDR. (C) 2009 Elsevier Inc. All rights reserved.