In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance

Abstract

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 ( N -(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien. © 1999 Cancer Research Campaign

UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase

“…Since gallotannin prevents the generation of ADP-ribose following DNA damage, ADP-ribose is a candidate inhibitor of ABC transporters in irradiated cells. Using inside-out membrane vesicles containing Pgp, 26,27 we demonstrated that ADP-ribose directly inhibits the export activity. Significant Pgp inhibition occurred at doses of ADP-ribose as low as 100 nM, quite below the level observed in cells exposed to oxidative stress (5 mM).…”

“…To test the hypothesis that ADP-ribose, which is not penetrating viable cells, mediates the UVB-induced inhibition of ABC transporters, we employed inside-out membrane vesicles containing high amounts of the prototype ABCtransporter Pgp. 26,27 ADP-ribose, at a concentration of 10 mM, caused a virtually complete inhibition of the activity of Pgp (P¼0.0015) (Figure 5b). Pgp activity was comparable to that observed in the absence of the pump 'fuel' ATP (Figure 5b).…”

“…This system uses membrane vesicles that contain high amounts of Pgp. 26,27 The vesicles were immobilised on 96-well microtiter plates by incubation at 371C for 30 min. The plates were washed with PBS to remove unattached vesicles.…”

A Selective ATP-Binding Cassette Subfamily G Member 2 Efflux Inhibitor Revealed via High-Throughput Flow Cytometry

“…17-18 The submicromolar ABCB1 modulator 2 was chosen as it is known to reverse resistance to cytotoxic drugs such as doxorubicin and vincristine. 8,24 Quinoline MK571 ( 5 ), a specific inhibitor of ABCC1, was necessary to gauge any ABCC1 activity. 25 Also, reversan ( 6 ), identified as an active inhibitor of ABCB1 and ABCC1, was included as it contained a similar, pyrazolopyrimidine core.…”

Identification and Characterization of the Binding Sites of P-Glycoprotein for Multidrug Resistance-Related Drugs and Modulators

“…Furthermore, major toxicities associated with most of these compounds at the required concentrations to inhibit P-glycoprotein activity have prevented their widespread clinical use [172][173][174][175]. The requirement for more specific and potent P-glycoprotein inhibitors as MDR modulators has led to the development of second-generation modulators, such as the nonimmunosuppressive cyclosporin D analogue PSC 833 (Valspodar) [176], VX-710 (Biricodar) [102], the acridone carboxamide derivative GF120918 (GG918) [177] and the diketopiperazine derivative XR9051 [178]. Clinical trials have demonstrated some clinical benefit from the use of modulators such as PSC 833 [179,180].…”