RU49953: a non-hormonal steroid derivative that potently inhibits P-glycoprotein and reverts cellular multidrug resistance

Abstract

Progesterone and the antiprogestin RU38486 have been reported as non-transported modulators of P-glycoprotein-mediated drug efflux. However, their hormonal properties limit their potential for clinical trials. The present work shows that some derivatives from either progesterone/RU38486 or estradiol, displaying differential interaction with hormone receptors, bind to P-glycoprotein and chemosensitize the growth of MDR1-transfected cells to vinblastine more strongly than does RU38486. Structure comparison of the compounds indicates that the highly hydrophobic estradiol derivative RU49953, which does not interact with any hormone receptor, inhibits P-glycoprotein-mediated drug efflux very efficiently, as monitored by flow cytometry, and prevents drug site photoaffinity labeling by azidopine. It induces a much higher chemosensitization than the well-known P-glycoprotein modulator verapamil, which is itself more efficient than RU38486. RU49953 therefore constitutes a promising new lead for steroid-type modulators of multidrug resistance.

Flavonoid Structure-Activity Studies Identify 6-Prenylchrysin and Tectochrysin as Potent and Specific Inhibitors of Breast Cancer Resistance Protein ABCG2

“…These stepwise selections likely produce a number of side modifications in addition to ABCG2 overexpression, leading to questions about the accuracy of controls. This was stressed in several studies with either ABCG2 (4, 29, 36) or P-glycoprotein (37), where additional modifications of glutathione transferase and topoisomerase II activities were reported. This might explain, at least partly, the difficulties of Zhang et al to draw clear-cut structure-activity relationships and the high concentration of flavonoids required for complete chemosensitization (26).…”

Improved antitumoral properties of pure antiestrogen RU 58668-loaded liposomes in multiple myeloma

“…Like many steroids, RU could be exported from cancer cells displaying a multidrug resistance (MDR) phenotype due to the activity of P-gps [34,35]. RU 49953 is a specific P-gp inhibitor, stronger than verapamil itself and capable of reverting MDR [29]; we further analyzed its effects upon RUmediated inhibition of MM cell viability. RU 49953 had no cytotoxic effects compared to vehicle-treated cells (Fig.…”

“…For cell proliferation studies, cells were seeded in 6-well plates in triplicate (2 × 10 5 cells/well), in medium containing either vehicle or various RU concentrations. In some experiments, the specific P-glycoprotein (P-gp) inhibitor RU 49953 [29] (5 M) was added 1 h 30 prior to RU. Tonsils were obtained from healthy donors with their informed consent in accordance with the Helsinki protocol.…”

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…However, most of the first generation P-gp inhibitors were found to lack selectivity for P-gp and being substrates for other transporters and enzyme systems; this promiscuity resulted in unpredictable pharmacokinetic interactions in the presence of anticancer drugs [20]. Moreover, low affinity for P-gp, associated with the original therapeutic activity, required the use of high doses which resulted in unacceptable toxicity [6,21]. Second generation of P-gp inhibitors were developed, based on the selective optimization of side activity (SOSA) approach, to increase the potency and reduce toxicity, many of which were single enantiomers of the first generation drugs.…”