RT Journal Article
SR Electronic
T1 Overcoming P-glycoprotein mediated drug resistance with noscapine derivatives
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.083188
DO 10.1124/dmd.118.083188
A1 Divya Muthiah
A1 Georgia K Henshaw
A1 Aaron J DeBono
A1 Ben Capuano
A1 Peter Scammells
A1 Richard Callaghan
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/11/26/dmd.118.083188.abstract
AB The antitussive agent noscapine has previously been shown to inhibit the proliferation of cancer cells by disruption of tubulin dynamics. However, the efficacy of several anticancer drugs that inhibit tublin dynamics (vinca alkaloids and taxanes) is reduced by the multidrug resistance phenotype. In particular, these compounds are substrates for P-glycoprotein (P-gp) mediated extrusion from cells. Consequently, the anti-proliferative activity of noscapine, and a series of derivatives, was measured in drug sensitive and drug resistant cells that over-express P-gp. None of the noscapine derivatives displayed lower potency in cells over-expressing P-gp; thereby suggesting a lack of interaction with this pump. However, the cellular efflux of a fluorescent substrate by P-gp was potently inhibited by noscapine and the majority of derivatives. Further investigation with purified, reconstituted P-gp demonstrated that inhibition of P-gp function was due to direct interaction of noscapine derivatives with the transporter. Moreover, co-administration of vinblastine with two of the noscapine derivatives displayed synergistic inhibition of proliferation, even in P-gp expressing resistant cell lines. Therefore, noscapine derivatives offer a dual benefit of overcoming the significant impact of P-gp in conferring multidrug resistance and synergy with tubulin-disrupting anticancer drugs.