PT  - JOURNAL ARTICLE
AU  - Divya Muthiah
AU  - Georgia K. Henshaw
AU  - Aaron J. DeBono
AU  - Ben Capuano
AU  - Peter J. Scammells
AU  - Richard Callaghan
TI  - Overcoming P-Glycoprotein–Mediated Drug Resistance with Noscapine Derivatives
AID  - 10.1124/dmd.118.083188
DP  - 2019 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 164--172
VI  - 47
IP  - 2
4099  - http://dmd.aspetjournals.org/content/47/2/164.short
4100  - http://dmd.aspetjournals.org/content/47/2/164.full
SO  - Drug Metab Dispos2019 Feb 01; 47
AB  - The antitussive agent noscapine has been shown to inhibit the proliferation of cancer cells by disruption of tubulin dynamic. However, the efficacy of several anticancer drugs that inhibit tublin dynamics (vinca alkaloids and taxanes) is reduced by the multidrug resistance phenotype. These compounds are substrates for P-glycoprotein (P-gp)–mediated extrusion from cells. Consequently, the antiproliferative activity of noscapine and a series of derivatives was measured in drug-sensitive and drug-resistant cells that overexpress P-gp. None of the noscapine derivatives displayed lower potency in cells overexpressing 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 most 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, coadministration 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.