PT  - JOURNAL ARTICLE
AU  - Divya Muthiah
AU  - Georgia K Henshaw
AU  - Aaron J DeBono
AU  - Ben Capuano
AU  - Peter Scammells
AU  - Richard Callaghan
TI  - Overcoming P-glycoprotein mediated drug resistance with noscapine derivatives
AID  - 10.1124/dmd.118.083188
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.083188
4099  - http://dmd.aspetjournals.org/content/early/2018/11/26/dmd.118.083188.short
4100  - http://dmd.aspetjournals.org/content/early/2018/11/26/dmd.118.083188.full
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.