Overcoming P-Glycoprotein-Mediated Drug Resistance with Noscapine Derivatives

Divya Muthiah, Georgia K. Henshaw, Aaron J. DeBono, Ben Capuano, Peter J. Scammells, Richard Callaghan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)164-172
Number of pages9
JournalDrug Metabolism and Disposition
Volume47
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019

Cite this

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title = "Overcoming P-Glycoprotein-Mediated Drug Resistance with Noscapine Derivatives",
abstract = "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.",
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Overcoming P-Glycoprotein-Mediated Drug Resistance with Noscapine Derivatives. / Muthiah, Divya; Henshaw, Georgia K.; DeBono, Aaron J.; Capuano, Ben; Scammells, Peter J.; Callaghan, Richard.

In: Drug Metabolism and Disposition, Vol. 47, No. 2, 01.02.2019, p. 164-172.

Research output: Contribution to journalArticleResearchpeer-review

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