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Research ArticleArticle

Overcoming P-glycoprotein mediated drug resistance with noscapine derivatives

Divya Muthiah, Georgia K Henshaw, Aaron J DeBono, Ben Capuano, Peter Scammells and Richard Callaghan
Drug Metabolism and Disposition November 26, 2018, dmd.118.083188; DOI: https://doi.org/10.1124/dmd.118.083188
Divya Muthiah
1 Australian National University;
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Georgia K Henshaw
1 Australian National University;
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Aaron J DeBono
2 Monash University
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Ben Capuano
2 Monash University
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Peter Scammells
2 Monash University
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Richard Callaghan
1 Australian National University;
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  • For correspondence: richard.callaghan@anu.edu.au
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Abstract

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.

  • anticancer agents
  • efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
  • membrane-protein interactions
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (5)
Drug Metabolism and Disposition
Vol. 50, Issue 5
1 May 2022
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Research ArticleArticle

Overcoming P-glycoprotein mediated drug resistance with noscapine derivatives

Divya Muthiah, Georgia K Henshaw, Aaron J DeBono, Ben Capuano, Peter Scammells and Richard Callaghan
Drug Metabolism and Disposition November 26, 2018, dmd.118.083188; DOI: https://doi.org/10.1124/dmd.118.083188

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Research ArticleArticle

Overcoming P-glycoprotein mediated drug resistance with noscapine derivatives

Divya Muthiah, Georgia K Henshaw, Aaron J DeBono, Ben Capuano, Peter Scammells and Richard Callaghan
Drug Metabolism and Disposition November 26, 2018, dmd.118.083188; DOI: https://doi.org/10.1124/dmd.118.083188
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