Format

Send to

Choose Destination
Drug Metab Dispos. 2019 Feb;47(2):164-172. doi: 10.1124/dmd.118.083188. Epub 2018 Nov 26.

Overcoming P-Glycoprotein-Mediated Drug Resistance with Noscapine Derivatives.

Author information

1
Division of Biomedical Science and Biochemistry, Research School of Biology and Medical School, Australian National University, Canberra, Australian Capital Territory (D.M., G.K.H., R.C.), and Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria (A.J.D., B.C., P.J.S.), Australia.
2
Division of Biomedical Science and Biochemistry, Research School of Biology and Medical School, Australian National University, Canberra, Australian Capital Territory (D.M., G.K.H., R.C.), and Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria (A.J.D., B.C., P.J.S.), Australia richard.callaghan@anu.edu.au.

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.

PMID:
30478158
DOI:
10.1124/dmd.118.083188
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center