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Sci Rep. 2017 Aug 11;7(1):7972. doi: 10.1038/s41598-017-08062-2.

Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer.

Author information

1
Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, 605014, India.
2
DBT-Interdisciplinary Program in Life Sciences, Pondicherry University, Kalapet, Puducherry, 605014, India.
3
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 350, Taiwan, ROC.
4
Department of Biochemistry & Molecular Biology, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, 605014, India.
5
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 350, Taiwan, ROC. hphsieh@nhri.org.tw.
6
Department of Chemistry, National Tsing Hua University, Hsinchu, 350, Taiwan, ROC. hphsieh@nhri.org.tw.
7
Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, 605014, India. mohane@bicpu.edu.in.

Abstract

P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7-dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog - Pip1 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) - is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer.

PMID:
28801675
PMCID:
PMC5554262
DOI:
10.1038/s41598-017-08062-2
[Indexed for MEDLINE]
Free PMC Article

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