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

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 repo...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Safiulla Basha Syed, Hemant Arya, I-Hsuan Fu, Teng-Kuang Yeh, Latha Periyasamy, Hsing-Pang Hsieh, Mohane Selvaraj Coumar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8f1abc9fc04a4f1dbd447a375a78af9c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:8f1abc9fc04a4f1dbd447a375a78af9c
record_format	dspace
spelling	oai:doaj.org-article:8f1abc9fc04a4f1dbd447a375a78af9c2021-12-02T15:05:40ZTargeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer10.1038/s41598-017-08062-22045-2322https://doaj.org/article/8f1abc9fc04a4f1dbd447a375a78af9c2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08062-2https://doaj.org/toc/2045-2322Abstract 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.Safiulla Basha SyedHemant AryaI-Hsuan FuTeng-Kuang YehLatha PeriyasamyHsing-Pang HsiehMohane Selvaraj CoumarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-18 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Safiulla Basha Syed Hemant Arya I-Hsuan Fu Teng-Kuang Yeh Latha Periyasamy Hsing-Pang Hsieh Mohane Selvaraj Coumar Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer
description	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.
format	article
author	Safiulla Basha Syed Hemant Arya I-Hsuan Fu Teng-Kuang Yeh Latha Periyasamy Hsing-Pang Hsieh Mohane Selvaraj Coumar
author_facet	Safiulla Basha Syed Hemant Arya I-Hsuan Fu Teng-Kuang Yeh Latha Periyasamy Hsing-Pang Hsieh Mohane Selvaraj Coumar
author_sort	Safiulla Basha Syed
title	Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer
title_short	Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer
title_full	Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer
title_fullStr	Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer
title_full_unstemmed	Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer
title_sort	targeting p-glycoprotein: investigation of piperine analogs for overcoming drug resistance in cancer
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8f1abc9fc04a4f1dbd447a375a78af9c
work_keys_str_mv	AT safiullabashasyed targetingpglycoproteininvestigationofpiperineanalogsforovercomingdrugresistanceincancer AT hemantarya targetingpglycoproteininvestigationofpiperineanalogsforovercomingdrugresistanceincancer AT ihsuanfu targetingpglycoproteininvestigationofpiperineanalogsforovercomingdrugresistanceincancer AT tengkuangyeh targetingpglycoproteininvestigationofpiperineanalogsforovercomingdrugresistanceincancer AT lathaperiyasamy targetingpglycoproteininvestigationofpiperineanalogsforovercomingdrugresistanceincancer AT hsingpanghsieh targetingpglycoproteininvestigationofpiperineanalogsforovercomingdrugresistanceincancer AT mohaneselvarajcoumar targetingpglycoproteininvestigationofpiperineanalogsforovercomingdrugresistanceincancer
_version_	1718388779700453376

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

Ejemplares similares