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Inhibition of P-Glycoprotein Mediated Efflux of Paclitaxel by Coumarin Derivatives in Cancer Stem Cells: An In Silico Approach

[ Vol. 19 , Issue. 6 ]

Author(s):

Anushree Tripathi and Krishna Misra   Pages 497 - 506 ( 10 )

Abstract:


P-glycoprotein (P-gp) is well known to cause multidrug resistance (MDR) in cancer cells. This MDR leads to cancer recurrence which is a major obstacle in cancer treatment. High P-gp expression has been observed in the population of cancer stem cells (CSCs) having self-renewal potential. Early detection and inhibition of these CSCs is directly beneficial to cancer treatment. In this study coumarin derivatives are used to inhibit efflux process and thereby enhance bioavailability of various drugs like paclitaxel (PTX). This drug is most commonly used for the treatment of cancers of breast, ovary, head and neck. Coumarin derivatives can be used to reduce the growth of breast cancer stem cells through P-gp mediated efflux inhibition and paclitaxel bioavailability enhancement. With the use of computational approaches including molecular docking simulation and pharmacophore study, few coumarin derivatives have been found to be more potential inhibitors of P-gp mediated efflux. Based on high affinity inhibitors, new coumarin derivatives have been designed and docked at active site cavity of P-gps. Some newly designed coumarin derivatives were found to be more potent due to their higher binding affinity towards target protein. The finding that newly designed coumarins can be exploited for inhibition of P-gp mediated efflux in order to enhance paclitaxel bioavailability and can inhibit breast cancer stem cell growth is significant for designing potent anticancer drugs.

Keywords:

P-glycoprotein (P-gp), multidrug resistance (MDR), cancer stem cells (CSCs), coumarin derivatives, paclitaxel (PTX), efflux process.

Affiliation:

Division of Applied Science & Indo-Russian Center for Biotechnology (IRCB), Indian Institute of Information Technology, Allahabad-211012, India.



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