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Molecules 2017, 22(2), 199; doi:10.3390/molecules22020199

Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition

1
Institute of Pharmacognosy, University of Szeged, 6720 Szeged, Hungary
2
Interdisciplinary Centre for Natural Products, University of Szeged, Eötvös str. 6, 6720 Szeged, Hungary
3
Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm sq. 9, 6720 Szeged, Hungary
4
NMR Group, Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért Sq. 4, H-1111 Budapest, Hungary
Current address: Synthetic Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Temesvári krt. 62, 6726 Szeged, Hungary
*
Author to whom correspondence should be addressed.
Academic Editor: Constantinos M. Athanassopoulos
Received: 2 December 2016 / Revised: 18 January 2017 / Accepted: 18 January 2017 / Published: 25 January 2017
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
View Full-Text   |   Download PDF [771 KB, uploaded 25 January 2017]   |  

Abstract

P-glycoprotein (P-gp, ABCB1) over-expression, causing a multi-drug resistant (MDR) phenotype, is a major problem in cancer chemotherapy that urgently requires novel approaches. Our previous studies showed certain ecdysteroid derivatives as promising chemo-sensitizers against MDR and non-MDR cancer cell lines while also exerting mild to moderate inhibition of P-gp function. Here we report the preparation of a set of substituted 2,3-dioxolane derivatives of poststerone, a known in vivo metabolite of 20-hydroxyecdysone (20E). In contrast with previously studied ecdysteroid dioxolanes, the majority of the new compounds did not inhibit the efflux function of P-gp. Nevertheless, a strong, dose dependent sensitization to doxorubicin was observed on a P-gp transfected cancer cell line and on its susceptible counterpart. We also observed that the MDR cell line was more sensitive to the compounds’ effect than the non-MDR. Our results showed for the first time that the chemo-sensitizing activity of ecdysteroids can be fully independent of functional efflux pump inhibition, and suggest these compounds as favorable leads against MDR cancer. View Full-Text
Keywords: ecdysteroid metabolite; poststerone acetonide; ABCB1 efflux transporter; cancer; multi-drug resistance; chemo-sensitization; combination therapy ecdysteroid metabolite; poststerone acetonide; ABCB1 efflux transporter; cancer; multi-drug resistance; chemo-sensitization; combination therapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Hunyadi, A.; Csábi, J.; Martins, A.; Molnár, J.; Balázs, A.; Tóth, G. Backstabbing P-gp: Side-Chain Cleaved Ecdysteroid 2,3-Dioxolanes Hyper-Sensitize MDR Cancer Cells to Doxorubicin without Efflux Inhibition. Molecules 2017, 22, 199.

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