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Inhibition of P-glycoprotein activity to overcome multidrug resistance in cancer with new diterpene royleanones from Plectranthus spp.
* 1, 2 , 3 , 4 , 3 , 5 , 5 , 6 , 2 , 1, 2
1  Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Lisboa, Portugal
2  Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Portugal
3  Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Portugal
4  Red Glead Discovery AB, Medicon Village, SE-223 81 Lund, Sweden
5  Institute for Biological Research “Siniša Stanković“- National Institute of Republic of Serbia University of Belgrade, Serbia
6  LAQV/REQUIMTE, Departamento de Ciências Biológicas, Faculdade de Fármacia da Universidade do Porto, Portugal
Academic Editor: Jean Jacques Vanden Eynde

Abstract:

Multidrug resistance (MDR) is one of the major obstacles in cancer chemotherapy. MDR is often associated with overexpression of the efflux pump, P-glycoprotein (P-gp). The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs. In this context, we have recognized Plectranthus plants as potential sources of lead compounds. Accordingly, two natural diterpenoids, 6,7-dehydroroyleanone (1) and 7α-acetoxy-6β-hydroxyroyleanone (2) obtained from Plectranthus spp., exhibited promising cytotoxic activity.

In this work, the reactivity of 1 and 2 was studied to synthesize a library of new derivatives with P-gp inhibitory potential. The ability to inhibit P-gp activity was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R. Furthermore, molecular docking and molecular dynamics studies were conducted to explain the molecular interaction of royleanones with P-gp.

Royleanones 1 and 2 showed similar cytotoxic activity against cancer cell lines and MDR cancer cell lines. Two benzoylated derivatives displayed improved P-gp inhibition activity comparing to the natural ones (1 and 2). Interestingly, one of these derivatives also displayed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin and therefore could be considered as a novel P-gp inhibitor suitable in combination with classic anticancer drugs.

Keywords: Cancer; Multidrug resistance; P-glycoprotein activity; Plectranthus; Royleanone derivatives
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