Planta Med 2014; 80 - P1L5
DOI: 10.1055/s-0034-1394663

Lathyrane diterpenes from Euphorbia boetica and Euphorbia pedroi: Promising ABCB1 modulators for overcoming multidrug resistance

S Neto 1, C Vieira 1, AM Matos 1, A Mónico 1, R Ferreira 1, M Reis 1, C Pedro 1, AM Madureira 1, G Spengler 2, J Molnár 2, N Duarte 1, MJU Ferreira 1
  • 1Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649 – 003 Lisboa, Portugal
  • 2Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary

Euphorbia species have been a source of a great variety of structurally unique macrocyclic diterpenes, which have been reported to be potent modulators of multidrug resistance (MDR) in cancer cell lines [1]. MDR is a complex and multifactorial phenomenon that frequently hamper the successful treatment of cancer diseases. One of the most relevant mechanisms of MDR is related with the overexpression of transmembrane proteins of the superfamily of ATP-binding cassette (ABC) transporters, such as ABCB1 efflux pump (P-glycoprotein, Pgp) [2]. Aiming to obtain a high number of bioactive diterpenes in order to improve further structure-activity relationship studies, the phytochemical study of E. boetica and E. pedroi has been carried out. In this way, the air-dried powdered aerial parts of these plants were exhaustively extracted with methanol. The methanolic extracts were re-suspended in MeOH/H2O solution and sequentially extracted with hexane and ethyl acetate. The ethyl acetate soluble parts have been fractionated by chromatographic techniques, yielding several polyacylated lathyrane-type diterpenes, including nine new compounds. Some polyclyclic diterpenes, tetracyclic triterpenes and steroids were also isolated. All the structures were deduced from their physical and spectroscopic data, namely IR, MS, 1D- and 2D-NMR (COSY, HMQC, HMBC and NOESY). MDR reversal was investigated by flow cytometry, measuring the rhodamine-123 accumulation on mouse T-lymphoma cells. Compounds were tested at 2 and 20µM. The majority of the diterpenes tested showed to be very strong modulators of the efflux-pump activity of Pgp. Furthermore, some of these modulators were assayed, in vitro, for their effects in combination with doxorubicin, being able to synergistically enhance the antiproliferative activity of the anticancer drug.

Acknowledgements: FCT, Portugal (PTDC/QUI-QUI/099815/2008; PTDC/QEQ-MED/0905/2012; PEst-OE/SAU/UI4013/2011; PhD grants SFRH/BD/72915/2010 and SFRH/BD/84285/2012).

References:

1. Ferreira MJU, Duarte N, et al (2014) Phytochem Rev, advance online publication 1 March 2014; doi: 10.1007/s11101 – 014 – 9342 – 8. 2. Zahreddine H, Borden K (2013) Front Pharmacol 4: 1 – 8.