Search for P-glycoprotein modulators and apoptosis inducers on cancer cells among ergostane and stigmastane steroids

N. Duarte; C. Ramalhete; N. Gyémant; A. Varga; J. Molnár; M. J. U. Ferreira

doi:10.1055/s-2006-949852

Planta Medica, Table of Contents

Search for P-glycoprotein modulators and apoptosis inducers on cancer cells among ergostane and stigmastane steroids

N Duarte ¹, C Ramalhete ¹, N Gyémant ², A Varga ³, J Molnár ², MJU Ferreira ¹

¹CECF, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1600–083 Lisbon, Portugal
²Department of Medical Microbiology, University of Szeged, Szeged, Hungary
³Department of Molecular Parasitology, Humboldt University, Berlin, Germany

Abstract

One of the most effective strategies in biological systems to demonstrate resistance to cytotoxic drugs is the efflux of these compounds out of the cell, via membrane transporter proteins. This phenomenon is called multidrug resistance (MDR) and is a mediator of drug resistance observed in tumor cells and in microorganisms (in vivo and in vitro) [1]. There are numerous resistance mechanisms and the MDR phenotype alone, can not completely explain this occurrence. In fact, several other related proteins are also overexpressed in resistant tumors. Furthermore apoptosis also play a vital role in resistance [2]. Because apoptosis is a major modality by which different tumor cell types can be eliminated, the identification of new drugs able to induce the programmed cell death is an important goal in cancer therapy, and may provide new useful tools for the treatment of patients with drug resistance malignancies. In this context, plants could be potential sources for the isolation of new metabolites that could be used as lead molecules on the treatment of neoplasic diseases.

In our search for biologically active compounds from Euphorbia species, several ergostane and stigmastane steroids were isolated from the methanolic extract of Euphorbia lagascae, and its structures were deduced by the combination of physical and spectroscopic data (IR, MS, 1D and 2D NMR). The ability of some of the isolated steroids to modulate MDR reversion was investigated using mdr-1 (L5178) mouse lymphoma cell line. In addition, the apoptosis induction on the same cell line was also studied. 12H-benzophenothiazine was used as a positive control for apoptosis induction and verapamil for resistance reversal. The tested compounds were weak inducers of apoptosis in the studied mouse lymphoma cell line, but two of them were found effective on MDR reversion in a concentration dependent manner.

Acknowledgements: The authors thank Dr. Teresa Vasconcelos (ISA, University of Lisbon, Portugal) for identification of the plant.

References: 1. Borges-Walmsley, M. et al. (2003), Biochem. J. 376: 313–338. 2. Volm, M. (1998), Anticancer Res. 18: 2905–2917.