Planta Med 2006; 72 - P_051
DOI: 10.1055/s-2006-949851

Diterpenic compounds as antineoplasic agents in classical and atypical multidrug resistant cancer cells

N Duarte 1, H Lage 2, MJU Ferreira 1
  • 1CECF, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1600–083 Lisbon, Portugal
  • 2Charité Campus Mitte, Institute of Pathology,Schumannstr. 20/21, D-10117 Berlin, Germany

The successful chemotherapy of neoplasic diseases requires that the antitumor combination of drugs employed displays a sustained activity against malignant cells. Simultaneous resistance of cancer cells to multiple classes of structurally and mechanistically unrelated antitumor drugs can be defined as multidrug resistance (MDR), and it is one of the main causes of chemotherapy failure [1].

In addition with the classical multidrug phenotype mediated by increased activity of the ATP-binding cassette transporters P-gp / MDR1, that were responsible for the efflux of drugs out of the cells, there are other multidrug resistant tumors with resistance caused by different mechanisms. This is called atypical resistance and could be due to the decreased DNA topoisomerase (Topo II)-like activity. DNA topoisomerases are nuclear enzymes that are essential for DNA replication, transcription, chromosomal aggregation and DNA recombination. For these reasons, Topo II is one of the possible targets for the commonly used anticancer drugs [2].

The aim of this work is to study the antiproliferative effect of diterpenic compounds isolated from Euphorbia species in various human drug sensitive cancer cell lines (gastric, pancreatic and colon carcinomas) and in classical and atypical multidrug resistant sublines of these cell models. Etoposide was used as positive control. It could be demonstrated, that most of the drug resistant cell variants decreased the expression levels of both Topo II isoforms on mRNA level as well as on protein level. None of the tested compounds were as effective as etoposide, but some of them are much more effective in drug resistant cells that in drug sensitive cell lines. In conclusion, some of these compounds may be considered as potential new drugs for the treatment of drug-resistant human cancer cells.

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

References: 1. Avendaòo, C. et al. (2002), Curr. Med. Chem. 9: 159–193. 2. Lage, H. et al. (2000), Lancet Oncol. 1: 169–175.