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Antiproliferative activity of ent-abietane lactones against resistant human cancer cell lines
Multidrug resistance (MDR) is considered to be one of the main causes of chemotherapy failure. The mechanisms of MDR could be related with the intracellular drug distribution through overexpression of certain transport proteins (e.g. Pgp/MDR1). This type of MDR is often known as classical or typical MDR. However, it does not completely explain the phenomenon. Alternative forms of MDR have been described, known as atypical MDR that included, among others, the change in drug targets (e.g. decreased activity of Topoisomerase II) . 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 . The aim of this work was to study the antiproliferative effect of several ent-abietane diterpenic lactones, isolated from Euphorbia tuckeyana, in human cancer cell lines, which were derived from three different tumour entities: gastric (EPG85–257), pancreatic (EPP85–181) and colon (HT-29) carcinomas. The classical and atypical MDR sublines of these cell models were also investigated. IC50 values were determined by proliferation assays, after continuous exposure for 5 days. Relative resistance (RR) was also determined as the relation between the IC50 of the resistance cell line and the IC50 of the parental drug-sensitive cell line. In parental drug sensitive cell lines, all the tested compounds showed a weak antiproliferative effect. However, most of the drug resistant cancer sublines showed increased sensitivities to the studied compounds when compared to the parental sublines. Some of the tested compounds were found to be highly effective against the classical MDR subline of gastric carcinoma, showing RR of 0.08 and 0.09. The results obtained lead to conclude that, ent-abietane lactones may be considered as potential new drugs for the treatment of drug-resistant human cancer cells.
References: 1. Szakács, G. et al. (2006) Nat Rev Drug Discov. 5:219. 2. Lage, H. et al (2000) Lancet Oncol. 1:169.