New MDR modulators and apoptosis inducers from Euphorbia species

Several macrocyclic diterpenes with jatrophane or lathyrane skeletons were isolated from methanol extracts of Hungarian Euphorbia species and evaluated for multidrug resistance (MDR)-reversing activity on a human colon cancer cell line. MDR-reversing activity was tested by using a standard functional assay with Rhodamine 123 as a fluorescent substrate analogue of epirubicin. In the model of combination chemotherapy, the interactions between epirubicin and certain resistance modifiers were studied in vitro. Compound 8 proved to be the most active, exhibiting a synergistic interaction. The capacity of the most effective derivative to induce apoptosis was demonstrated by flow cytometric analysis and by staining with ethidium bromide and acridine orange, using human mdrl gene-transfected mouse lymphoma cells and a human cervical adenocarcinoma cell line. The selected diterpene was able to induce moderate apoptosis in the tested cell lines. The data presented here indicate that naturally occurring Euphorbia diterpenes can be regarded as effective lead compounds for the reversal of MDR.