Effects of piceatannol derivatives in the antiproliferative activity of the anticancer-drug doxorubicine and on apoptosis induction in MDR cancer cell lines

Historically, plants have provided a source of novel drug compounds and have shown great promise in the treatment of diseases, particularly cancers. A great number of phytochemicals have been demonstrated to have antitumor activity in various experimental systems. Their mechanism of action may affect many different targets of the signal transduction pathway that modulate gene expression, cell cycle progression, proliferation, cell mortality, metabolism and apoptosis [1].

In this study, piceatannol, was isolated from the methanolic extract of Euphorbia lagascae L. defatted seeds. This compound was methylated with diazomethane to afford three derivatives that were identified by their physical and spectroscopic data. Piceatannol and the three methylated derivatives were evaluated as multidrug resistance modulators, by using the rhodamine 123 exclusion test, and apoptosis inducers on multidrug resistant mouse lymphoma cells. Furthermore, the antiproliferative effects of the anticancer drug doxorubicine in combination with one of these resistance modifiers were studied on human MDR1 gene transfected mouse lymphoma and doxorubicine resistant human breast cancer cell lines. Verapamil and 12H-benzo(α)-phenothiazine were used as positive controls for the MDR and apoptosis assays, respectively.

Piceatannol and its methylated derivatives can be considered as apoptosis inducers. On the other hand, one of the methylated compounds was found to be a powerful inhibitor of p-glycoprotein activity, and has shown in combination with doxorubicine, an additive effect on human MDR1 gene transfected mouse lymphoma cells.

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

Reference: 1. HemaIswarya, S. et al. (2006), Phytotherapy Res. 20: 239–249.