Synergistic effects between macrocyclic diterpenes and doxorubicine on resistant cancer cells

The large structural diversity and complexity of plant-derived compounds makes them a very important source of leads in drug discovery and development. Due to the widespread increase of multidrug resistance (MDR), particularly in areas such as oncology and infectious diseases, there is an urgent need to identify new and effective molecules, which can act either as anticancer and antimicrobial drugs, or modulators of multidrug resistance.[1] MDR is often associated with the overexpression of P-glycoprotein (Pgp), which can prevent the accumulation of drugs by expelling them from the cell membrane before they are able to interact with their cellular targets.[2] Euphorbia species have been a source of a great variety of macrocyclic diterpenes, with the lathyrane and jatrophane skeleton, which have been reported to be potent modulators of MDR in cancer cell lines.[3], [4] In our search for biologically active compounds from plants, three new macrocyclic diterpenes with the jatrophane skeleton have been isolated from the methanolic extract of Euphorbia tuckeyana (whole plant) by chromatographic methods. Moreover, one lathyrane diterpene previously isolated from Euphorbia lagascae [5] was derivatized using several reagents, to afford three new ester diterpenes. All the structures were deduced from their physical and spectroscopic data (IR, MS, 1D and 2D NMR). Their multidrug resistance modulating properties were evaluated using the rhodamine-123 assay, in both MDR1-gene transfected and parental mouse lymphoma cell lines. Verapamil was used as a positive control. Furthermore, the antiproliferative effects of the anticancer drug doxorubicine, in combination with these macrocyclic diterpenes, were studied on the same cell lines, showing a synergistic effect. All of the tested compounds were able to reverse MDR on human MDR1 gene transfected mouse lymphoma cells, being much more active than the positive control. Jatrophane diterpenes were found to be potent inhibitors, exhibiting a dose dependent activity.

References: [1] Butler, M. et al (2006) Biochem. Pharmacol. 71: 919; [2] Hendrich, A. et al (2003) Bioch. Biophys. Res. Com. 304: 260; [3] Duarte, N. et al (2007) Bioorg. Med. Chem. 15: 546; [4] Corea, G. et al. (2005) J. Med. Chem. 48: 7055; [5] Duarte, N. et al (2006) Planta Med. 72: 162.