Spathulenol inhibit the human ABCB1 efflux pump

Since multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy, the search for new compounds that can be used as adjuvants of chemotherapy is urgent. This study focuses on the evaluation of cytotoxicity and MDR reversal activity of eleven compounds representing diverse structural types of Asteraceae sesquiterpenes. Xanthatin, 4-epixanthanol, sintenin, cnicin, 4′-acetylcnicin, 3b-hydroxycostunolide, desacetylmatricarin, paulitin, isoalantolactone, chrysanin and spathulenol were tested, by flow cytometry, for their activities as modulators of the efflux of rhodamine123 by the human ABCB1 (commonly known as P-gp) pump. Two cell lines were used: a L5178 mouse T-cell lymphoma cell line (PAR cell line) and the L5178 mouse T-cell lymphoma cells transfected with pHa MDR1/A retrovirus (MDR cell line). It was observed (figure 1) that spathulenol highly promoted the accumulation of rhodamine123 (substrate of the ABCB1) by the MDR cells, which over-expresses the ABCB1 efflux pump. Spathulenol, sintenin and desacetylmatricarin presented moderate or low cytotoxicity with IC50 higher than 6µM, while the remaining compounds presented higher cytotoxicity against the two cell lines tested. The results with spathulenol suggest that this compound is a good candidate to be used in combination chemotherapy of MDR cancer and therefore is worthy for further in vivo studies.

Fig.1: Histogram of activity of 2 and 20µM of spathulenol on the retention of rhodamine 123 by the MDR mouse lymphoma cells

Acknowledgements: This work was supported by Hungarian Research Fund (OTKA K72771) grant. The author thanks Dr. Imre Ocsovszki for the flow cytometry measurements. A. Vasas acknowledges the János Bolyai Scholarship of the Hungarian Academy of Sciences.