Natural sesquiterpene lactones as inhibitiors of leukaemia-associated transcription factor c-Myb

The transcription factor c-Myb is essential for immature hematopoietic cell proliferation. It has been discovered that changes in the c-myb gene are responsible for development of some kinds of acute lymphatic leukaemia. Inhibition of this target might be of interest as a novel therapeutic strategy [1]. Up to present, however, no inhibitor is known that might be used in therapy. Our main interest is directed towards sesquiterpene lactones (STLs). Such compounds show a wide variety of biological activities and some are known to inhibit transcription factors, e.g. NF-κB. We have recently discovered that some STLs inhibit transcription of a c-Myb regulated gene. Especially the helenanolide Mexicanin-I (structure as depicted) showed high potency as a c-Myb inhibitor [2]. Based on a bioassay that reflects a direct connection between fluorescence and c-Myb activity, we found that Mexicanin-I at concentrations of 1, 3 and 10µM inhibits the c-Myb induced fluorescence activity to 66, 42 and 16%, respectively, compared to an untreated control. It has been verified by MTT-assay, that these results are not solely based on cytotoxic effects. A selection of further STLs of different structural types was shown to cause effects of varying magnitude in this assay. Furthermore, several crude extracts of Asteraceae were tested and the active compounds obtained by bioactivity-guided isolation. Based on the chemical structures of the investigated compounds, it is possible to draw first conclusions about structure-activity-relationships.

Fig.1: Mexicanin-I

Acknowledgements: Financial Support from the José Carreras Leukämie-Stiftung is most gratefully acknowledged.

References: 1. Ramsay, R.G. et al. (2008), Nature Rev. Cancer 8: 523–534.

2. Klempnauer K.-H. et al. in preparation.