Search for new natural ligands of the antiapoptotic protein Bcl-xL from Malaysian plants

Bcl-xL is an antiapoptotic protein of the Bcl-2 family located in the membrane of the mitochondria of eukaryote cells. Its involvement in the programmed cell death through the activation of caspase pathway was widely studied and discussed [1,2]. The overexpression of Bcl-xL in cancer cells was reported to have an antiapoptotic effect on tumour and to confer a multidrug resistance [3]. Therefore, the study of the interaction between Bcl-xL and some new ligands appeared to be a very good strategy in the search for new anticancer drugs. Consequently, a biological screening was carried out on 1476 ethyl acetate extracts from various parts of 670 Malaysian plants. The binding activity against Bcl-xL was evaluated using an affinity displacement assay based on Bcl-xL/Bak (BH3 domain) interaction (fluorescence polarization assay). Only 18 extracts revealed a noticeable activity. Among them, the bark extract of Xylopia sp. (Annonaceae) exhibited a significant binding activity: 31% at 10µg/mL. The phytochemical study of the plant was undertaken and bioguided fractionation using silica gel chromatography and HPLC led to the isolation of several ent-trachylobane terpenoids (1), identified by spectroscopic and crystallographic methods. Access to chemodiversity was attempted through bioconversion of the major compound 1 (ent-trachyloban-18-oic acid) using a panel of microorganisms. This work describes biological activity of this chemical series and their structure-activity relationships. Thanks to this screening program of Malaysian plant extracts on Bcl-xL, we were able to discover natural compounds that might be good candidates for further studies in the oncological domain.

Acknowledgement: This work was supported by an ICSN-CNRS grant to one of us (A.L.).

References: 1. Danial, N.N. (2007) Clin. Cancer Res. 13:7254–7262.

2. Adams, J.M., Cory, S. (1998) Science 281:1322–1326.

3. Castilla, C. et al. (2006) Endocrinology 147:4960–4967.