The Department of Biomedicine

Seminar: Dr. Laurent Désaubry

Development of novel anticancer and cardioprotective agents that target prohibitins and the translation initiation factor eIF4a

Figure. Anticancer mechanisms of flavaglines
Figure. Anticancer mechanisms of flavaglines. (A) Inhibition of the activation of CRAF by Ras. (B,C) Translocation of AIF and caspase-12 to induce apoptosis. (D) Inhibition of eIF4A overcoming resistance to therapies targeting BRAF or MEK.
Dr. Laurent Désaubry

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Dr. Laurent Désaubry*
CNRS Research Director, Professor
CNRS-Strasbourg University, France
Tianjin University of Science and Technology (TUST), China

Flavaglines are a family of anticancer natural products that relieve the resistance to cancer chemotherapies and display a strong cytotoxicity that is specific to cancer cells in a low nanomolar range.1,2 Not only flavaglines are not toxic to non-cancer cells, but they protect normal cells from various stresses. Thus, we demonstrated for the first time that these compounds protect the heart and neurons from the adverse effects of cancer chemotherapies involving anthracyclines and cisplatin.2-4 With our collaborators, we also identified the scaffold proteins prohibitins-1 and -2 (PHB1/2)5 as the molecular targets of flavaglines.6 We found that flavaglines and another PHB ligand, fluorizoline, block the interaction between PHBs and C-RAF and, thereby, inhibit C-RAF, which is critical to survival and proliferation of cancer cells.6,7 Flavaglines also directly inhibit another emerging target in oncology, the translation initiation factor eIF4a. In vivo data indicate that flavaglines could greatly improve the treatment of chemoresistant metastatic melanoma.8

1. Basmadjian C. et al. Flavaglines: potent anticancer drugs that target prohibitins and the eIF4 helicase. Future Med. Chem. 5, 2185-97 (2013).
2. Ribeiro N. et al. Flavaglines as potent anticancer and cytoprotective agents. J Med Chem 55, 10064–10073 (2012).
3. Bernard Y. et al. The Flavaglines alleviate doxorubicin cardiotoxicity: implication of Hsp27. Plos One 6, e25302, (2011).
4. Qureshi R. et al. FL3, a synthetic flavagline and ligand of prohibitins, protects cardiomyocytes via STAT3 from doxorubicin toxicity. Plos One. 11, e0141826 (2015).
5. Thuaud F. et al. Prohibitin ligands in cell death and survival: mode of action and therapeutic potential. Chem. Biol. 20, 316–331 (2013).
6. Polier G. et al. The natural anticancer compounds rocaglamides inhibit the Raf-MEK-ERK pathway by targeting prohibitin 1 and 2. Chem. Biol. 19, 1093-104 (2012).
7. Yurugi H. et al. Oncogene 36: in press (2017).
8. Boussemart L. et al. eIF4F is a key and targetable convergence nexus of multiple resistance mechanisms to anti-RAF and anti-MEK cancer therapies. Nature 513, 105–109 (2014).

Chairperson: Anni Vedeler, Anni.Vedeler@uib.no, The Department of Biomedicine