P5.02 - Development of Novel Anticancer Agents that Target Prohibitins and the Translation Initiation Factor eIF4A

Abstract

ABSTRACT Flavaglines are a family of anticancer natural products that relieve the resistance to certain cancer chemotherapies and display a strong cytotoxicity that is specific to cancer cells [ 1 ]. We identified the first synthetic flavaglines that inhibit cell proliferation and viability (IC50 ≈ 1 nM) at lower doses than did the parent natural compounds [ 1 ]. These synthetic flavaglines retain their potency against multiresistant cell lines, induce apoptosis independently of “classical” apoptosis pathways and potentiates the effects of chemotherapeutic agents. Not only flavaglines are not toxic to non-cancer cells, but they can protect normal cells from various stresses. Indeed, we demonstrated that these compounds could protect myocardial and neuronal cells from anthracyclines and cisplatin-induced cytotoxicity [ 1 , 2 ]. Flavaglines can exert their anticancer activity via several mechanisms. We demonstrated that they bind to prohibitins-1 and -2, (PHB1 and PHB2) which are pleiotropic proteins that act as a hub for many signaling pathways to regulate metabolism, cell migration, division and survival (3). We demonstrated that the binding of flavaglines to PHBs prevents interaction between PHBs and CRaf and, thereby, inhibits CRaf activation and subsequently CRaf-MEK-ERK signaling, which is critical to survival and proliferation of cancer cells (4). Flavaglines also directly inhibit another emerging target in oncology, the translation initiation factor eIF4A. In vivo data indicate that inhibition of eIF4A by flavaglines could overcome most of the resistance mechanisms arising in BRAF(V600)-metastatic melanoma (5). Flavaglines thus appear as appealing potential anticancer agents, warranting further investigations especially in the context of cancer depending on the MAP-kinase pathway. Download : Download full-size image 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.