RESEARCH ARTICLE FL3, a Synthetic Flavagline and Ligand of Prohibitins

Aims The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flava-glines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxo-rubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated. Methods and Results Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimeriza-tion of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, sup-presses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyo-cytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3. Conclusion Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems