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The mechanism of action of new antitumor drug FL118

 

FL118 is identified as one of the high efficiency FDA-approved camptothecin analogues owning to its good antitumor effect by inhibiting human survivin expression. Recently, Ling et al. demonstrated the mechanism of FL118 antitumor action. The drug suppress tumor growth by promotion of MdmX degradation and consequent stimulation of p53 signaling. The article was published on Cancer Research.

 

It has been reported that p53 signaling can induce senescence and apoptosis of lymphoma as well as colon cancer in mouse models. The activation of p53 is determined by perturbation of p53/Mdm2 feedback loop mediated by MdmX. Researchers found FL118 induced a decrease of Mdm2-p53 interactions and a increase of Mdm2-MdmX interactions at the same level, indicating a change of Mdm2 target from p53 to MdmX. Therefore, FL118 inhibits Mdm2-mediated p53 polyubiquitination and monoubiquitination, and promotes Mdm2-mediated MdmX ubiquitination, as a result, stimulates p53 signaling and leads to senescence in colorectal cancer cells. In addition, FL118 also enable to induce p53-independent apoptosis in those cells. The findings indicate FL118 is an superior antitumor agent and holds a promising potential as a novel  therapeutic strategy.

 

Reference:
Cancer Res. 2014 Dec 15;74(24):7487-97. 

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