| Recently, the novel small chemical molecule FL118 has been reported and seems a promising agent because of its superior anti-tumor activity in head and neck cancer in vivo and in colon cancer cells in vitro. FL118 has shown to specifically inhibit anti-apoptotic proteins (e.g. survivin) and induce pro-apoptotic proteins (e.g. Bax and Bim)7. Also, FL118 cell killing is mediated regardless of the p53 status.;Here, we investigated the mechanism of action of FL118 in retinoblastoma in monotherapy and in combination therapy with the well-established topoisomerase inhibitor topotecan23 and the platinum-based agent cisplatin 26. In addition, we generated p53 and Mdmx gene knockdown models in vitro in retinoblastoma tumor cells to study the effect of these genes on FL118 cytotoxicity. We observed a synergistic effect of the combination therapy according to one single experiment. We observed that p53 plays a significant role in FL118 drug cytotoxicity and Mdmx slightly modifies FL118 cytotoxicity. In addition, Fl118 activates p53 via an ATM-independent manner, but the exact mechanism of p53 activation still remains unknown.;We believe FL118-based mono- and combination therapies merit further investigations in more retinoblastoma cell lines, and new knowledge on this novel compound will hopefully lead to its clinical trials for improved cancer treatment in the future. |
