Disruption of the reprogrammed energy management system of malignant cells is a prioritized goal of targeted cancer therapy. Two regulators of this system are the Fer kinase, and its cancer cell specific variant, FerT, both residing in subcellular compartments including the mitochondrial electron transport chain. E260 is a newly developed inhibitor of Fer and FerT with a Kd of 0.85 µM. Onset of death was observed in the E260-treated cells, with an EC50 value of 400 nM after 24 h of treatment and an EC50 of 300 nM after 48 h. Importantly, no death was seen in normal human fibroblasts (Hfb) or normal human epithelial cells, that were treated with E260 under the same conditions. In two other CC cell lines, HCT116 and SW48, which are derived from grade II and grade IV colon carcinoma tumors, respectively, the EC50 values for E260 after 24 h of treatment were above 5 µM. Treatment of the grade IV SW48 cells with 2 µM E260 for 48 h led to their complete death, HCT116 cells treated under these conditions reached only 25% cell death. E260 exhibited an EC50 of 3.2 µM after 72 h treatment of non-metastatic PANC-1 cells. In comparison, SU.86.86 which are metastatic ductal carcinoma cells, proved to be more susceptible to E260 with an EC50 of 1.1 µM after 72 h of treatment. Moreover, a decrease of 35%–40% was observed in the cellular ATP level of CC cells treated with 2 µM E260 for 12 h, a time point preceding the onset of death. In immuno-compromised “Nude” mice introduced with SW620 cells, administration of E260 (25 mg/kg or 50 mg/kg) led to a significant attenuation of tumor progression throughout the experiment, and to a 10-fold decrease in average tumor volume after 22 days of treatment[1].
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