Abstract
The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of Pseudomonas Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of E.coli and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC50 values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.
Highlights
Prostate cancer (PCa) is the second most common malignancy in men worldwide
epidermal growth factor (EGF)-PE40 or EGF-PE24mut, morphological were observed in the PCa cells towards cell death, whereas no signs of cell death or changes were observed in the PCapointing cells pointing towards cell death, whereas no signs of cell death morphological changes were observed in WST-1 viability assay, we found or morphological changes were observed in Chinese hamster ovary (CHO) cells (Figure S1)
Using WST-1 viability assay, we found that EGF-PE40 and EGF-PE24mut reduced the viability of all PCa cell lines6 of in13a time and concentration dependent manner (Figure 5a, Table 1)
Summary
Prostate cancer (PCa) is the second most common malignancy in men worldwide. More than. Seven immunodominant B-cell epitopes of domain III are mutated targeted toxins EFG-PE40 and EGF-PE24mut on different PCa cell lines, representing advanced to alanines (R427A, R458A, D463A, R467A, R490A, R505A, R538A) [34]. We tested the targeted toxins stages of the disease, in view of protein biosynthesis inhibition, cytotoxicity and induction of EFG-PE40 and EGF-PE24mut on different PCa cell lines, representing advanced stages of the disease, apoptosis. We found that both are promising candidates for further development to be used for the in view of protein biosynthesis inhibition, cytotoxicity and induction of apoptosis. Are promising candidates for further development to be used for the future treatment of PCa
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