Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer.
Alexandra FischerIsis WolfHendrik FuchsAnie Priscilla MasilamaniPhilipp WolfPublished in: Toxins (2020)
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.
Keyphrases
- epidermal growth factor receptor
- growth factor
- tyrosine kinase
- advanced non small cell lung cancer
- prostate cancer
- cell cycle arrest
- induced apoptosis
- cancer therapy
- escherichia coli
- small cell lung cancer
- endoplasmic reticulum stress
- cell death
- oxidative stress
- newly diagnosed
- radical prostatectomy
- ejection fraction
- drug delivery
- prognostic factors
- binding protein
- biofilm formation
- staphylococcus aureus
- dna binding
- smoking cessation
- replacement therapy
- patient reported