Verapamil enhances the toxicity of conjugates of epidermal growth factor with Pseudomonas exotoxin and antitransferrin receptor with Pseudomonas exotoxin.
Verapamil, a clinically important calcium channel blocker, has been found to cause a 40-fold enhancement of killing of the human KB cell line by a cytotoxic conjugate of epidermal growth factor with Pseudomonas exotoxin (EGF-PE). Synergistic effects of verapamil and EGF-PE are also seen on HeLa D98 cells and a human epidermal carcinoma cell line, A431. Verapamil also potentiates the effect of a toxic conjugate formed between Pseudomonas exotoxin and a monoclonal antibody to the human transferrin receptor (anti-TFR-PE) and enhances the effect of Pseudomonas exotoxin (PE) alone. Two other calcium antagonists were tested. Diltiazem enhances the cytotoxic effect of EGF-PE, but nifedipine does not. Verapamil does not affect the binding and uptake of 125I-EGF by KB cells, but it significantly delays the disappearance of internalized 125I-EGF from the cells. Density gradient fractionation studies using cell homogenates suggest that 125I-EGF accumulates in an undegraded form in lysosomes when cells are treated with verapamil. By immunofluorescence microscopy using an antibody to PE, EGF-PE was found to accumulate in lysosomes; by electron microscopy the lysosomes had an abnormal appearance. The effects of verapamil on toxicity of EGF-PE and lysosomal function appear to be related. However, it is not known whether the enhanced toxicity of EGF-PE in the presence of verapamil is due to its delayed degradation in lysosomes or some more general effect of verapamil on membrane permeability.
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D005098:Exotoxins / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000276:immunology*; D011990:Receptors, Transferrin; D012878:Skin Neoplasms / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D004110:Diltiazem; D004815:Epidermal Growth Factor; D005098:Exotoxins; D009543:Nifedipine; D011956:Receptors, Cell Surface; D011990:Receptors, Transferrin; D014700:Verapamil; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A