Verapamil enhances the toxicity of conjugates of epidermal growth factor with Pseudomonas exotoxin and antitransferrin receptor with pseudomonas exotoxin
- 1 September 1984
- journal article
- research article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 120 (3), 271-279
- https://doi.org/10.1002/jcp.1041200303
Abstract
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.This publication has 18 references indexed in Scilit:
- Inhibition of Human Acute Lymphoblastic Leukemia Cells by Immunotoxins: Potentiation by ChloroquineScience, 1984
- Divergence of epidermal growth factor and transferrin during receptor-mediated endocytosisBiochemistry, 1983
- Verapamil enhances the efficiency of DNA-mediated gene transfer in mammalian cellsBiochemical and Biophysical Research Communications, 1983
- Adenovirus-induced release of epidermal growth factor and pseudomonas toxin into the cytosol of KB cells during receptor-mediated endocytosisCell, 1983
- Selective killing of malignant cells in a leukaemic rat bone marrow using an antibody–ricin conjugateNature, 1982
- Epidermal growth factor-toxin A chain conjugates: EGF-Ricin A is a potent toxin while EGF-diphtheria fragment A is nontoxicCell, 1980
- Two species of lysosomal organelles in cultured human fibroblastsCell, 1979
- 125I-labeled human epidermal growth factor. Binding, internalization, and degradation in human fibroblasts.The Journal of cell biology, 1976
- Calcium antagonists and islet function. I. Inhibition of insulin release by verapamilDiabetes, 1975
- Calcium Antagonists and Islet Function: I. Inhibition of Insulin Release by VerapamilDiabetes, 1975