Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrhea
| Autor: | Onur Cil, Alan S. Verkman, Tianying Duan, Jay R. Thiagarajah |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Diarrhea
0301 basic medicine Cell Membrane Permeability Potassium Channels Colon medicine.drug_class Afatinib Cystic Fibrosis Transmembrane Conductance Regulator Pyrimidinones Pharmacology Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine ErbB Neoplasms Acetamides Oxazines Potassium Channel Blockers medicine Animals Humans Pyrroles Channel blocker Clotrimazole Intestinal Mucosa Protein Kinase Inhibitors Epithelial polarity Chemistry Epithelial Cells Trityl Compounds General Medicine Apical membrane Potassium channel Rats respiratory tract diseases ErbB Receptors Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Chloride channel Female Research Article medicine.drug |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.126444 |
| Popis: | Diarrhea is a major side effect of ErbB receptor tyrosine kinase inhibitors (TKIs) in cancer chemotherapy. Here, we show that the primary mechanism of ErbB TKI diarrhea is activation of basolateral membrane potassium (K(+)) channels and apical membrane chloride (Cl(–)) channels in intestinal epithelia and demonstrate the efficacy of channel blockers in a rat model of TKI diarrhea. Short-circuit current in colonic epithelial cells showed that the TKIs gefitinib, lapatinib, and afatinib do not affect basal secretion but amplify carbachol-stimulated secretion by 2- to 3-fold. Mechanistic studies with the second-generation TKI afatinib showed that the amplifying effect on Cl(–) secretion was Ca(2+) and cAMP independent, was blocked by CF transmembrane conductance regulator (CFTR) and K(+) channel inhibitors, and involved EGFR binding and ERK signaling. Afatinib-amplified activation of basolateral K(+) and apical Cl(–) channels was demonstrated by selective membrane permeabilization, ion substitution, and channel inhibitors. Rats that were administered afatinib orally at 60 mg/kg/day developed diarrhea with increased stool water from approximately 60% to greater than 80%, which was reduced by up to 75% by the K(+) channel inhibitors clotrimazole or senicapoc or the CFTR inhibitor (R)-BPO-27. These results indicate a mechanism for TKI diarrhea involving K(+) and Cl(–) channel activation and support the therapeutic efficacy of channel inhibitors. |
| Databáze: | OpenAIRE |
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