Erythromycin inhibits the proliferation of HERG K+ channel highly expressing cancer cells and shows synergy with anticancer drugs

Abstract

To investigate the effects of erythromycin on the proliferation of the human ether-a-go-go related gene (HERG) K(+) channel highly expressing cancer cells and its synergy with antitumor chemotherapeutic agents. Human fibrosarcoma cell of the line HT-1080, murine colon carcinoma cells of the line C26, human colon carcinoma cells of the line HT-29, human pulmonary epithelial cells of the line A549, and human neuroblastoma cells of the line SH-SY5Y were cultured. Western blotting was used to detect the protein expression of the HERG K(+) channel protein. Erythromycin, taxol, and vincristine were added into the culture fluid. to observe the proliferation of the cancer cells. Collagen I was used to coat 96-well plate, HT-29 cells were put into, and Erythromycin, taxol, and vincristine were added, MTT method was used to examine the cell adhesion. SDS-PAGE was used to detect the secretion of gelatinase. Flow cytometry was used to detect the cell cycle and apoptosis. The coefficient of drug interaction (CDI) was calculated. HERG K(+) channel expression was found in both HT-29 human colon carcinoma cells and C26 murine colon carcinoma cells. The expression level in HT-29 cells was higher than that in the positive control SHSY5Y neuroblastoma cells. Erythromycin suppressed the proliferation of HT-29 and C26 cells in a dose-dependent manner. There existed a remarkable G(2)/M arrest after the cells were exposed to erythromycin. Induction of apoptosis in HT-29 cells and inhibition of cell adhesion to collagen I were found. Erythromycin inhibited the secretion of MMP-2 from HT-29 cells in a dose-dependent manner. At sub-cytotoxic concentration, erythromycin potentiated the cytotoxicity of vincristine, taxol, and hydroxyl-camptothecin to C26 cells. The IC(50) values for vincristine and vincristine plus erythromycin (50 micromol/L) were 62.65 nmol/Land and 4.68 nmol/L respectively. Erythromycin inhibits the proliferation and induces the apoptosis of cancer cells with high HERG K(+) channel expression. Synergy is found in the combination of erythromycin with other anticancer agents.