HERG K+ channel related chemosensitivity to sparfloxacin in colon cancer cells
- Jian-Hua Gong
- Xiu-Jun Liu
- Bo-Yang Shang
- Shu-Zhen Chen
- Yong-Su Zhen
Published online on: Tuesday, June 1, 2010
Potassium channels are essential for the regulation of cell proliferation. As reported, HERG protein is overexpressed in a wide range of human tumors, including colon carcinoma. The aim of this study was to investigate the effects of antibacterial agents sparfloxacin (SPFX), a blocker of HERG channel, on HERG K+ channel highly expressing colon cancer cells. Expression of HERG and apoptosis correlative proteins was examined by Western blotting. The MTT assay was used to detect the cytotoxicity of drugs and drug combination in vitro. Gene transfection was used to examine the changes in herg-related chemosensitivity. Cell apoptosis was analyzed by flow cytometry. The migration and invasion capacity of tumor cells by SPFX was determined by gelatin zymography assay and Boyden chamber. The in vivo efficacy of SPFX was assessed in murine colon carcinoma C26 in BALB/c mice and human colon carcinoma HCT116 xenografts in nude mice. High expression of HERG protein was detected in colon cancer C26, HCT116 and HT-29 cells. The cell viability of the colon cancer cells was inhibited by SPFX in a dose-dependent manner. SPFX induced apoptosis and inhibited migration and invasion of colon cancer HCT116 cells. The increase in apoptosis was associated with a decrease in procaspase-3 and Bcl-2 protein expression. Study with herg-transfected HEK293 cells and siRNA-knock down HCT116 cells confirmed that the cell viability inhibition by SPFX was correlated with HERG expression. When combined with 5-fluorouracil, SPFX showed synergistic anti-proliferation activity in HCT116 and HT-29 cells. Furthermore, SPFX inhibited the growth of human colon carcinoma HCT116 xenografts and showed synergistic effect with 5-fluorouracil in vivo. Our finding suggested that SPFX could be a biochemical modulator in treatment of colon cancer with chemotherapeutic drugs.