Amlodipine and Verapamil, Voltage-Gated Ca2+ Channel Inhibitors, Suppressed the Growth of Gastric Cancer Stem Cells

Background The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for gastric cancer. The present study investigated ion channel expression profiles in gastric CSCs (GCSCs). Methods Cells strongly expressing CD44 were separated from MKN74 cells, a human gastric cancer cell line, by fluorescence-activated cell sorting (FACS), and GCSCs were identified based on tumorsphere formation. Gene expression profiles in GCSCs were examined by a microarray analysis. Results Among MKN74 cells, CD44 messenger RNA levels were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to cisplatin. The microarray analysis revealed that the expression of several genes related to voltage-gated Ca 2+ channels (VGCCs), including CACNA2D1 and CACNB4, was upregulated. The cytotoxicities of the CACNA2D1 inhibitor amlodipine and the CACNB4 inhibitor verapamil were greater at lower concentrations in CSCs than in non-CSCs, and markedly reduced tumorsphere numbers. Tumor volumes were significantly smaller in a xenograft nude mouse model treated with amlodipine or verapamil in combination with cisplatin than in that treated with cisplatin alone. Conclusions The present results indicate that VGCCs play a role in maintaining CSCs, and demonstrated the potential of their specific inhibitors, amlodipine and verapamil, as targeted therapeutic agents against gastric cancer.