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

Abstract

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 Ca2+ 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.

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Acknowledgments

This study was supported by Grants-in-Aid for Scientific Research (C) [17K10602, 17K10710, 18K08628, 18K08689, 19K09202, and 19K09182] and a Grant-in-Aid for Young Scientists (19K18160) from the Japan Society for the Promotion of Science.

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Contributions

AS, KK, MK, HS, TK, HI, TA, HK, SK, TK, HF, KO, and EO designed the research. AS, KK, and EO wrote the paper. AS, KK, MK, HS, and TK performed cell culture, molecular biology, and several experiments.

Corresponding author

Correspondence to Atsushi Shiozaki MD, PhD.

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Atsushi Shiozaki, Keita Katsurahara, Michihiro Kudou, Hiroki Shimizu, Toshiyuki Kosuga, Hiroshi Ito, Tomohiro Arita, Hirotaka Konishi, Shuhei Komatsu, Takeshi Kubota, Hitoshi Fujiwara, Kazuma Okamoto, and Eigo Otsuji have no conflicts of interest or financial ties to declare.

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Shiozaki, A., Katsurahara, K., Kudou, M. et al. Amlodipine and Verapamil, Voltage-Gated Ca2+ Channel Inhibitors, Suppressed the Growth of Gastric Cancer Stem Cells. Ann Surg Oncol (2021). https://doi.org/10.1245/s10434-021-09645-0

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