The role of voltage gated T-type Ca²⁺ channel isoforms in mediating “capacitative” Ca²⁺ entry in cancer cells

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• 作者：Lloyd S. Gray ; Edward Perez-Reyes ; Juan Carlos Gamorra ; Doris M. Haverstick ; Michael Shattock ; Linda McLatchie ; Jane Harper ; Gavin Brooks ; Tiffany Heady ; Timothy L. Macdonald
• 关键词：Non-excitable cells ; HEK293 ; Voltage gated ; Neoplasms ; Therapy ; Calcium channels ; T-type ; Cell division ; Drug effects
• 刊名：Cell Calcium
• 出版年：2004
• 出版时间：December 2004
• 年：2004
• 卷：36
• 期：6
• 页码：489-497
• 全文大小：173 K

文摘

The mechanism by which Ca²⁺ enters electrically non-excitable cells is unclear. The sensitivity of the Ca²⁺ entry pathway in electrically non-excitable cells to inhibition by extracellular Ni²⁺ was used to direct the synthesis of a library of simple, novel compounds. These novel compounds inhibit Ca²⁺ entry into and, consequently, proliferation of several cancer cell lines. They showed stereoselective inhibition of proliferation and Ca²⁺ influx with identical stereoselective inhibition of heterologously expressed Cav3.2 isoform of T-type Ca²⁺ channels. Proliferation of human embryonic kidney (HEK)293 cells transfected with the Cav3.2 Ca²⁺ channel was also blocked. Cancer cell lines sensitive to our compounds express message for the Cav3.2 T-type Ca²⁺ channel isoform, its δ25B splice variant, or both, while a cell line resistant to our compounds does not. These observations raise the possibility that clinically useful drugs can be designed based upon the ability to block these Ca²⁺ channels.