Inhibition of cell growth and intracellular Ca²⁺ mobilization in human brain tumor cells by Ca²⁺ channel antagonists

Abstract

The effects of various Ca²⁺ channel agonists and antagonists on tumor cell growth were investigated using U-373 MG human astrocytoma and SK-N-MC human neuroblastoma cell lines. Classical Ca²⁺ channel antagonists, verapamil, nifedipine, and diltiazem, and inorganic Ca²⁺ channel antagonists, Ni²⁺ and Co²⁺, inhibited growth of these tumor cells in a dose-dependent manner. Except Ni²⁺, these Ca²⁺ channel antagonists did not induce a significant cytotoxicity, suggesting that the growth-inhibitory effects of these drugs may be the result of the influence on the proliferative signaling mechanisms of these tumor cells. In contrast, Bay K-8644, a Ca²⁺ channel agonist, neither enhanced the growth of tumor cells nor increased intracellular Ca²⁺ concentration, indicating that voltage-sensitive Ca²⁺ channels may not be involved in tumor cell proliferation. Moreover, growth-inhibitory concentrations of Ca²⁺ channel antagonists significantly blocked agonist (carbachol or serum)-induced intracellular Ca²⁺ mobilization, which was monitored using Fura-2 fluorescence technique. These results suggest that the inhibition of the growth of human brain tumor cells induced by Ca²⁺ channel antagonists may not be the result of interaction with Ca²⁺ channels, but may be the result of the interference with agonist-induced intracellular Ca²⁺ mobilization, which is an important proliferative signaling mechanism.