Cations and calmodulin in normal and neoplastic cell growth regulation

Abstract

The purpose of this presentation is to review pertinent literature pertaining to the role of divalent cations and calmodulin in regulating growth of nonneoplastic and neoplastic cells and to examine the anticancer efficacy of some calmodulin inhibitors. Although normal eukaryotic cell replication and proliferation is closely controlled by a complex system of endogenous substances, it is likely that the coordination of purposeful interactions between these substances is the ultimate responsibility of two groups of cellular components, namely the divalent cations Ca2+ and Mg2+ and the versatile intracellular Ca2+-binding protein calmodulin (CaM). When free Ca2+ enters normal cells, it acts as a positive signal for proliferation; this action appears to be specifically associated with the late G1 phase, just prior to DNA synthesis. This period is designated G1/S and is considered to contain Pardee's "restriction point." Reduction of extracellular Ca2+ concentrations between physiological levels (1-0.1 mM) results in gradually reduced rates of cell proliferation; at Ca2+ concentrations of 0.1 mM or less, normal cell proliferation is reversibly inhibited. Since an extracellular concentration of about 0.7 mM Mg2+ is required for Ca2+ to initiate cell replication, it has been proposed that Ca2+ and Mg2+ act in concert via a common mechanism, however, in contrast to Ca2+, Mg2+ appears to be required throughout the entire cell cycle. Intracellular Ca2+ can activate CaM which, in turn, can modulate various cellular processes that affect cell proliferation, including cyclic nucleotide metabolism, protein phosphorylation, polyamine metabolism, prostaglandin metabolism, Ca2+ transport, DNA synthesis, and microtubular function including mitosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium/Calmodulin-Dependent Kinase I and Calcium/Calmodulin-Dependent Kinase Kinase Participate in the Control of Cell Cycle Progression in MCF-7 Human Breast Cancer Cells

“…Calcium and its intracellular receptor calmodulin are common to all regulatory transitions of the cell cycle (14). Mouse or human cells cultured in medium containing low concentrations of calcium cease cellular division and accumulate in G 1 (27). The calmodulin inhibitors W-7 and W-13 prevent proliferation and colony formation in breast cancer cells and other cell lines (28).…”

A study on the levels of calmodulin and DNA in human lung cancer cells

“…Being a central pluripotent regulator of cell functions, it plays an important role in the growth and proliferation of cells (Chafouleas et al, 1982;Sasaki and Hidaka, 1982;Means and Rasmussen, 1988). It was reported that the CaM level was higher in cancer cells than in normal cells and there was a positive correlation between the growth rate and CaM level of cancer cells (Criss and Kakjuchi, 1982;Wei et al, 1982;Hickie et al, 1983). Until now, there has been no paper concerning the relationship between CaM level and the development of lung cancers.…”

Effect of calmodulin inhibitors on viability and mitochondrial potential of Plasmodium falciparum in culture

“…Epifluorescence microscopy was used to monitor rhodamine 123 (RH123) retention in parasite mitochondria as previously described (12 Phenothiazine concentrations required to affect P. falciparum, similar to those required to inhibit virtually all the other parasitic protozoa previously studied, have also been shown to have pronounced activity against transformed cells (2,8,20), to inhibit mitosis in cultured mammalian cells (1), and to be toxic for macrophages (43). Furthermore, there is a serious discrepancy between therapeutic levels of the phenothiazines in blood and their antiparasitic potency.…”