Cell proliferation is critically dependent on the regulated movement of ions across various cellular compartments. The antimycotic drug clotrimazole (CLT) has been shown to inhibit movement of Ca2+ and K+ across the plasma membrane. Our results show that CLT inhibits the rate of cell proliferation of normal and cancer cell lines in a reversible and dose-dependent manner in vitro. Moreover, CLT depletes the intracellular Ca2+ stores and prevents the rise in cytosolic Ca2+ that normally follows mitogenic stimulation. In mice with severe combined immunodeficiency disease (SCID) and inoculated intravenously with MM-RU human melanoma cells, daily subcutaneous injections of CLT induced a significant reduction in the number of lung metastases. Modulation of early ionic mitogenic signals and potent inhibition of cell proliferation both in vitro and in vivo are new and potentially useful clinical effects of CLT.

SummaryInteractions between endothelium and vascular smooth muscle cells play a major role in the biology of the blood vessel wall. Growth factors released from endothelial cells control in part the normal and pathological proliferation of vascular smooth muscle cells. Endothelial deposits of C5b-9 proteins, the membrane attack complex of complement (MAC), have been found in a variety of pathological tissues in which cell proliferation is an early characteristic abnormality, including atherosclerosis. We have explored a possible bridging role for terminal complement C5b-9 proteins in eliciting focal signals for cell proliferation by releasing growth factors from endothelial cells. We found that both bovine aortic and human umbilical vein cells respond to the MAC by releasing basic fibroblast growth factor and platelet-derived growth factor. These mitogens stimulate DNA synthesis in Swiss 3T3, vascular smooth muscle, and glomerular mesangial cells. Based on these findings, we propose that complement-induced release of mitogens from endothelial cells is a novel pathogenic mechanism for proliferative disorders.

Coronary heart disease (CHD) is the major cause of death in the developed world and screening for conventional cardiovascular risk factors fails to identify more than 50% of the individuals who will present with acute coronary syndromes. Chronic inflammation appears to play a significant role in the initiation and development of atherosclerosis. Recent investigations have shown an association between inflammatory markers such as C-reactive protein (CRP) and CHD. These markers have proven useful as prognostic indicators in acute coronary syndromes and in predicting future coronary events in apparently healthy men and women. The availability of high sensitivity CRP (hs-CRP) assays has been crucial in exploring the role of this acute phase reactant in primary prevention settings. In this review, we discuss the evidence associating these inflammatory markers, especially CRP, with the pathogenesis of atherosclerosis and acute coronary syndromes, and we address the mechanism of risk as well as the clinical utility of this marker.

Background: We have previously shown that the membrane attack complex (MAC) of complement stimulates cell proliferation and that insertion of homologous MAC into the membranes of endothelial cells results in the release of potent mitogens, including basic fibroblast growth factor (bFGF). The mechanism of secretion of bFGF and other polypeptides devoid of signal peptides, such as interleukin 1 (IL-1) is still an open problem in cell biology. We have hypothesized that the homologous MAC pore itself could constitute a transient route for the diffusion of biologically active macromolecules in and out of the target cells. Materials and Methods: Human red blood cell ghosts and artificial lipid vesicles were loaded with labeled growth factors, cytokines and IgG, and exposed to homologous MAC. The release of the '25I-macromolecules was followed as a function of time. The incorporation of labeled polypeptides and fluorescent dextran (MW: 10,000) was measured in MAC-impacted human red blood cells and human umbilical endothelial cells (HUVEC), respectively. Results: Homologous MAC insertion into HUVEC resulted in the massive uptake of 10-kD dextran and induced the release of bFGF, in the absence of any measurable lysis. Red blood cell ghosts preloaded with bFGF, IL-l1,3, and the a-chain of interferon-y (IFN-'y) released the polypeptides upon MAC insertion, but they did not release preloaded IgG. MAC-impacted ghosts took up radioactive IFN-,y from the extracellular medium. Vesicles loaded with IL-1 released the polypeptide when exposed to NAC. Conclusions: The homologous MAC pore in its nonlytic form allows for the export of cytosolic proteins devoid of signal peptides that are not secreted through the classical endoplasmic reticulum/Golgi exocytotic pathways. Our results suggest that the release, and perhaps the uptake, of biologically active macromolecules through the homologous MAC pore is a novel biological function of the complement system in mammals.

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