In U-937 promonocytes, misteltoe lectin I increases basal [Ca2+]i, enhances histamine H1- and complement C5a-receptor-mediated rises in [Ca2+]i, and induces cell death

Abstract

Mistletoe lectin I (ML I) from Viscum album inhibits cell growth and induces apoptosis (programmed cell death) in several cell types. Because increases in cytosolic Ca2+ concentration ([Ca2+]i) constitute a signal for the induction of apoptosis, we studied the effects of ML I on basal [Ca2+]i, receptor-mediated rises in [Ca2+]i and cell viability, using human U-937 promonocytes as model system. Treatment of U-937 cells with ML I (30-100 ng/ml) significantly increased basal [Ca2+]i. ML I (10-30 ng/ml) enhanced histamine-induced rises in [Ca2+]i up to five-fold. The effect of histamine was inhibited by clemastine but not by famotidine, indicative for its mediation via H1-receptors. ML I additionally enhanced the stimulatory effect of complement C5a on [Ca2+]i, whereas the effect of ATP was unaffected. ML I did not induce responsiveness of U-937 cells towards a bacteria-derived chemotactic peptide. ML I up to 10 ng/ml did not affect cell viability and growth of U-937 cells. ML I at 30 ng/ml moderately inhibited cell growth and reduced cell viability. At 100 ng/ml, ML I was strongly cytotoxic. Our data support the view that Ca2+ plays a role as intracellular signal molecule in the induction of apoptosis and point to an accelerating role of H1- and C5a-receptors in the regulation of this process.

Biologically active compounds from European mistletoe (Viscum albumL.)1

“…That process was observed in higher MLI concentrations (30-100 ng/mL) in vitro on U-937 promonocytes; however, MLI [Ca 2+ ] i raising property was also sustained in lower concentrations (10-30 ng/mL) by means of histamine H 1 -and complement C5a-induced rises up to fivefold. This effect was not observed in the case of the closely related HL-60 cell line (induction of cell death was observed but no rise in [Ca 2+ ] i mediated by H 1 receptor; Wenzel-Seifert et al 1997), which indicates distinct apoptosis regulation pathways in different cell lines (Wenzel-Seifert et al 1997;Nicotera et al 1994). It also concerns the action of MLI itself because the variability in vulnerability to MLI of different cell lines was reported.…”

“…It also concerns the action of MLI itself because the variability in vulnerability to MLI of different cell lines was reported. For example, the treatment of THP-1 leukemia with MLI (25 ng/mL) caused an increase in [Ca 2+ ] i (Gabius et al 1992), whereas U-937 promonocytes did not react in this manner at similar MLI concentrations (Wenzel-Seifert et al 1997). That variation is also observed in the case of cytotoxic effects of MLI, e.g., the mouse macrophages are highly sensitive to the cytotoxic action of MLI , whereas the guinea pig macrophages are resistant (Metzner et al 1985).…”

“…Büssing et al (1996) reported MLIII to be most active in the induction of apoptic cell death of cultured human lymphocytes, which is in agreement with the findings of Dietrich et al (1992), who showed MLIII to be the most potent (followed by MLII and MLI) in the growth inhibition of leukemic Molt4 cells. Wenzel-Seifert et al (1997) demonstrated, in apoptosis induction studies, that MLI can cause significant increases in intracellular Ca 2+ concentration ([Ca 2+ ] i ), which constitute a signal for the activation of Ca 2+ -dependent endonucleases (Nicotera et al 1994) and, in consequence, of apoptosis. That process was observed in higher MLI concentrations (30-100 ng/mL) in vitro on U-937 promonocytes; however, MLI [Ca 2+ ] i raising property was also sustained in lower concentrations (10-30 ng/mL) by means of histamine H 1 -and complement C5a-induced rises up to fivefold.…”

Oncopharmacological Perspectives of a Plant Lectin (Viscum album Agglutinin‐I): Overview of Recent Results from In vitro Experiments and In vivo Animal Models, and Their Possible Relevance for Clinical Applications

“…Thus it could be found that VAA-I (100 ng/ml)-induced apoptosis changes into increasing necrosis after 48 h (32). In cultures of U937 promonocytes, VAA-I (30–100 ng/ml) causes an increased cytosolic Ca 2+ concentration which, among other factors, is a sign of apoptosis (33). In addition, VAA-I could enhance the stimulating effect of histamine (H 1 ) and complement (C5a) on cytosolic Ca 2+ concentrations that play an accelerating role in the regulation of apoptosis.…”

Zukunft der Misteltherapie aus pharmakologischer Sicht

“…In Kultur von U-937-Promonozyten bewirkt VAA-I (30±100 ng/ml) eine erho È hte zytosolische Ca 2+ -Konzentration, welche u. a. ein Signal fu È r die Apoptose ist [40]. Ausserdem konnte VAA-I die stimulierende Wirkung von Histamin (H 1 ) und Komplement (C5a) auf die zytosolische Ca 2+ -Konzentration, welche eine beschleunigende Rolle in der Apoptoseregulation spielt, versta Èrken [40]. Nicht nur Lektine mit RIP-Aktivita Èt verursachen Apoptose.…”