Abstract
BackgroundTetrandrine inhibits tumor cell proliferation and demonstrates chemoprevention in cancer models. Speculation on the association between its effects on K+ and Ca2+ channels and cancer chemoprevention has been made. Thapsigargin also affects K+ and Ca2+ conductance. Thapsigargin, however, is a weak tumor promoter in the two-stage model of mouse skin carcinogenesis, yet it can induce apoptosis in androgen-independent prostatic cancer cells. I have postulated that arachidonic acid release from cells in culture is associated with cancer chemoprevention. The effects of tetrandrine and thapsigargin on arachidonic acid release from human colon carcinoma and rat liver cells and prostacyclin production by rat liver cells are compared in the current studies.ResultsTetrandrine and thapsigargin stimulate arachidonic acid release from human colon carcinoma and rat liver cells and prostacyclin production in rat liver cells. The stimulation by tetrandrine is not affected by incubation with actinomycin D, 100 mM KCl, the [Ca2+]i chelator, 1,2-bis (o-amino-5-fluorophenoxy) ethane-N,N,N',N',-tetraacetic acid tetraacetoxymethylester (BAPTA/AM) or in the absence of extracellular Ca2+. In contrast, stimulation by thapsigargin is inhibited by incubation with actinomycin D, 100 mM KCl, BAPTA/AM or in the absence of extracellular Ca2+.ConclusionBoth tetrandrine and thapsigargin stimulate arachidonic acid release, but based on the different results obtained in the presence of actinomycin D, the [Ca2+]i chelator, 100 mM KCl and in the absence of extracellular Ca2+, the mechanisms leading to this release and pathways leading to apoptosis and/or cancer chemoprevention may be different. Stimulations by tetrandrine may be mediated by activation of a secretory phospholipase A2, whereas thapsigargin's stimulations may be mediated by the cytoplasmic Ca2+-dependent phospholipase A2.
Highlights
Tetrandrine inhibits tumor cell proliferation and demonstrates chemoprevention in cancer models
THAP is classified as a weak tumor promoter as measured in the two-stage model of mouse skin carcinogenesis [16]
It has been proposed that the cancer chemopreventative properties attributed to TET reside in its ability to effect ion channels which leads to inhibition of cell proliferation and apoptosis [9]
Summary
Tetrandrine inhibits tumor cell proliferation and demonstrates chemoprevention in cancer models. Thapsigargin, is a weak tumor promoter in the two-stage model of mouse skin carcinogenesis, yet it can induce apoptosis in androgen-independent prostatic cancer cells. Tetrandrine (TET), a bisbenzylisoquinoline (Fig. 1a), isolated from the root of the plant Stephania tetrandra has a number of potential medicinal properties. These include blockage of voltage-gated Ca2+ channels [1], large-conductance Ca2+ activated K+ (BK) channels, and intracellular Ca2+ pumps [1,2,3,4,5,6]. THAP, like TET, blocks intracellular calcium pumps resulting in increased cytoplasmic Ca2+, ([Ca2+]i) [reviewed in 15] THAP induces apoptosis in many cells including human neuroblastoma, colon cancer and prostate cancer cells and thymocytes [17,20,21,22]
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