Tetrandrine and thapsigargin release arachidonic acid from cells in culture and stimulate prostacyclin production in rat liver cells, but may do so by different pathways.
BACKGROUND
Tetrandrine 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.


RESULTS
Tetrandrine 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+.


CONCLUSIONS
Both 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.
Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA. llevine@brandeis.edu
Lawrence
L
Levine
D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D044182:Benzylisoquinolines / Q000302:isolation & purification / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002478:Cells, Cultured; D019073:HT29 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D019284:Thapsigargin / Q000302:isolation & purification / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000470:Alkaloids; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D002273:Carcinogens; D016718:Arachidonic Acid; C009438:tetrandrine; D019284:Thapsigargin