Angoline and chelerythrine, benzophenanthridine alkaloids that do not inhibit protein kinase C.
Starting with an extract derived from the stem of Macleaya cordata (Papaveraceae) that was active in the process of inhibiting phorbol 12,13-dibutyrate binding to partially purified protein kinase C (PKC), the benzophenanthridine alkaloid angoline was isolated and identified. This discovery appeared in context, as a related benzophenanthridine alkaloid, chelerythrine, has been reported to mediate a variety of biological activities, including potent and selective inhibition of protein kinase C (PKC). However, in our studies, angoline was not observed to function as a potent inhibitor of PKC. Moreover, we were unable to confirm the reported inhibitory activity of chelerythrine. In a comprehensive series of studies performed with various PKC isozymes derived from a variety of mammalian species, neither chelerythrine nor angoline inhibited activity with high potency. To the contrary, chelerythrine stimulated PKC activity in the cytosolic fractions of rat and mouse brain in concentrations up to 100 microM. In addition, chelerythrine and angoline did not inhibit [3H]phorbol 12,13-dibutyrate binding to the regulatory domain of PKC at concentrations up to 40 microg/ml, and no significant alteration of PKC-alpha, -beta, or -gamma translocation was observed with human leukemia (HL-60) cells in culture. Further, chelerythrine did not inhibit 12-O-tetradecanoylphorbol 13-acetate-induced ornithine decarboxylase activity with cultured mouse 308 cells, but angoline was active in this capacity with an IC50 value of 1.0 microg/ml. A relatively large number of biological responses have been reported in studies conducted with chelerythrine, and alteration of PKC activity has been considered as a potential mechanism of action. In light of the current report, mechanisms independent of PKC inhibition should be considered as responsible for these effects.
Program for Collaborative Research in the Pharmaceutical Sciences and Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, Chicago, Illinois 60612, USA.
S K
SK
Lee
W G
WG
Qing
W
W
Mar
L
L
Luyengi
R G
RG
Mehta
K
K
Kawanishi
H H
HH
Fong
C W
CW
Beecher
A D
AD
Kinghorn
J M
JM
Pezzuto
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D053119:Benzophenanthridines; D001667:Binding, Competitive; D001921:Brain / Q000201:enzymology; D002417:Cattle; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010617:Phenanthridines / Q000494:pharmacology*; D010704:Phorbols / Q000494:pharmacology; D010944:Plants / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010617:Phenanthridines; D010704:Phorbols; C113966:angoline; C016299:chelerythrine; D011493:Protein Kinase C; D009955:Ornithine Decarboxylase