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Differential activation by daphnetoxin and mezerein of PKC-isotypes alpha, beta 1, delta and zeta

Title
Differential activation by daphnetoxin and mezerein of PKC-isotypes alpha, beta 1, delta and zeta
Type
Article in International Scientific Journal
Year
2001
Authors
Saraiva, L
(Author)
FFUP
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Pinto, E
(Author)
FFUP
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Portugal, H
(Author)
Other
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Journal
Title: Planta MedicaImported from Authenticus Search for Journal Publications
Vol. 67
Pages: 787-790
ISSN: 0032-0943
Publisher: Thieme
Scientific classification
FOS: Medical and Health sciences > Basic medicine
Other information
Authenticus ID: P-000-SNB
Abstract (EN): Daphnetoxin, a mezerein derivative, was isolated from the stem bark of Daphne gnidium. Mezerein is a PKC activator that exhibits antileukemic properties. However, daphnetoxin and its analogue 12-hydroxydaphnetoxin were described as being devoid of this effect. In the present study daphnetoxin and mezerein were compared as PKC activators on classical (a and beta1), novel (delta) and atypical (zeta) isoforms, using an alternative in vivo yeast phenotypic assay. The aim was to clarify if daphnetoxin is a PKC activator and if the differences between the antiproliferative effect of mezerein and of its analogue daphnetoxin may be ascribed to differences on their potency or selectivity as PKC activators. Yeast samples expressing each of the mammalian PKC isoforms tested were incubated with daphnetoxin or mezerein. Growth inhibition caused by these drugs was assumed to be due to PKC activation since it did not occur when expression was not induced. Mezerein inhibited the growth of yeast expressing PKC alpha (IC50 = 1190 +/- 237 nM; n = 20), PKC beta1 (IC50 = 908 +/- 46 nM; n = 20), and PKC delta (IC50 = 141 +/- 25 nM; n = 20) but not of yeast expressing PKC. Daphnetoxin also inhibited the growth of yeast expressing isoforms alpha, beta1 and delta, being more potent than mezerein on PKC alpha (IC50 = 536 +/- 183 nM; n = 20; P < 0.05), as potent as mezerein on PKC<beta>1 (IC50 = 902 +/- 129 nM; n = 20) and less potent than mezerein upon PKC delta (IC50 = 3370 +/- 492 nM; n = 20; P < 0.05). These results show that daphnetoxin is a potent PKC activator but with a selectivity different from that of mezerein. It is suggested that the lack of antileukemic and antiproliferative effects of daphnetoxin may be due to its lower potency to activate PKC<delta>.
Language: English
Type (Professor's evaluation): Scientific
No. of pages: 4
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