Pterocarpans phaseollin and neorautenol isolated from Erythrina addisoniae induce apoptotic cell death accompanied by inhibition of ERK phosphorylation.
The genus Erythrina (Leguminosae), consisting of over 100 different species, is distributed in tropical regions. In traditional medicine, Erythrina species are used to treat cancer, but little is known about the anticancer mechanisms. From the stem bark of Erythrina addisoniae Hutch. & Dalziel, six prenylated pterocarpans were isolated and analysed for pharmacological activity: While calopocarpin, cristacarpin, orientanol c, and isoneorautenol showed only a weak or moderate toxicity in H4IIE hepatoma cells (EC(50)-value> 25 microM), the toxicity of neorautenol and phaseollin was in the low micromolar range (EC(50)-value: 1 and 1.5 microM, respectively). We further focused on these two substances showing that both increased caspase 3/7 activity and nuclear fragmentation as markers for apoptotic cell death. Neorautenol (10 microM, 2h), but not phaseollin induced the formation of DNA strand breaks (comet assay). Both substances showed no effect on NF-kappaB signalling (SEAP assay: basal activity and stimulation with TNF-alpha), on the other hand both pterocarpans (10 microM, 2 h) decreased the activation of the ERK kinase (p44/p42), an mitogen activated protein kinase which is associated with cell proliferation. We conclude that the pterocarpans phaseollin and neorautenol may be responsible for the anticarcinogenic actions of the plant extract reported in the literature. Further analysis of these substances may lead to new pharmacons to be used in cancer therapy.
Wätjen
W
W
Heinrich-Heine-Universität, Institute of Toxicology, 40001, Düsseldorf, Germany. wim.waetjen@uni-duesseldorf.de
Kulawik
A
A
Suckow-Schnitker
A K
AK
Chovolou
Y
Y
Rohrig
R
R
Ruhl
S
S
Kampkötter
A
A
Addae-Kyereme
J
J
Wright
C W
CW
Passreiter
C M
CM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053904:DNA Breaks, Single-Stranded; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004895:Erythrina / Q000737:chemistry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D007529:Isoflavones / Q000302:isolation & purification / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010766:Phosphorylation; D024301:Plant Bark; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology*; D054876:Prenylation; D036343:Pterocarpans / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D000094162:Phytoalexins
D000972:Antineoplastic Agents, Phytogenic; D053148:Caspase 3; D053179:Caspase 7; D048049:Extracellular Signal-Regulated MAP Kinases; D007529:Isoflavones; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D010936:Plant Extracts; D036343:Pterocarpans; C526657:neorautenol; C053345:phaseollin (isoflavan); D000094162:Phytoalexins; C505410:Casp3 protein, rat