Kushen flavonoids induce apoptosis in tumor cells by inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities.
In this report, the mechanism of the antitumor activities of Kushen flavonoids (KS-Fs) were explored. KS-Fs and kurarinone (Kur), a single flavonoid compound, were able to induce apoptosis of H460 and Eca-109 cells in vitro and H460 cells in vivo. The apoptosis inducing effect was enhanced in the presence of Taxol. In H460 xenograft mice treated with Kur, down-regulation of Bcl-2 and up-regulation of caspase 8 and caspase 3 in tumors were observed by immunohistochemical staining. In addition, KS-Fs and Kur were able to inhibit TNFalpha-induced NF-kappaB activation in 293 cells mediated by the decreased IkappaBalpha phosphorylation. Further the effects of KS-Fs and Kur on multiple receptor tyrosine kinase activities were explored. In cell-based assays, KS-Fs and Kur inhibited the EGF-induced EGF receptor phosphorylation in A431 cells and a constitutively activated Her-2 in MDA-MB-453s cells. In enzymatic assays, KS-Fs and Kur inhibited KDR, but not PDGF BR activities. In A431 xenograft mice treated with Kur, an inhibition of EGF receptor phosphorylation in tumors was observed. These results reveal a novel mechanism by which KS-Fs induces apoptosis in tumors by acting on multiple cellular targets including the inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities.
Han
Jun
J
Department of Biology, Hutchison Medipharma Ltd., Zhang Jiang Hi-Tech Park, Shanghai 201203, China.
Sun
Mingyu
M
Cui
Yumin
Y
Wang
Tao
T
Zhang
Weihan
W
Guo
Mingchuan
M
Zhou
Yuan
Y
Liu
Wei
W
Zhang
Meifang
M
Duan
Jifeng
J
Xiong
Sidong
S
Yao
Minghui
M
Yan
Xiaoqiang
X
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D008517:Phytotherapy; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D016328:NF-kappa B; C411319:kurarinone; D020794:Receptor Protein-Tyrosine Kinases; C494416:kushen