Recibufogenin

26121043

Huachansu, a traditional Chinese medicine prepared from the dried toad skin, has been used in clinical studies for various cancers in China. Resibufogenin is a component of huachansu and classified as bufadienolides. Resibufogenin has been shown to exhibit the anti-proliferative effect against cancer cells. However, the molecular mechanism of resibufogenin remains unknown. Here we report that resibufogenin induces G1-phase arrest with hypophosphorylation of retinoblastoma (RB) protein and down-regulation of cyclin D1 expression in human colon cancer HT-29 cells. Since the down-regulation of cyclin D1 was completely blocked by a proteasome inhibitor MG132, the suppression of cyclin D1 expression by resibufogenin was considered to be in a proteasome-dependent manner. It is known that glycogen synthase kinase-3β (GSK-3β) induces the proteasomal degradation of cyclin D1. The addition of GSK-3β inhibitor SB216763 inhibited the reduction of cyclin D1 caused by resibufogenin. These effects on cyclin D1 by resibufogenin were also observed in human lung cancer A549 cells. These findings suggest that the anti-proliferative effect of resibufogenin may be attributed to the degradation of cyclin D1 caused by the activation of GSK-3β.

Colorectal cancer; Metastasis; Necroptosis; Receptor-interacting protein kinase 3; Resibufogenin.

Resibufogenin Induces G1-Phase Arrest Through the Proteasomal Degradation of Cyclin D1 in Human Malignant Tumor Cells

Masami Ichikawa 1 , Yoshihiro Sowa 1 , Yosuke Iizumi 1 , Yuichi Aono 1 , Toshiyuki Sakai 1

2015 Jun 29;

30168902

Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has received considerable attention for its potency in cancer therapy. However, the anticancer effects and the underlying mechanisms of RB on pancreatic cancer remain elusive. Here, we found that RB inhibited the viability and induces caspase-dependent apoptosis in human pancreatic cancer cells Panc-1 and Aspc. Resibufogenin-induced apoptosis was through inhibition of constitutive nuclear factor-κB (NF-κB) activity and its target genes’ expression, which was caused by downregulation of transforming growth factor-β-activated kinase 1 (TAK1) levels and suppression of IκB kinase activity in Panc-1 and Aspc cells. This induction of TAK1-mediated NF-κB inactivation by RB was associated with increased glycogen synthase kinase-3 (GSK-3) phosphorylation and subsequent suppression of its activity. Moreover, RB-induced GSK-3 phosphorylation/inactivation acted through activation of protein kinase C but not Akt. Finally, RB suppressed human pancreatic tumor xenograft growth in athymic nude mice. Thus, our findings reveal a novel mechanism by which RB suppresses TAK1-mediated NF-κB activity through protein kinase C-dependent inhibition of GSK-3. Our findings provide a rationale for the potential application of RB in pancreatic cancer therapy.

glycogen synthase kinase-3; nuclear factor-κB; protein kinase C; resibufogenin; transforming growth factor-β-activated kinase 1.

Resibufogenin Suppresses Transforming Growth Factor-β-Activated Kinase 1-mediated Nuclear factor-κB Activity Through Protein Kinase C-dependent Inhibition of Glycogen Synthase Kinase 3

Lu Liu 1 2 , Yang Liu 1 , Xiaojia Liu 1 , Na Zhang 1 , Genxiang Mao 3 , Qingxuan Zeng 1 , Mingxiao Yin 1 , Danqing Song 1 , Hongbin Deng 1

2018 Nov