Berbamine Enhances the Antineoplastic Activity of Gemcitabine in Pancreatic Cancer Cells by Activating Transforming Growth Factor‐β/Smad Signaling

Abstract

Drug-resistance to gemcitabine chemotherapy in pancreatic cancer is still an unsolved problem. Combinations of other chemotherapy drugs with gemcitabine have been shown to increase the efficacy of gemcitabine-based treatment. In this study, the effect of berbamine on the antitumor activity of gemcitabine was evaluated in human pancreatic cancer cell lines Bxpc-3 and Panc-1, and the underlying mechanisms were explored. Our results demonstrated that berbamine exhibited a time-and dose-dependent inhibitory effect in the pancreatic cancer cell lines. Berbamine enhanced gemcitabine-induced cell growth inhibition and apoptosis in these cells. Combined treatment of berbamine and gemcitabine resulted in down-regulation of anti-apoptotic proteins (Bcl-2, BclxL) and up-regulation of pro-apoptotic proteins (Bax, Bid). More importantly, berbamine treatment in combination with gemcitabine activated the transforming growth factor-b/Smad (TGF-b/Smad) signaling pathway, as a result of a decrease in Smad7 and an increase in transforming growth factor-b receptor II (TbRII) expression. Changes in downstream targets of Smad7, such as up-regulation of p21 and down-regulation of cMyc and Cyclin D1 were also observed. Therefore, berbamine could enhance the antitumor activity of gemcitabine by inhibiting cell growth and inducing apoptosis, possibly through the regulation of the expression of apoptosis-related proteins and the activation of TGF-b/Smad signaling pathway. Our study indicates that berbamine may be a promising candidate to be used in combination with gemcitabine for pancreatic cancer treatment. Anat Rec,

Berbamine induces SMMC-7721 cell apoptosis via upregulating p53, downregulating survivin expression and activating mitochondria signaling pathway

“…Therefore, this study observed the nucleus morphology of the SMMC-7721 cells, and the nucleus illustrated as fragmentary and polymorphonuclear in 20, 40 µmol/l berbamine treatment, which suggests that the classical apoptotic morphology was appeared in the berbamine treatment cells. Meanwhile, the apoptosis rate was also evaluated by using the flow cytometry assay, and results revealed that berbamine at concentration of 20 and 40 µmol/l significantly induced apoptosis compared to the control group, which suggests that berbamine processes the function of anti-apoptosis in SMMC-7721 cells, and is consistent with previous study ( 19 , 27 ).…”

A map describing the association between effective components of traditional Chinese medicine and signaling pathways in cancer cells in vitro and in vivo

“…In HepG2, PLC/PRF/5, SK-Hep-1, and SNU398 cells, berbamine plays a role in blocking the Ca 2+ channel through inhibition of Ca 2+ /calmodulin-dependent protein kinase II (introduction). In Bxpc-3 and Panc-1 human pancreatic cancer cell lines, berbamine can enhance antitumor activity of gemcitabine through activating the TGF-β/Smad pathway (75). A derivative of berbamine is reported to induce apoptosis of A2058, A375, G361, SK-MEL-28, and SK-MEL-5 human melanoma cell lines via inhibition of the jak2/STAT3 signaling pathway (76).…”

Berbamine Inhibits Cell Proliferation, Migration, and Invasion and Induces Cell Apoptosis of A549 Cells Via Regulating C-Maf, PI3K/Akt and MDM2-P53 Pathways

“…Previous studies have demonstrated that the antitumor effects of BBM in a variety of tumors, including breast cancer [19], myeloma [7,20], hepatoma [9,21], prostatic neoplasms [9], pancreatic carcinoma [22] and lung cancer [23]. Jin [22] con rmed that BBM signi cantly downregulated the expression of the antiapoptotic proteins such as Bcl-2 and Bcl-xL and inhibited proliferation in pancreatic carcinoma cells. Du [24] found that BBM induced cell apoptosis and inhibited the cell proliferation through the PI3K/Akt pathway in lymphoma, the expressions of PI3K and p-Akt/Akt were down-regulated.…”