Local Delivery of Gemcitabine Inhibits Pancreatic and Cholangiocarcinoma Tumor Growth by Promoting Epidermal Growth Factor Receptor Degradation

Abstract

Gemcitabine is clinically used to treat certain types of cancers, including pancreatic and biliary cancer. We investigated the signal transduction pathways underlying the local antitumor effects of gemcitabine-eluting membranes (GEMs) implanted in pancreatic/biliary tumor-bearing nude mice. Here, we report that GEMs increased the E3 ubiquitin ligase c-CBL protein level, leading to degradation of epidermal growth factor receptor (EGFR) in SCK and PANC-1 cells. GEMs decreased the RAS and PI3K protein levels, leading to a reduction in the protein levels of active forms of downstream signaling molecules, including PDK, AKT, and GSK3β. GEM reduced proliferation of cancer cells by upregulating cell cycle arrest proteins, particularly p53 and p21, and downregulating cyclin D1 and cyclin B. Moreover, GEMs reduced the levels of proangiogenic factors, including VEGF, VEGFR2, CD31, and HIF-1α, and inhibited tumor cell migration and invasion by inducing the expression of E-cadherin and reducing that of N-cadherin, snail, and vimentin. We demonstrated that local delivery of gemcitabine using GEM implants inhibited tumor cell growth by promoting c-CBL-mediated degradation of EGFR and inhibiting the proliferation, angiogenesis, and epithelial–mesenchymal transition of pancreatic/biliary tumors. Use of gemcitabine-eluting stents can improve stent patency by inhibiting the ingrowth of malignant biliary obstructions.

Preclinical evaluation of endoscopic placement of a steroid-eluting metal stent in an in vivo porcine benign biliary stricture model

“…Local treatment using drug-eluting stents was first applied to malignant strictures 28 , 29 . Local anti-tumor effects using paclitaxel-eluting stents have been demonstrated in malignant biliary strictures caused by extrahepatic bile duct cancer.…”

Preclinical Evaluation of Endoscopic Placement of a Steroid-eluting Metal Stent in an In Vivo Porcine Benign Biliary Stricture Model

“…Local treatment using drug-eluting stents was rst applied to malignant strictures. 29,30 Local anti-tumor effects using paclitaxel-eluting stents have been demonstrated in malignant biliary strictures caused by extrahepatic bile duct cancer. Likewise, steroid-eluting stents are expected to have local anti-brotic effects in BBS.…”

The new insight of treatment in Cholangiocarcinoma

“…The results showed that there was no statistical significance in OS, PFS and ORR [58], and the combination therapy significantly increased blood and skin adverse effects reaction. The difference is that the local administration of Gemcitabine reported by Korean scholars can promote the degradation of EGFR and inhibit the growth of CCA [59]. The synergistic mode of Gemcitabine and EGFR have brought new inspiration to future research on the treatment of CCA.…”