The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine.
The heparan sulfate mimetic PG545 has been shown to exert anti-angiogenic and anti-metastatic activity in vitro and in vivo cancer models. Although much of this activity has been attributed to inhibition of heparanase and heparan sulfate-binding growth factors, it was hypothesized that PG545 may additionally disrupt Wnt signaling, an important pathway underlying the malignancy of pancreatic cancer. We show that PG545, by directly interacting with Wnt3a and Wnt7a, inhibits Wnt/β-catenin signaling leading to inhibition of proliferation in pancreatic tumor cell lines. Additionally, we demonstrate for the first time that the combination of PG545 with gemcitabine has strong synergistic effects on viability, motility and apoptosis induction in several pancreatic cell lines. In an orthotopic xenograft mouse model, combination of PG545 with gemcitabine efficiently inhibited tumor growth and metastasis compared to single treatment alone. Also, PG545 treatment alone decreased the levels of β-catenin and its downstream targets, cyclin D1, MMP-7 and VEGF which is consistent with our in vitro data. Collectively, our findings suggest that PG545 exerts anti-tumor activity by disrupting Wnt/β-catenin signaling and combination with gemcitabine should be considered as a novel therapeutic strategy for pancreatic cancer treatment.
['Jung|Deok-Beom|DB|', 'Yun|Miyong|M|', 'Kim|Eun-Ok|EO|', 'Kim|Jaekwang|J|', 'Kim|Bonglee|B|', 'Jung|Ji Hoon|JH|', 'Wang|Enfeng|E|', 'Mukhopadhyay|Debabrata|D|', 'Hammond|Edward|E|', 'Dredge|Keith|K|', 'Shridhar|Viji|V|', 'Kim|Sung-Hoon|SH|']
D020533:Angiogenesis Inhibitors D000818:Animals D000971:Antineoplastic Combined Chemotherapy Protocols D040761:Biomimetic Materials D063646:Carcinogenesis D021441:Carcinoma, Pancreatic Ductal D045744:Cell Line, Tumor D003841:Deoxycytidine D004357:Drug Synergism D005260:Female D006801:Humans D051379:Mice D008819:Mice, Nude D010190:Pancreatic Neoplasms D011897:Random Allocation D012503:Saponins D060449:Wnt Signaling Pathway D023041:Xenograft Model Antitumor Assays D051176:beta Catenin
heparan sulfate mimetic PG545 Wnt/β-catenin gemcitabine pancreatic cancer