title: The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine.
abstract: 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.
authors: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors: Deok-Beom
authors: DB
authors: Jung
authors: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors: Miyong
authors: M
authors: Yun
authors: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.|Korean Medicine Clinical Trial Center, Kyung Hee University, Seoul, South Korea.
authors: Eun-Ok
authors: EO
authors: Kim
authors: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors: Jaekwang
authors: J
authors: Kim
authors: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors: Bonglee
authors: B
authors: Kim
authors: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors: Ji Hoon
authors: JH
authors: Jung
authors: Department of Biochemistry and Molecular Biology, MN, USA.
authors: Enfeng
authors: E
authors: Wang
authors: Department of Biochemistry and Molecular Biology, MN, USA.
authors: Debabrata
authors: D
authors: Mukhopadhyay
authors: Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia.
authors: Edward
authors: E
authors: Hammond
authors: Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia.
authors: Keith
authors: K
authors: Dredge
authors: Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Viji
authors: V
authors: Shridhar
authors: College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors: Sung-Hoon
authors: SH
authors: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D012503:Saponins / Q000008:administration & dosage / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D020533:Angiogenesis Inhibitors; C495270:CTNNB1 protein, human; C557899:PG 545; D012503:Saponins; D051176:beta Catenin; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: PG545; Wnt/β-catenin; gemcitabine; heparan sulfate mimetic; pancreatic cancer