FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

Liu, Lu; Zhi, Qiaoming; Shen, Meng‐Ru; Gong, Fei‐Ran; Zhou, Binhua P.; Lian, Lian; Shen, Bairong; Chen, Kai; Duan, Weiming; Wu, Mengyao; Tao, Min; Li, Wei

doi:10.18632/oncotarget.9975

Cited by 27 publications

(23 citation statements)

References 69 publications

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“…As shown in Fig. 3C and D , Rg3 downregulated the Ki-67 level, a major prognostic factor of tumors in general ( 17 ). Immunohistochemical assays further confirmed that Rg3 treatment downregulated the levels of stemness markers, CD24, CD44 and EpCAM, in the orthotopic xenografts ( Fig.…”

Section: Resultsmentioning

confidence: 75%

“…IL1A (interleukin 1 alpha) and IL1B (interleukin 1 beta) are members of the interleukin 1 cytokine family, which are involved in various immune responses, inflammatory processes, and hematopoiesis and also play crucial roles in the tumorigenesis of colorectal cancer ( 27 ). IL8 (interleukin 8), PLAUR (plasminogen activator, urokinase receptor), and THPO (thrombopoietin) participate in angiogenesis in a WNT/β-catenin pathway-dependent manner ( 17 ). PGF (placental growth factor) encodes a growth factor found in the placenta that is homologous to VEGF (vascular endothelial growth factor).…”

Section: Discussionmentioning

confidence: 99%

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Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo

et al. 2017

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Anti-angiogenic therapy has been successfully applied to treat colorectal cancer (CRC). Ginsenoside Rg3, derived from the Chinese herb ginseng, has anti-vascularization effects and can inhibit tumor growth and metastasis, and can sensitize cancer cells to chemotherapy. Therefore, in the present study, we investigated whether Rg3 could be appropriate for CRC treatment. Growth of CRC cells was assessed by an MTT (methyl thiazolyl tetrazolium) assay in vitro and using orthotopic xenograft models in vivo. mRNA expression was evaluated using real-time PCR. Protein levels were tested by western blotting, flow cytometry and immunohistochemistry. Migration was determined using a wound-healing assay. Stemness was further confirmed using a plate clone formation assay. We found that Rg3 repressed the growth and stemness of CRC cells both in vitro and in vivo. Rg3 also impaired the migration of CRC cells in vitro. Rg3 downregulated the expressions of angiogenesis-related genes, and repressed the vascularization of CRC xenografts. In addition, Rg3 strengthened the cytotoxicity of 5-Fluorouracil and oxaliplatin against orthotopic xenografts in vivo. Moreover, Rg3 downregulated the expressions of B7-H1 and B7-H3, high expressions of which were associated with reduced overall survival (OS) of CRC patients. Hence, Rg3 not only repressed the growth and stemness of CRC cells, but could also remodel the tumor microenvironment through repressing angiogenesis and promoting antitumor immunity. Therefore, Rg3 could be a novel therapeutic for the CRC treatment.

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Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo

et al. 2017

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“…CD133 promotes β-catenin signaling and therefore inhibits cancer cell differentiation 37 , and indicates infinitive growth 38 . Besides, it is reported that FH535 represses cancer cell stemness in pancreatic cancer, reducing the CD24+/CD44+ population 14 . Based on the knowledge above, we estimated cancer cell stemness by testing expression of CD24, CD44 and CD133.…”

Section: Discussionmentioning

confidence: 99%

“…FH535 is a dual small molecule inhibitor of peroxisome proliferator-activated receptors (PPARs) and β-catenin/TCF/LEF 10 . Previous studies demonstrated that FH535 inhibits the growth of colon, lung, breast, pancreatic and hepatocellular cancer cells 10 - 13 , and represses pancreatic cancer xenograft growth and angiogenesis 14 .…”

Section: Introductionmentioning

confidence: 99%

FH535 Inhibits Proliferation and Motility of Colon Cancer Cells by Targeting Wnt/β-catenin Signaling Pathway

Chen¹,

Rao²,

Huang³

et al. 2017

J. Cancer

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Aberrant Wnt/β-catenin pathway activation is frequently observed in human colorectal cancer (CRC) and has become a promising target for CRC treatment. Our study aimed to evaluate the effect of FH535, a small molecule inhibitor of Wnt/β-catenin pathway, on two colon cancer cell lines, HT29 and SW480. We found FH535 significantly inhibited colon cancer cell proliferation in vitro and induced cell cycle arrest. Moreover, FH535 inhibited colon cancer xenograft growth in vivo. Wound-healing assay and Transwell assay revealed that FH535 notably suppressed migration and invasion of SW480 cells. FH535 also repressed expression of cancer stem cell markers, CD24, CD44 and CD133 in HT29 cells. Real time-quantitative PCR and Western blotting revealed that targeting Wnt/β-catenin pathway using FH535 effectively downregulated target genes including cyclin D1 and survivin at mRNA and protein level, which contributed to the FH535-induced inhibitory effect on colon cancer cell proliferation. As mechanisms for suppressing cancer cell motility, FH535 downregulated expression of matrix metalloproteinase-7 and -9, Snail and vimentin. RNA sequencing revealed that FH535 prominently altered multiple biological pathways associated with DNA replication, cell cycle and metabolism. Our study highlights the anti-cancer effect of FH535 on colon cancer and presents its potential in colon cancer treatment.

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“…FH535 is considered as twofold small molecule inhibitor of β-catenin/TCF/LEF and peroxisome proliferator-activated receptors (PPARs) [ 17 ]. Earlier studies revealed that FH535 hampers the growth of colon, lung, breast, hepatocellular cancer cells [ 18 ], and suppresses angiogenesis and pancreatic cancer xenograft growth [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Taxifolin, a natural flavonoid interacts with cell cycle regulators causes cell cycle arrest and causes tumor regression by activating Wnt/ β -catenin signaling pathway

et al. 2018

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BackgroundNew approaches for the prevention of colon cancer perseveres an essential necessity. Though, resistance to existing chemo-preventive drugs is moderately predominant in colon carcinogenesis. Taxifolin (dihydroquercetin) is a flavononol, have shown virile biological activities against few cancers. The current study was designed to investigate and equate antitumor activity of Taxifolin (TAX) in colorectal cancer cell lines and in HCT116 xenograft model in a comprehensive approach.MethodsTwo human colorectal cancer cell lines HCT116 and HT29, were used. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazoliumbromide (MMT) protocol was performed to elucidate the impact of TAX and β- catenin inhibitor (FH535) on the viability of HCT116 and HT29 cell lines. Apoptosis /cell cycle assay was performed. Data interpretation was done with a FACScan (Becton Dickinson, NJ). About 1 × 104 cells per sample were harvested. Histograms of DNA were analyzed with ModiFitLT software (verity Software House, ME, USA). Western blotting and RT-PCR were performed for protein and gene expression respectively in in vitro and in vivo.ResultsWe found that TAX induced cytotoxicity in colorectal cells in a dose-dependent manner and time dependent approach. Further, our data validated that administration of TAX to human colorectal cancer HCT116 and HT29 cells resulted in cell growth arrest, variation in molecules controlling cell cycle operative in the G2 phase of the cell cycle and apoptosis in a concentration dependent approach. Further our results concluded that TAX administration decreases expression of β-catenin gene, AKT gene and Survivin gene and protein expression in in vitro and in vivo.ConclusionOur findings proposed that targeting β-catenin gene may encourage the alterations of cell cycle and cell cycle regulators. Wnt/β-catenin signaling pathway possibly takes part in the genesis and progression of colorectal cancer cells through regulating cell cycle and the expression of cell cycle regulators.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4959-4) contains supplementary material, which is available to authorized users.

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FH535, a β-catenin pathway inhibitor, represses pancreatic cancer xenograft growth and angiogenesis

Cited by 27 publications

References 69 publications

Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo

Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo

FH535 Inhibits Proliferation and Motility of Colon Cancer Cells by Targeting Wnt/β-catenin Signaling Pathway

Taxifolin, a natural flavonoid interacts with cell cycle regulators causes cell cycle arrest and causes tumor regression by activating Wnt/ β -catenin signaling pathway

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