مقالات پذیرفته شده در هشتمین کنگره بین المللی زیست پزشکی
PNU-74654 inhibits colon cancer progression by disrupting the Wnt/beta-catenin pathway
PNU-74654 inhibits colon cancer progression by disrupting the Wnt/beta-catenin pathway
Seyedeh-Najibeh Nasiri,1,*Amirhossein yazdi,2Amir Avan,3Majid Khazaei,4
1. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 2. Department of Anatomy and Cell Biology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 3. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 4. Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Introduction: Colorectal cancer (CRC) is one of the leading causes of cancer mortality, primarily due to its propensity to metastasize and resistance to conventional therapies. This study investigates the therapeutic potential of PNU-74654, a novel inhibitor of the Wnt/β-catenin signaling pathway, in combination with 5-fluorouracil (5-FU). We evaluated the antiproliferative effects of PNU-74654 on the CT-26 cells and assessed its impact on cell growth, migration, invasion, and apoptosis by various assays. In addition, we used an animal model to analyze the efficacy of PNU-74654 alone and in combination with 5-FU. This study aimed to inhibit colorectal cancer progression through disruption of the Wnt/β-catenin pathway by PNU-74654.
Methods: The antiproliferative -effect of PNU-74654 was evaluated cell models. The activity of agents on cell growth, migration, invasion, cell cycle, and apoptosis was evaluated by MTT, gene expression, respectively. The oxidant/antioxidant levels were also assessed by determining the level of MDA, SOD, as well as using the DCFH-DA assay. We used an animal model of CRC to investigate PNU-74654 activity alone and in combination with 5-FU followed by histological staining and biochemical and gene expression analyses by RT-PCR and western blot.
Results: PNU-74654, a Wnt/β-catenin pathway inhibitor, was investigated for its anti-tumor effects in the colorectal cancer (CRC) models, alone and in combination with 5-fluorouracil (5-FU). PNU-74654 inhibited cell growth and migration, and enhanced the anti-tumor activity of 5-FU in CRC cells. Mechanistically, PNU-74654 modulated key proteins such as Cyclin D1 and survivin, and reduced migration by affecting E-cadherin expression. In an animal model, the combination of PNU-74654 and 5-FU significantly suppressed tumor growth through induction of reactive oxygen species, down-regulation of superoxide dismutase (SOD), and modulation of inflammatory markers MCP-1, P53, and TNF-α. These findings demonstrate that targeting the Wnt pathway with PNU-74654 disrupts CRC cell proliferation and migration while improving the efficacy of 5-FU, supporting further investigation of this combined therapeutic approach for colorectal cancer treatment.
Conclusion: The study demonstrates that PNU-74654, a Wnt/β-catenin pathway inhibitor, reduces tumor growth and enhances apoptosis in colorectal cancer (CRC) cells. It effectively suppresses cyclin D1 expression and exhibits synergistic effects with 5-fluorouracil (5-FU) in decreasing cell viability. PNU-74654 also increases oxidative stress by inhibiting superoxide dismutase (SOD) activity, leading to enhanced apoptosis. Additionally, it elevates p53 expression and pro-inflammatory cytokines like TNF-α and MCP-1 in CRC cells. Overall, these findings suggest that PNU-74654 targets the Wnt pathway to inhibit cell proliferation and migration while promoting apoptosis, indicating its potential as a therapeutic strategy for CRC treatment. Further research is needed to explore its clinical applications.