Farzad Rahmani1, Fereshteh Asgharzadeh2, Amir Avan3, Farnaz Barneh4, Mohammad Reza Parizadeh5, Gordon A Ferns6, Mikhail Ryzhikov7, Mohammad Reza Ahmadian8, Elisa Giovannetti9, Mohieddin Jafari10, Majid Khazaei11, Seyed Mahdi Hassanian12. 1. Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Iranshahr University of Medical Siences, Iranshahr, Iran. 2. Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 3. Metabolic syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 4. Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5. Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Metabolic syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. 6. Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK. 7. Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO, USA. 8. Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, 40223, Germany. 9. Cancer Pharmacology Lab, AIRC Start-up, University Hospital of Pisa, Pisa, Italy; Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. 10. Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Finland. 11. Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: KhazaeiM@mums.ac.ir. 12. Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.; Metabolic syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: hasanianmehrm@mums.ac.ir.
Abstract
AIMS: Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. This study was aimed to explore the regulatory effects of RGS on proliferative, pro-fibrotic and inflammatory factors in DSS- induced colitis mice model. MATERIALS AND METHODS: The present study integrates systems and molecular biology approaches to investigate the therapeutic potency of RGS in an experimental model of colitis specifically examining its effects on the PI3K/AKT and NF-κB signaling pathways. KEY FINDINGS: Analysis of time-resolved proteome profiling showed that PI3K-AKT inhibitors regulate expression of many proteins in all stages of inflammation, fibrogenesis and extracellular matrix remodeling. Consistent with our in-silico findings, RGS improved colitis disease activity as assessed by changes in body weight, degree of stool consistency, rectal bleeding and prolapse. RGS also reduced oxidative stress markers and colon histopathological score by decreasing inflammatory responses in colon tissues. Moreover, expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1β, TNF-α, INF-γ, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways. SIGNIFICANCE: This study clearly demonstrates the anti-proliferative, anti-inflammatory and anti-fibrotic effects of RGS in colitis that may have implications for the treatment of colitis and colitis-associated cancer.
AIMS: Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. This study was aimed to explore the regulatory effects of RGS on proliferative, pro-fibrotic and inflammatory factors in DSS- induced colitismice model. MATERIALS AND METHODS: The present study integrates systems and molecular biology approaches to investigate the therapeutic potency of RGS in an experimental model of colitis specifically examining its effects on the PI3K/AKT and NF-κB signaling pathways. KEY FINDINGS: Analysis of time-resolved proteome profiling showed that PI3K-AKT inhibitors regulate expression of many proteins in all stages of inflammation, fibrogenesis and extracellular matrix remodeling. Consistent with our in-silico findings, RGS improved colitis disease activity as assessed by changes in body weight, degree of stool consistency, rectal bleeding and prolapse. RGS also reduced oxidative stress markers and colon histopathological score by decreasing inflammatory responses in colon tissues. Moreover, expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1β, TNF-α, INF-γ, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways. SIGNIFICANCE: This study clearly demonstrates the anti-proliferative, anti-inflammatory and anti-fibrotic effects of RGS in colitis that may have implications for the treatment of colitis and colitis-associated cancer.