Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway

Farzad Rahmani; Milad Hashemzehi; Amir Avan; Farnaz Barneh; Fereshteh Asgharzadeh; Reyhaneh Moradi Marjaneh; Atena Soleimani; Mohammadreza Parizadeh; Gordon A Ferns; Majid Ghayour Mobarhan; Mikhail Ryzhikov; Amir Reza Afshari; Mohammad Reza Ahmadian; Elisa Giovannetti; Mohieddin Jafari; Majid Khazaei; Seyed Mahdi Hassanian

doi:10.1016/j.cellsig.2021.110069

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway

Cell Signal. 2021 Sep:85:110069. doi: 10.1016/j.cellsig.2021.110069. Epub 2021 Jun 29.

Authors

Farzad Rahmani¹, Milad Hashemzehi², Amir Avan³, Farnaz Barneh⁴, Fereshteh Asgharzadeh⁵, Reyhaneh Moradi Marjaneh⁵, Atena Soleimani⁶, Mohammadreza Parizadeh⁷, Gordon A Ferns⁸, Majid Ghayour Mobarhan⁹, Mikhail Ryzhikov¹⁰, Amir Reza Afshari¹¹, Mohammad Reza Ahmadian¹², Elisa Giovannetti¹³, Mohieddin Jafari¹⁴, Majid Khazaei¹⁵, Seyed Mahdi Hassanian¹⁶

Affiliations

¹ Iranshahr University of Medical Sciences, Iranshahr, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
² Tropical and Communicable Diseases Research Centre, Iranshahr University of Medical Sciences, Iranshahr, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
³ Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad, Iran.
⁴ Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
⁵ Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁶ Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁷ Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad, Iran.
⁸ Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK.
⁹ Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad, Iran.
¹⁰ Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO, USA.
¹¹ Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
¹² Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany.
¹³ 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.
¹⁴ Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Finland.
¹⁵ Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad, Iran. Electronic address: KhazaeiM@mums.ac.ir.
¹⁶ Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad, Iran. Electronic address: hasanianmehrm@mums.ac.ir.

PMID: 34214591
DOI: 10.1016/j.cellsig.2021.110069

Abstract

Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action.

Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC).

Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9.

Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.

Keywords: Colon cancer; Ras signaling; Rigoserib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cell Line, Tumor
Cell Proliferation
Colorectal Neoplasms* / pathology
Glycine / analogs & derivatives
Humans
Signal Transduction
Sulfones / pharmacology
Xenograft Model Antitumor Assays

Substances

Sulfones
ON 01910
Glycine