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

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Rahmani , F , Hashemzehi , M , Avan , A , Barneh , F , Asgharzadeh , F , Marjaneh , R M , Soleimani , A , Parizadeh , M , Ferns , G A , Mobarhan , M G , Ryzhikov , M , Afshari , A R , Ahmadian , M R , Giovannetti , E , Jafari , M , Khazaei , M & Hassanian , S M 2021 , ' Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway ' , Cellular Signalling , vol. 85 , 110069 . https://doi.org/10.1016/j.cellsig.2021.110069

Title: Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway
Author: Rahmani, Farzad; Hashemzehi, Milad; Avan, Amir; Barneh, Farnaz; Asgharzadeh, Fereshteh; Marjaneh, Reyhaneh Moradi; Soleimani, Atena; Parizadeh, Mohammadreza; Ferns, Gordon A.; Mobarhan, Majid Ghayour; Ryzhikov, Mikhail; Afshari, Amir Reza; Ahmadian, Mohammad Reza; Giovannetti, Elisa; Jafari, Mohieddin; Khazaei, Majid; Hassanian, Seyed Mahdi
Contributor organization: Research Program in Systems Oncology
Institute for Molecular Medicine Finland
Date: 2021-09
Language: eng
Number of pages: 14
Belongs to series: Cellular Signalling
ISSN: 0898-6568
DOI: https://doi.org/10.1016/j.cellsig.2021.110069
URI: http://hdl.handle.net/10138/345953
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.
Subject: Rigoserib
Ras signaling
Colon cancer
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: acceptedVersion

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