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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number110069
JournalCellular Signalling
Volume85
DOIs
Publication statusPublished - 1 Sep 2021

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