Abstract 470P
Background
Systems biology and molecular biology approaches have been integrated to investigate the mechanisms of the anti-tumour effects of Rigosertib (RGS), either alone or in combination with 5-FU in colorectal cancer (CRC).
Methods
The present study integrates systems biology and molecular biology approaches to investigate the mechanisms of the anti-tumour effects of Rigosertib (RGS), either alone or in combination with 5-FU in colorectal cancer (CRC). Real-Time Polymerase-Chain-Reaction (RT-PCR), western blot and immunohistochemistry methods were used in this analysis.
Results
RGS inhibited cell proliferation and cell cycle progression in a Cell-type specific manner including SW480, Caco2, and CT-26 cell lines, and this 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 tumour models. We also found that RGS induced cell senescence in tumour tissues by increasing ROS generation, up-regulating pro-inflammatory cytokine expression, impairing oxidant/anti-oxidant balance, and through down-regulation of anti-oxidant proteins. RGS also inhibited angiogenesis and the metastatic behaviour of CRC cells by regulating the expression of CD31, E-cadherin and inhibiting the activities of matrix metalloproteinases-2 and 9 in tumour models, and potentially increased patients’ survival by down-regulating CD31.
Conclusions
This study has better delineated the RGS anti-tumour mechanisms and these findings support the clinical application of this potent RAS signaling inhibitor, either alone or in combination with standard regimens, for the management of patients with CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Seyed Mahdi Hasanian Mehr.
Funding
Mashhad University of Medical Sciences (Grant No. 951406), and the Biotechnology Development Council of the Islamic Republic of Iran (Grant No. 960301) to Seyed Mahdi Hasanan Mehr and National Institute for Medical Research Development (Grant No. 965391) to Majid Khazaei, Student Research Committee of Mashhad University of Medical Sciences (Grant No.961662) to Farzad Rahmani, and the European Network on Noonan Syndrome and Related Disorders (NSEuroNet, 01GM1602B); the German Federal Ministry of Education and Research (BMBF) – German Network of RASopathy Research (GeNeRARe, 01GM1902C).
Disclosure
All authors have declared no conflicts of interest.