Evaluation of the anti-neoplastic effects of the novel retinoid MIR002 compared to its parent molecule ST1926 on colorectal cancer cells

Abstract

Colorectal cancer (CRC) is assigned as one of the most common cancers worldwide and falls in the second position regarding its prevalence among other cancers. The molecular carcinogenesis of CRC development involves specific well-defined genetic mutations. Treatment of CRC is stage dependent and might include surgery, radiotherapy along with chemotherapy. Indeed, several chemotherapeutic molecules are currently used in clinic for treatment of CRC while drug toxicity and cancer resistance remain major concerns for all available treatments. Knowing that, new molecules are currently under development and improvement, with retinoids being one of the most promising classes. Retinoids are vitamin A derivatives that have been studied extensively in the field of cancer. Both natural and synthetic retinoids proved efficacy in blood malignancies and a variety of solid tumors including colorectal cancer making their improvement and testing a hotspot for research. Accordingly, several molecules have been synthesized and tested with retinoid-related molecules (RRMs) being the novel and most promising class of molecules. CD437 and ST1926 were the most prominent molecules of this class. After halting ST1926 and the failure of other retinoids in clinical trials, MIR002 was derived in 2017 from ST1926 and is suggested to bypass the shortcomings of the previous molecules. Our study aimed to investigate the anti-proliferative features of MIR002 compared to ST1926 on two CRC cell lines, HCT116 and HT29. Our results showed that both drugs are potent inhibitors of cell growth and viability. Their probable mode of action suggests the induction of DNA damage shown by g-H2AX upregulation. Additionally, the investigations of apoptotic proteins indicated that ST1926 and MIR002, like previously studied RRMs, induce apoptosis in a p53-dependent and -independent manner. Similarly, the cleavage of PARP in HCT116 cells proved the activation of caspase cascade to induce apoptosis. However, in HT29 cell lines, other apoptotic pathways are suggested that require further investigations and identification. Our study verified the anti-neoplastic effects of ST1926 on CRC cells and enforced previous results. Additionally, it investigated for the first time the effects of the promising retinoid MIR002 and indicated that it has potent anti-neoplastic features against CRC cell lines.