Synthesis of Novel Dinucleobase-Hydrazide Triazine Derivatives and Their Anti-Cancer Activity in Colorectal Cancer Cells

Abstract

Background: Colorectal cancer remains a principal cause of cancer-related deaths worldwide in both males and females. Despite significant advances in colorectal cancer therapies, the treatment regimen is still insufficient. Indeed, the anti-metabolite drug, 5-fluorouracil, is highly efficient in treating colorectal cancer treatment; however, its clinical application has extremely declined due to cellular drug resistance. This urges the need for the urgent need of more advanced anti-cancer drugs in order to overcome emerging problems such as multidrug resistance and metastasis. Here, we propose nucleoside analogues as new synthetic agents that act as an effective chemotherapeutic drug in colorectal cancer and suppress their malignant phenotype.

Methods and results: We investigated the anti-cancer activities of nucleoside analogues on the tumor hallmarks such as proliferation, migration, adhesion and angiogenesis. Treatment of human colon cancer cell line, HCT116, with increasing concentrations of nucleoside analogues showed anti-proliferative activity. Additionally, wound healing assay and, respectively, showed that these nucleosides significantly decreased cell migration, while aggregation assay showed an increase in cell aggregation. Furthermore, our analogues inhibited angiogenesis by reducing blood vessel density in CAM assay. These effects were concomitant with the downregulation of focal adhesion kinase and mitogen-activated protein kinases, ERK1/2 and p38.

Conclusion: Taken together, our findings suggest that novel synthetic nucleoside analogues seem to be effective therapeutic drugs against colorectal cancer.