The Inhibition of Colorectal Cancer Growth by the Natural Product Macrocarpal I

Colorectal Cancer
03/11/2020

Free Radic Biol Med. 2020 Oct 30:S0891-5849(20)31591-4. doi: 10.1016/j.freeradbiomed.2020.10.317. Online ahead of print.

ABSTRACT

BACKGROUND: Presently, few small molecule compounds are used as targeted therapy drugs in the treatment of colorectal cancer (CRC). It is important to identify new small molecule compounds, which can be used in the treatment of CRC.

METHODS: In this study, we selected four protein molecules as drug targets: PRL-3 (Phosphatase of regenerating liver 3), CLIC4 (Chloride intracellular channel 4), THBS2 (Thrombospondin 2), and BGN (Biglycan). These protein molecules were associated with the growth and metastasis of CRC cells. Small molecular compounds were screened on the basis of their target structures. Thus, five small molecule compounds were screened from each target structure, and three small molecule compounds (macrocarpal I, sildenafil, and neoandrographolide) were found to bind with two drug targets at the same time. Further experiments revealed that the inhibition rate of macrocarpal I was the highest in CRC cells. Therefore, we determined the effects of macrocarpal I on proliferation, apoptosis, cytoskeleton of CRC cells, and subcutaneous tumorigenesis in nude mice. Furthermore, RNA-seq analysis was performed to determine the molecular mechanism through which macrocarpal I inhibited the progression of CRC.

RESULTS: We found that macrocarpal I could effectively inhibit proliferation, colony formation of CRC cells, and subcutaneous tumorigenesis in nude mice. Moreover, it also destroyed the cytoskeleton of CRC cells and promoted apoptosis. The effects on kinase activity, cytoskeleton, and DNA repair is the mechanism of macrocarpal I to inhibiting CRC growth.

CONCLUSION: Macrocarpal I is a small molecule compound that can effectively inhibit the progression of CRC. Thus, macrocarpal I is a therapeutic compound that shows promising results in the treatment of advanced CRC.