Characterization of novel natural compound derivatives with cancer-selective cytotoxicity

BackgroundColorectal cancer (CRC) is one of the most frequent and lethal cancers in the world. The current medical treatment for CRC primarily includes combination of multiple chemotherapeutic, targeted and/or immunotherapeutic drugs. However, these approaches are still not fully successful and cause numerous and severe side effects for the patient. Therefore, there is an urgent need to discover novel and cancer-selective drugs for CRC treatment. As many other natural compounds, a-Mangostin and Paeonol possess anti-cancer properties, but both of these compounds have low solubility and low membrane permeability.Methodsa-Mangostin and Paeonol derivatives were chemically synthesized to increase cytotoxicity versus cancer cell over non-transformed cells. The anticancer properties of these compounds were investigated on human colon cancer cell lines by employing cell viability, apoptosis and cell-cycle analyses. Transcriptome of cancer cells treated with natural compounds were also analyzed by total RNA-sequencing. Finally, we investigated their effects on human colon organoids derived from healthy and cancerous tissue of the same patient.ResultsWe found the two derivative compounds (a-Mangostin-1 (aMan1) and Paeonol-1 (Pae1)) more efficiently induced cytotoxicity in HCT116, HT-29, and SW48 colorectal cancer cell lines than the parental compounds. Both, aMan1 and Pae1 arrested HCT116 cells in G1 and HT-29 and SW48 cells in G2/M phase of the cell cycle. aMan1 and Pae1 induced selective transcriptional responses in CRC cells involving genes related to metabolic stress and DNA damage response signaling pathways. Both aMan1 and Pae1 induced apoptosis in human cancer cells and organoids derived from tumor tissue without affecting the viability of human non-cancer cells and intestinal organoids derived from healthy tissue.ConclusionsOur findings increase the knowledge about natural compound derivatives as anticancer compounds and open new research options on the derivation of lead compounds aimed to the development of novel CRC chemotherapeutic drugs that selectively target cancer, but not healthy cells.