α-Mangostin (aMan) and Paeonol (Pae) have shown anticancer and anti-inflammatory properties. However, these two natural compounds have no clinical value because of their low solubility and low membrane permeability. In this study, we screened chemically synthesized derivatives from these two natural compounds as potential novel chemicals that increase cancer cell cytotoxicity over nontransformed human cells. We found that two derivative compounds, named α-Mangostin-1 (aMan1) and Paeonol-1 (Pae1) more efficiently and more specifically induced cytotoxicity in HCT116, HT29, and SW48 colorectal cancer cell lines than the parental compounds. Both aMan1 and Pae1 arrested HCT116 cells in the G1 phase and HT29 and SW48 cells in the G2–M phase of the cell cycle. Both aMan1 and Pae1 induced apoptosis in human colorectal cancer cells, through a caspase-dependent mechanism. aMan1 and Pae1 induced selective transcriptional responses in colorectal cancer cells involving genes related to metabolic stress and DNA damage response signaling pathways. Finally, experiments on primary colon organoids showed that both derivatives were able to kill cancer-derived organoids without affecting the viability of organoids derived from healthy tissue, where the parental compounds and the currently used chemotherapeutic drug irinotecan failed. In conclusion, our findings expand the knowledge of natural compound derivatives as anticancer agents and open new avenues of research in the derivation of lead compounds aimed at developing novel chemotherapeutic drugs for colorectal cancer treatment that selectively target cancer, but not healthy cells.
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.
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