Investigation of efficacy and mechanisms of pro-apoptotic natural products for colon cancer treatment

Abstract

Colorectal cancer is a leading cause of cancer death worldwide. Current colorectal cancer therapies include surgery, chemotherapy, radiation therapy, and immunotherapy. However, the severe side effects and limited drug responses reduce the efficacy of chemotherapy in treating colon cancer. Developing innovative anti-cancer agents from natural resources with low toxicity could be an attractive approach. This study aimed to investigate the effects of natural products on colon cancer and their underlying mechanisms of action. The first one under investigation was the water extract of Amauroderma rugosum (ARW), which is also known as blood Lingzhi. The results revealed that ARW had cytotoxic effects on colon cancer cells in vivo and in vitro. A network pharmacology study and western blot analysis demonstrated that the cytotoxic action of ARW was mediated by JNK phosphorylation and increased cleaved-caspase 9 levels, both of which triggered apoptosis. ARW also showed a synergistic effect with the conventional chemotherapy drug 5-fluorouracil. The second study focused on Amauroderma rugosum polysaccharides (ARPS). Cellular and animal studies showed that ARPS exhibited the same cytotoxic effect on colon cancer as ARW. It implied that polysaccharide was the primary active element responsible for the anti-cancer effect of ARW. The third study examined the anti-colon cancer properties of 3,19-dihydroxy-6,23- dioxo-12-ursen-28-oic acid (UOA), a triterpenoid from Uncaria tomentosa. UOA had a strong cytotoxic effect on the HCT116 colon cancer cells and suppressed tumor growth in the HCT116 xenograft mice model. UOA was also found to have a synergistic effect with the chemotherapeutic drug 5-fluorouracil. UOA achieved cytotoxicity by inducing apoptosis and autophagy. According to the network pharmacology, its mechanism of action may link to the inhibition of prostanoid EP2 receptors, inactivating the AKT/mTOR-dependent pathway and thereby stimulating caspase cascades and autophagy. In conclusion, the natural products AR and UOA have demonstrated robust proapoptotic activity on colon cancer cells. The findings suggest that they could be promising novel therapeutic agents for the treatment of colon cancer, warranting further exploration and development. Word counts: 323