The new andrographolide derivative AGS-30 induces apoptosis in human colon cancer cells by activating a ROS-dependent JNK signalling pathway.

BACKGROUND: The anti-cancer activity of andrographolide (Andro) has been extensively demonstrated in recent years. It is supposed that modifying the chemical structure of Andro can improve its efficacy and reduce its toxicity. PURPOSE: In this study, the anti-cancer effect of a 14ß-(2'-chlorophenoxy) derivative of andrographolide known as AGS-30 was investigated, and its underlying mechanisms were also explored. STUDY DESIGN/METHODS: Different cancer cells were used to evaluate and compare the in vitro anti-cancer effects of Andro and AGS-30. Human colon cancer cells HT-29 and HCT-116 were used to study the underlying anti-cancer mechanisms of AGS-30. HT-29 cells xenografted in nude mouse model was used to compare the in vivo anti-tumour efficacies of Andro and AGS-30. RESULT: In vitro studies showed that AGS-30 possessed an anti-cancer effect by inhibiting the viability, colony formation and migration of cancer cells. It significantly induced the generation of reactive oxygen species (ROS), caused the loss of mitochondrial membrane potential and triggered the apoptosis in colon cancer cells. These effects of AGS-30 were more potent than those of Andro. In addition, the expression levels of proteins associated with apoptosis, including phospho-JNK1/2 as well as cleaved caspase 9, caspase 3, and poly(ADP ribose) polymerase, were elevated in AGS-30-treated colon cancer cells. Moreover, these elevated levels of the proteins were inhibited by the antioxidant N-acetylcysteine and the JNK inhibitor SP600125, suggesting the involvement of ROS/JNK-dependent mechanisms in AGS-30-induced apoptosis. The in vitro anti-cancer effect could be reproduced in an HT-29 colon cancer cell xenografted nude mouse model. CONCLUSION: The anti-cancer effect of AGS-30 is stronger than that of Andro. AGS-30 induces apoptosis of colon cancer cells through ROS/JNK-dependent pathway. Our findings may provide insights for the future development of derivatives of Andro as novel chemotherapeutic agents.

AGS-30, an andrographolide derivative, suppresses tumor angiogenesis and growth in vitro and in vivo.

Poor bioavailability and limited efficacy are challenges associated with using andrographolide as a therapeutic agent. We recently synthesized AGS-30, a new andrographolide derivative, in our laboratory. In this study we investigated the potential anti-tumor effect of AGS-30 and the underlying mechanisms, particularly those related to angiogenesis. Results from our in vitro experiments showed that AGS-30 exerted anti-angiogenic effects by inhibiting endothelial cell proliferation, migration, invasion, and tube formation. Phosphorylation and activation of angiogenesis-related signaling molecules (e.g., vascular endothelial growth factor [VEGF] receptor 2, mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2, mechanistic target of rapamycin [mTOR], protein kinase B [Akt], and p38) were markedly reduced by AGS-30. Meanwhile, AGS-30 potently inhibited cell proliferation and phosphorylation of cell survival-related proteins (e.g., Akt, mTOR, and ERK1/2) and decreased the expression of VEGF in HT-29 colon cancer cells. AGS-30 blocked microvessel sprouting in a rat aortic ring model and blood vessel formation in zebrafish embryos and a mouse Matrigel plug model. Additionally, AGS-30 suppressed tumor growth and angiogenesis in HT-29 colon cancer cell xenografts in nude mice. These effects were not observed when same concentration of andrographolide, the parent compound of AGS-30, was used. Thus, AGS-30 exerted a strong antitumor effect by inhibiting tumor cell growth and angiogenesis and is a candidate compound for the treatment of cancer.

Discovery and preliminary SAR of 14-aryloxy-andrographolide derivatives as antibacterial agents with immunosuppressant activity.

Antibacterials (which restore gut flora balance) and immunosuppressants (which correct immune defects) are two important and effective therapeutic agents for the treatment of inflammatory bowel disease (IBD) in clinical use today. Since the structural skeleton of andrographolide, isolated from Andrographis paniculata, has become known as a natural antibiotic with anti-inflammation and heat-clearing and detoxifying properties, 14-aryloxy andrographolide derivatives have been designed, synthesized, and tested for their antibacterial effects on E. coli, S. aureus, and E. faecalis, which are related to IBD. It has been discovered in this study that the andrographolide skeleton is more selective against E. faecalis, the 14-aryloxy group with basicity is important for antibacterial functions, and the 14-(8'-quinolinyloxy) group is a good pharmacophore with antibacterial activity. In addition, we found that 7b1 and 8b1 are good and selective inhibitors of E. faecalis; two 14ß-(8'-quinolinyloxy) andrographolide derivatives, 6b17 and 9b, exhibit good activity against E. coli, S. aureus, and E. faecalis. Likewise and importantly, further exploration of immunosuppressant activity for IBD shows that compound 7b1 is a selective inhibitor of the TNF-α/NF-κB signaling pathway, whereas 8b1 is selectively active against the TLR4/NF-κB signaling pathway; moreover, the compounds 6b17 and 9b are active in inhibiting the IL-6/STAT3, TLR4/NF-κB, and TNF-α/NF-κB signaling pathways. Based on these results, we have further focused on the development of dual function inhibitors of IBD as antibacterial and immunosuppressant agents by structural modification of andrographolide.