Cinchonine: Multifaceted Roles in Cancer Treatment and as a GLP - 1R Agonist

Cinchonine is cinchonan in which a hydrogen at position 9 is substituted by hydroxy (S configuration). It occurs in the bark of most varieties of Cinchona shrubs, and is frequently used for directing chirality in asymmetric synthesis. It has a role as a metabolite. It is a cinchona alkaloid and an (8xi)-cinchonan-9-ol. It derives from a hydride of a cinchonan.

Cinchonine activates endoplasmic reticulum stress-induced apoptosis in human liver cancer cells

Liver cancer remains a major health issue because it is the sixth most common malignancy and the third principal cause of cancer deaths worldwide. Despite the progress of potentially curative treatments, liver transplantation and surgical resection remain the first choice for liver cancer patients. Natural compounds have been widely used for cancer prevention and treatment because of its multi-level, multi-target and coordinated intervention effects. Cinchonine (C19H22N2O) is a natural compound which has been effectively used as antimalarial drug along with quinine, quinidine and cinchonidine and all these agents were separated from Cinchona bark. Interestingly, all these agents have been found with antitumor effects and among which cinchonine has much lower toxicity and higher activity. However, whether cinchonine could be used as an antitumor agent against liver cancer remains elusive. Cinchonine is a natural compound present in Cinchona bark. It exerts multidrug resistance reversal activity and synergistic apoptotic effect with paclitaxel in uterine sarcoma cells. Whether cinchonine is effective against human liver cancer, however, remains elusive. It was demonstrated that cinchonine inhibited cell proliferation and promoteed apoptosis in liver cancer cells in a dose-dependent manner. The Balb/c-nude mice experiment revealed that it suppressed HepG2 xenograft tumor growth in mice. The findings indicated that it promoted ER stress-induced apoptosis in liver cancer cells and suggested that cinchonine may have a potential beneficial effect for liver cancer treatment.[1]

Previous studies have reported that cinchonine is an inhibitor of human platelet aggregation through the inhibition of Ca2+ influx and PKC pathways in platelets. Cinchonine has been shown to possess a suppressive effect on adipogenesis and it also attenuates inflammation in the adipose tissue of mice fed on the High-Fat-Diet.  High levels of misfolded proteins can disrupt cellular homeostasis, induce ER stress, and might eventually lead to apoptosis. We found that cinchonine dramatically increased GRP78/CHOP protein levels and promoted PERK and eIF2a phosphorylation, suggesting that cinchonine activated ER stress response. We further observed that prolonged it exposure promoted caspase-3 activation and PARP1 cleavage in liver cancer cells, suggesting that it activate ER stress-induced apoptosis in liver cancer cells. Moreover, we also observed that cinchonine significantly suppressed HepG2 xenograft tumors growth in mice and also activated caspase-3 activation in vivo. Bel-7402 cell was not very sensitive to cinchonine treatment, and perhaps it contains less amount of GRP78 or CHOP protein levels, which should be test in the future.In conclusion, cinchonine promotes ER-stress in liver cancer which in turn activating caspase-3-dependent apoptosis both in vitro and in vivo. These results suggest cinchonine might be a potential antitumor drug in the treatment of human liver cancer.

Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist

In recent years, the cost of traditional drug development has increased significantly. In addition, the development cycles are long and the success rate is low, which are critical factors restricting drug development. Under such adverse factors, drug repurposing, namely repositioning and reevaluating marketed or investigational drugs for identifying and confirming new indications, has become an important method for drug discovery. Connectivity Map (CMap) is a crucial tool for drug repurposing by screening compounds that can generate gene expression profiles similar to that of the target drug. Currently, there is significant interest in the identification and development of nonpeptide agonists using this tool.Here, we analyzed the small intestine transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, and identified that cinchonine exerted GLP-1R agonist-like effects using CMap. Cinchonine, a quinoline alkaloid extracted from cinchona bark, has been used effectively as an antimalarial drug along with quinine, and quinidine. It has been suggested that cinchonine is less toxic than other quinine-related compounds. In the present study, we investigated the effect of cinchonine on hyperglycemia and NASH as a potential oral small-molecule GLP-1R agonist.[2]

Weight loss is linked to reduced hepatic steatosis. Preclinical and clinical studies using GLP-1R agonists demonstrate that reductions in hepatic steatosis, inflammation, and liver injury are generally associated with weight loss. As expected, cinchonine dose-dependently reduced body weight gain in ob/ob-GAN NASH mice, which was consistent with decreased food intake. In addition, 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP, and LDH levels. Importantly, 100 mg/kg cinchonine was found to ameliorate hepatic steatosis and hepatic fibrosis in NASH mice.In addition to its antimalarial effect, cinchonine has been reported to inhibit human platelet aggregation via reducing calcium ion influx and inhibiting the protein kinase C pathway in platelets. In addition, cinchonine can inhibit toll-like receptor 2- (TLR2-) and TLR4-mediated signaling cascades, and attenuate pro-inflammatory cytokine levels in high-fat diet-induced obesity mice. Cinchonine was also recently reported to induce apoptosis of HeLa and A549 cells by inhibiting transforming growth factor-β-activated kinase 1 and protein kinase B through binding to tumor necrosis factor receptor associated factor 6. Therefore, although we found that cinchonine lowered blood glucose and ameliorated NASH by activating GLP-1R, it cannot be excluded that it has other mechanisms to enhance or attenuate these effects. In conclusion, this study demonstrated that cinchonine, as a potential oral small-molecule GLP-1R agonist, reduces blood glucose and ameliorates NASH. Our findings confirm the importance of drug repurposing for the discovery of GLP-1R agonists. Although further exploration is needed, the discovery of cinchonine still provides feasible methods and ideas for the development of small-molecule GLP-1R agonists.

References

[1]Jin ZL, Yan W, Qu M, Ge CZ, Chen X, Zhang SF. Cinchonine activates endoplasmic reticulum stress-induced apoptosis in human liver cancer cells. Exp Ther Med. 2018 Jun;15(6):5046-5050. doi: 10.3892/etm.2018.6005. Epub 2018 Mar 29. PMID: 29805529; PMCID: PMC5952100.

[2]Xue, Huan et al. “Cinchonine, a Potential Oral Small-Molecule Glucagon-Like Peptide-1 Receptor Agonist, Lowers Blood Glucose and Ameliorates Non-Alcoholic Steatohepatitis.” Drug design, development and therapy vol. 17 1417-1432. 11 May. 2023, doi:10.2147/DDDT.S404055