Nobiletin May Inhibit Tumor Activity in Cholangiocarcinoma


A compound often found in citrus fruits, nobiletin, could be a less toxic and more effective treatment for cholangiocarcinoma.

A recent study indicates that nobiletin (NBT) may inhibit cholangiocarcinoma (CCA) activity. CCA is usually not diagnosed until it has reached an advanced stage and there are no significant treatment options currently available for the advanced stage of the disease. NBT is a potent, natural medicine that was found to suppress CCA cell proliferation in vitro and in vivo, according to a study published in the International Journal of Biological Sciences.

“NBT decreased the proliferation of CCA via targeting [Glycogen synthase kinase-3 beta] (GSK3β),” the study authors wrote. “The study clarified that NBT could be a potential drug for the therapeutic of CCA.”

Researchers ultimately identified GSK3β as a target for NBT, because GSK3β can cause tumor-related disease activity. CCA is a hepatobiliary cancer that is characterized by uncontrolled cell proliferation and leads to a high mortality rate.

CCA is produced from bile duct epithelial cells and is the second most common primary liver tumor. Surgery is the only cure; however, it is only given to patients with early-stage disease, according to the study. Even still, patients often have recurrence, with a survival rate of 5 years.

Researchers explored the mechanisms of NBT that inhibit CCA activity. NBT, which has has displayed anti-tumor activity for multiple types of cancer cells, functions by arresting the cancer cell cycle. NBT, which is a huge component in orange peels, can also inhibit tumor proliferation and accelerates cell apoptosis, according to the study authors.

A mice model was used to study the in vivo ­anti-tumor activity, creating groups of mice that either received a low dose or high dose of NBT. In other groups, the mice either received cisplatin or combined treatment of low dose NBT with cisplatin.

“Even low NBT (25 mg/kg) combined with cisplatin can improve the efficacy of cisplatin,” the study authors wrote in the report.

The cell cycle regulates each stage of cell growth. In a healthy body, mutant/abnormal cells should not grow past the G0/G1, S2, or G2/M checkpoints, according to the study. The researchers explored how NBT affects the cell cycle with flow cytometry. They said that the results showed that NBT could stop the development of cancer cells at early growth G0/G1 phases. More specifically, the data showed that 25 to 50 mg/kg of NBT treatment could inhibit tumor growth.

Additionally, the data from the in vitro experiments suggest that NBT has no cytotoxicity, which could signify that it is a safer alternative to chemotherapy for CCA patients with recurrent tumors and malignancies, according to the study authors.

“NBT could inhibit CCA proliferation, and the pharmacological activity of NBT in CCA was attributed to its direct binding to GSK3β. We suggested that NBT might be a potential natural medicine in CCA treatment,” the study authors wrote in the report.


You, Liping, Lin, Jiacheng, Yu, Zhuo, et al. Nobiletin suppresses cholangiocarcinoma proliferation via inhibiting GSK3β. Int J Biol Sci 2022; 18(15):5698-5712. doi:10.7150/ijbs.78345. Accessed October 28, 2022.

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