Monthly Scientific Update – August 2022 (Preclinical Study Finds that Brusatol may Slow Intrahepatic Cholangiocarcinoma Growth)

Kelly Butler, Dr. Reham Abdel-Wahab

Brusatol, a traditionally used Chinese herbal medicine, is currently being explored as a potential cancer treatment in preclinical studies. While the research is still in its early stages,  several studies have found promising results in models of multiple cancer types.

A recent laboratory study focused specifically on intrahepatic cholangiocarcinoma (ICC) and found that brusatol may slow ICC growth. To begin, the researchers analyzed two different ICC cell lines with and without brusatol treatment. For both cell types, brusatol exposure increased cell death and decreased cell proliferation. It also hindered cell migration and invasion, which are necessary for metastasis in human disease. Compared to gemcitabine—a current standard of care for ICC—brusatol had a more significant inhibitory impact and was effective at lower doses. 

Continuing analysis of the ICC cell lines and providing mechanistic insight, the study found that brusatol may inhibit cancer growth by modulating PI3K/Akt signaling. When activated by adding phosphate groups, proteins in the PI3K/Akt pathway (e.g., PI3K, AKT, and mTOR) promote cell proliferation and survival. The study found lower levels of phosphorylated PI3K, AKT, and mTOR in the brusatol-treated ICC cell lines, suggesting that brusatol decreases PI3K/Akt signaling and thereby inhibits cell proliferation and promotes cell death (schematic overview in Figure 1).

Based on these promising results and to take a further step, the study tested whether brusatol treatment would slow tumor growth in a mouse model of ICC. The researchers implanted human tumor samples into mice to best mimic human disease and found that brusatol-treated mice had smaller tumors than untreated mice. In accordance with the cell line studies, tumors from brusatol-treated mice had lower levels of phosphorylated mTOR, PI3K, and AKT proteins; inactivation of PI3K/Akt signaling was thus a likely driver of decreased tumor size in the brusatol-treated mice. The treated mice also maintained healthy liver and kidney function, suggesting that brusatol may be well tolerated at therapeutic doses.

These preclinical results provide promising but preliminary evidence that brusatol could be an effective therapy for ICC.  Future studies should validate the safety and efficacy of brusatol in additional animal models and (if favorable) begin clinical trials.

Figure 1: Schematic overview of how brusatol may inhibit ICC growth

Kelly Butler

Kelly Butler is an NIH Postbac Research Fellow and the Founding Director of SAFE

Reham Abdel-Wahab

Reham Abdel-Wahab is the Cholangiocarcinoma Foundation's Director of Research and Chief Scientific Officer.