A Combination of γ-Tocotrienol and Brusatol for the Treatment of Lung Cancer

Lung cancer is the leading cause of cancer deaths in the United States. While progress has been made in developing effective therapeutics for the treatment of lung cancer, lung cancer has a 5-year survival rate of just 18.6%. There is a demand for novel treatment approaches that can effectively target cancer cells while inducing minimal adverse effects on the patient’s quality of life. Nutritional approaches (nutraceuticals) may be a viable option. Vitamin E contains two vitamers: tocopherols and tocotrienols. Tocotrienols are potent antioxidants that have exhibited anti-cancer effects in preclinical models. Additionally, brusatol, a novel compound isolated from the plant, Brucea Javanica, inhibits cancer growth in preclinical models. Independently, tocotrienols and brusatol reduce cancer progression, likely through differing mechanisms. It is likely that a combination of tocotrienol and brusatol synergistically inhibits cancer progression. However, the efficacy of a combination of tocotrienols and brusatol against lung cancer has not been investigated. Therefore, the aim of this project was to determine if the combination of γ-tocotrienol and brusatol inhibit lung cancer growth and to determine the mechanism of action of this combination therapy. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC). We utilized A549 cells, which are a model of NSCLC. A549 cells were treated with media supplemented with vehicle, tocotrienol (TT; 20 µm), brusatol (Bru; 10 nM), and tocotrienol and brusatol combined (20 µm TT + 10 nM Bru). Cell proliferation was measured at days 0, 3, and 6. Protein was collected after 24 hours of treatment for analysis of proteins of interest. TT, Bru, and TT+Bru significantly reduced lung cancer proliferation at day 3 (8.0, 23.0, and 7.6% of control, respectively) and at day 6 (7.8, 13.3, 8.0% of control, respectively). TT, Bru, and TT+Bru tended to reduce expression of STAT3 (a transcription factor important for cancer cell growth) but not significantly. Expression of cyclin D1 appears to be reduced by Bru and TT+Bru. Genes in the antioxidant system were differentially affected by TT, Bru, and TT+Bru. These studies suggest that a combination of TT and Bru may be an effective treatment for lung cancer. Ongoing studies in the lab will optimize dosages of these treatments and elucidate effects on cellular signaling pathways mediating the anti-cancer effects of this combination therapy.