Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

Abstract

The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.

Combination of siRNA-directed gene silencing with epigallocatechin-3-gallate (EGCG) reverses drug resistance in human breast cancer cells

“…Flavonoids are generally safe and are associated with low toxicity, making them ideal candidates for cancer chemopreventive agents. Several flavonoid compounds have been reported to be potent Nrf2 inhibitors, such as epigallocatechin 3-gallate, luteolin, and brusatol [28,46,47]. The chemopreventive effects of green tea have been attributed to polyphenolic ingredients that have potent antioxidant properties.…”

A dual role for autophagy in a murine model of lung cancer

“…For detection of Cxcl5 in the sera, we used a Mouse Cxcl5 ELISA kit following the manufacturer's instructions (Abcam, ab100719). For inhibitor experiments in primary pneumocytes, the Hif1a inhibitor 3-(2-(4-Adamantan-1-yl-phenoxy)-acetylamino)-4-hydroxybenzoic acid methyl ester (10 mM; Santa Cruz, sc-205346), the Nrf2 inhibitor brusatol 53 (100 nM; Chemical Book, #14907-98-3) and the ROS scavenger N-acetyl-L-cysteine (5 mM, Sigma, #A7250) were added to the cells 6 h after AdCre infection.…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…134 In addition, the tumor stroma has been reported to express high levels of Nrf2 and Nrf2 inhibitors proposed as an anticancer strategy. 135 Hence, Nrf2 may represent double-edged sword, and this must be considered when administering Nrf2 activators as interventional drugs. Whether sustained or hyperactivation of Nrf2 in the context of fibrosis may predispose to cancer is unknown.…”