A quassinoid with diverse biological activities
Brusatol is a quassinoid that has been found in B. javanica and has diverse biological activities, including antimalarial, lipolytic, antioxidative, anticancer, and anti-inflammatory properties.1,2,3,4 It is active against chloroquine-resistant isolates of P. falciparum (EC50 = 7.58 ng/ml) and induces lipolysis in 3T3-L1 adipocytes when used at a concentration of 160 nM.1,2 Brusatol (40 nM) reduces nuclear erythroid 2-related factor 2 (Nrf2) ubiquitination and degradation and Nrf2 target gene expression in A549 lung cancer cells.3 It enhances cytotoxicity induced by cisplatin in A549 cells when used at a concentration of 40 nM in vitro and in an A549 mouse xenograft model when administered at a dose of 2 mg/kg. Brusatol also inhibits LPS-induced production of TNF-α, pro-IL-1β, prostaglandin E2 , and nitric oxide (NO) in RAW 264.7 macrophages. It reduces diarrhea and the severity of histopathological injury, as well as increases colonic levels of catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD), in a mouse model of ulcerative colitis when administered at doses of 0.5 and 1 mg/kg.4
1.Lee, K.-H., Tani, S., and Imakura, Y.Antimalarial agents, 4. Synthesis of a brusatol analog and biological activity of brusatol-related compoundsJ. Nat. Prod.50(5)847-851(1987) 2.Lahrita, L., Moriai, K., Iwata, R., et al.Quassinoids in Brucea javanica are potent stimulators of lipolysis in adipocytesFitoterapia137104250(2019) 3.Ren, D., Villeneuve, N.F., Jiang, T., et al.Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanismProc. Natl. Acad. Sci. USA108(4)1433-1438(2011) 4.Zhou, J., Wang, T., Dou, Y., et al.Brusatol ameliorates 2, 4, 6-trinitrobenzenesulfonic acid-induced experimental colitis in rats: Involvement of NF-κB pathway and NLRP3 inflammasomeInt. Immunopharmacol.64264-274(2018)
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Cell experiment: |
CT-26 cells in logarithmic growth are seeded onto a 96-well plate at a density of 4×103 cells/well. After 24 h of incubation at 37°C, fresh medium containing a series of concentrations of Brusatol (0.05, 0.15, 0.45, 1.35, 4.05 and 12.15 μg/mL) and CDDP (0.05, 0.15, 0.45, 1.35, 4.05 and 12.15 μg/mL) is added at 100 μL/well; each concentration is used to treat six replicate wells. After 48 h of incubation at 37°C, the cells are further incubated with MTT (10 mg/mL) at 37°C for 4 h. The supernatant is then removed and the precipitate is dissolved with 100 μL DMSO. Absorbance is measured using a microplate reader at a wavelength of 490 nm. Cytotoxicity is expressed as the concentration of Brusatol and CDDP that inhibit cell growth by 50% (IC50 value). The inhibitory rate is calculated. The possible synergistic effect of Brusatol combined with CDDP is investigated by exposing CT-26 cells to various concentrations of each agent alone or in combination for 48 h. The synergistic effect is assessed using CalcuSyn software 2.0[2]. |
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Animal experiment: |
Mice[3]Athymic nude mice are used. Mice 4-6 wk old are injected with A549 cells. Once the tumors reach 80 mm3 (for the two times five-time Cisplatin treatment regimen) or 280 mm3 (for the single five-time Cisplatin treatment regime), mice are randomly allocated into four groups and treated i.p. with DMSO, Cisplatin (2 mg/kg), Brusatol (2 mg/kg), or in combination every other day for a total of five times. After the initial five-time Cisplatin treatment regimen, treatment stops for 1 wk to allow mice to recover before the second five-time Cisplatin treatment regimen is repeated[3]. |
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参考文献: [1]. Olayanju A, et al. Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammaliancells to chemical toxicity-implications for therapeutic targeting of Nrf2. Free Radic Biol Med. 2015 Jan;78:202-12. |
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