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Background: Pancreatic cancer (PanCa), ranked as the 4th leading cause of cancer-related death worldwide, exhibits an dismal 5-year survival rate of less than 5 %. Chronic pancreatitis (CP) is a known major risk factor for PanCa. Brusatol (BRT) possesses a wide range of biological functions, including the inhibition of PanCa proliferation. However, its efficacy in halting the progression from CP to pancreatic carcinogenesis remains unexplored., Methods: We assess the effects of BRT against pancreatic carcinogenesis from CP using an experimentally induced CP model with cerulein, and further evaluate the therapeutic efficacy of BRT on PanCa by employing Kras tm4Tyj Trp53 tm1Brn Tg (Pdx1-cre/Esr1*) #Dam/J (KPC) mouse model., Results: Our finding demonstrated that BRT mitigated the severity of cerulein-induced pancreatitis, reduced pancreatic fibrosis and decreased the expression of α-smooth muscle actin (α-SMA), which is a biomarker for pancreatic fibrosis. In addition, BRT exerted effects against cerulein-induced pancreatitis via inactivation of NLRP3 inflammasome. Moreover, BRT significantly inhibited tumor growth and impeded cancer progression., Conclusions: The observed effect of BRT on impeding pancreatic carcinogenesis through targeting NLRP3 inflammasome suggests its good potential as a potential agent for treatment of PanCa., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Brusatol (Bru), a bioactive compound found in Brucea sumatrana, exerts antitumour effects on several malignancies. However, the role and molecular mechanism of Bru in squamous cell carcinoma of the oesophagus (ESCC) remain unclear. Here, we found that Bru decreased the survival of ESCC cells. Subsequently, the ferroptosis inhibitors, deferoxamine and liproxstatin-1, rescued Bru-induced cell death, indicating that ferroptosis plays a major role in Bru-induced cell death. Furthermore, Bru promoted lipid peroxidation, glutathione (GSH) depletion, and ferrous iron overload in vitro. Consistent with these in vitro results, Bru significantly inhibited tumour growth in KYSE150 xenograft nude mice by triggering ferroptosis. Mechanistically, nuclear factor E2-related factor 2 (NRF2) inactivation via increased ubiquitin-proteasome degradation was found to be a vital determinant of ferroptosis induced by Bru. Notably, Bru significantly decreases GSH synthesis, iron storage, and efflux by downregulating the expression of NRF2 target genes (glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), ferritin heavy chain 1 (FTH1), and solute carrier family 40 member 1 (SLC40A1)), resulting in the accumulation of lethal lipid-based reactive oxygen species (ROS) and intracellular enrichment of chelated iron. Taken together, our findings indicate that ferroptosis is a novel mechanism underlying Bru-induced antitumour activity and will hopefully provide a valuable compound for ESCC treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

Brusatol (Bru), a Chinese medicine Brucea javanica extract, has a variety of antitumour effects. However, its role and underlying mechanism in melanoma have not been fully elucidated. In this study, we found that brusatol inhibited melanoma cell proliferation and migration and promoted cell apoptosis in vitro, in addition to suppressing melanoma cell tumorigenesis in vivo. Further studies on the mechanism revealed that brusatol significantly downregulated the expression of stearoyl-CoA desaturase 1 (SCD1). Increased SCD1 expression could impair the antitumour effects of brusatol on melanoma cells. Subsequently, we found that HOXB9, an important transcription factor, was directly bound to the promoter of SCD1, facilitating its transcription. Overexpression of HOXB9 inhibited brusatol-induced SCD1 reduction and promoted cell survival. Furthermore, our results revealed that miR-122-5p was significantly increased in response to brusatol treatment and led to a decrease in HOXB9 in melanoma. Collectively, our data suggested that the miR-122-5p/HOXB9/SCD1 axis might play an important role in the antitumour effects of brusatol and that brusatol might have potential clinical implications in melanoma therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cancer is currently the most important problem endangering human health. As antitumor drugs have always been the most common methods for treating cancers, searching for new antitumor agents is of great significance. Brusatol, a quassinoid from the seeds of Brucea javanica, exhibits a potent tumor-suppressing effect with improved disease outcome. Studies have shown that brusatol not only shows potential tumor inhibition through multiple pharmacological effects, such as promoting apoptosis and inhibiting metastasis but also exhibits significant synergistic antitumor effects in combination with chemotherapeutic agents and overcoming chemical resistance in a wide range of cancer types. In this paper, the antitumor effects and mechanisms of brusatol were reviewed to provide evidence that brusatol has the exact antitumor efficacy of chemotherapeutic agents and show the potential of brusatol to be developed as a promising antitumor drug., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chemotherapy resistance remains to be the primary barrier to acute myeloid leukemia (AML) treatment failure. Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been well established as a truly pleiotropic transcription factor. Inhibition of Nrf2 function increases the sensitivity of various chemotherapeutics and overcomes chemoresistance effectively. Brusatol (Bru) has been reported to decrease Nrf2 protein expression specifically by ubiquitin degradation of Nrf2. However, it remains elusive whether combination of Brusatol and Cytarabine (Ara-C) elicits a synergistic antitumor effect in AML. Our results demonstrated that combination of Ara-C and Brusatol synergistically exerted remarkable pro-apoptosis effect in HL-60 and THP-1 cells. Mechanistically, synergistic anti-tumor effect of Ara-C/Brusatol in AML cells is mediated by attenuating Nrf2 expression. To our surprise, Nrf2 inhibition by Brusatol causes downregulation of the expression of glycolysis-related proteins and decreased glucose consumption and lactate production, whereas the level of ROS production was unaffected. The activation of Nrf2 by Sulforaphane (SFP) could reverse the chemotherapeutic effect and changes of glycolysis of concomitant of Ara-C with Brusatol in AML cell lines. Additionally, Ara-C/Brusatol co-treatment decreased Glucose-6-phosphate dehydrogenase (G6PD) protein expression and increased the sensitivity of Ara-C. Moreover, the mouse xenograft in vivo experiment confirmed that combining Ara-C with Brusatol exerted stronger antileukemia than Ara-C alone. The efficacy, together with the mechanistic observations, reveals the potential of simultaneously giving these two drugs and provides a rational basis for targeting glucose catabolism in future clinical therapeutic approach., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Brucea javanica oil (BJO), one of the main products of Brucea javanica, has been widely used in treating different kinds of malignant tumors. Quassinoids are the major category of anticancer phytochemicals of B. javanica. However, current researches on the anti-cancer effect of BJO mainly focused on oleic acid and linoleic acid, the common major components of dietary edible oils, essential and characteristic components of B. javanica like quassinoids potentially involved remained unexplored. In the current investigation, we developed an efficient HPLC method to detect brusatol, a characteristic quassinoid, and comparatively scrutinized the anti-hepatocellular carcinoma (anti-HCC) effect of BJO, brusatol-free BJO (BF-BJO), and brusatol-enriched BJO (BE-BJO) against hepatoma 22 (H22) in mice. High-performance liquid chromatography (HPLC) was utilized to identify the components in BJO. BE-BJO was extracted with 95 % ethanol. The anti-tumor effect of BJO, BF-BJO and BE-BJO was comparatively investigated, and the potential underlying mechanism was explored in H22 ascites tumor-bearing mice. The results indicated that BJO and BE-BJO significantly prolonged the survival time of H22 ascites tumor-bearing mice, while BF-BJO exhibited no obvious effect. BJO and BE-BJO exhibited pronounced anti-HCC activity by suppressing the growth of implanted hepatoma H22 in mice, including ascending weight, abdominal circumference, ascites volume and cancer cell viability, with a relatively wide margin of safety. BJO and BE-BJO significantly induced H22 cell apoptosis by upregulating the miRNA-29b gene level and p53 expression. Furthermore, BJO and BE-BJO treatment substantially downregulated Bcl-2 and mitochondrial Cytochrome C protein expression, and upregulated expression levels of Bax, Bad, cytosol Cytochrome C, caspase-3 (cleaved), caspase‑9 (cleaved), PARP and PARP (cleaved) to induce H22 cells apoptosis. Brusatol was detected in BJO and found to be one of its major active anti-HCC components, rather than fatty acids including oleic acid and linoleic acid. The anti-HCC effect of BJO and BE-BJO was intimately associated with the activation of miRNA-29b, p53-associated apoptosis and mitochondrial-related pathways. Our study gained novel insight into the material basis of BJO in the treatment of HCC, and laid a foundation for a novel specific standard for the quality evaluation of BJO and its commercial products in terms of its anti-cancer application., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Brusatol, a natural quassinoid isolated from a traditional Chinese herbal medicine known as Bruceae Fructus, has recently been reported to possess powerful cytotoxic effects against various cancer cell lines, highlighting its potential as an anti-cancer drug. However, the precise molecular mechanisms by which Brusatol exerts its anti-cancer effects remain poorly understood in hepatocellular carcinoma (HCC). In this study, we demonstrated that Brusatol inhibited cell viability, proliferation and induced apoptosis in liver cancer lines. Furthermore, Brusatol could activate autophagy in diverse liver cell lines, and the autophagy inhibitor chloroquine (CQ) reversed Brusatol-induced apoptosis in Bel7404 cells. In addition, we found that Brusatol inhibited PI3K/Akt/mTOR. Brusatol may also inhibit invasion, migration and the epithelial-mesenchymal transition (EMT). In a human liver xenograft tumor model in nude mice, immunohistochemistry showed that Brusatol significantly inhibited tumor invasion and proliferation. Taken together, these results revealed that Brusatol effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction, probably via the PI3K/Akt/mTOR pathway, and inhibited tumor invasion and migration in vivo and in vitro. All above indicated that Brusatol is an encouraging anti-tumor drug candidate or a supplement to the current chemotherapeutic systematic plan., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)