Bruceantin

The seeds of Brucea javanica.

Bruceantin(NSC165563) is first isolated from Brucea antidysenterica, a tree used in Ethiopia for the treatment of cancer, and activity was observed against B16 melanoma, colon 38, and L1210 and P388 leukemia in mice. IC50 value: Target: anticancer Cell differentiation was induced and c-MYC was down-regulated, suggesting a mechanistic correlation between c-MYC down-regulation and induction of cell differentiation or cell death. Treatment of HL-60 and RPMI 8226 cell lines induced apoptosis, and this involved the caspase and mitochondrial pathways. Moreover, an in vivo study using RPMI 8226 human-SCID xenografts demonstrated that bruceantin induced regression in early as well as advanced tumors, and these significant antitumor responses were facilitated in the absence of overt toxicity.

References:
[1]. Cuendet M, et al. Multiple myeloma regression mediated by bruceantin. Clin Cancer Res. 2004 Feb 1;10(3):1170-9. [2]. Cuendet M, et al. Antitumor activity of bruceantin: an old drug with new promise. J Nat Prod. 2004 Feb;67(2):269-72.

Synthesis of A/B-ring partial analogs of bruceantin as potential antimalarial agents.[Pubmed:16789880]

Med Chem. 2005 Jan;1(1):3-11.

Bruceantin (1), a classical quassinoid with the highest reported antimalarial activity among the quassinoids examined thus far, was selected as a natural product lead for the design of a series of A/B-ring analogs. A viable strategy for the synthesis of the series was developed. The functionalized A-ring and the C-15 ester moiety in Bruceantin are incorporated in all designed compounds. The preliminary bioassay results will be discussed in detail.

NF-kappaB inhibitors from Brucea javanica exhibiting intracellular effects on reactive oxygen species.[Pubmed:20944100]

Anticancer Res. 2010 Sep;30(9):3295-300.

AIM: Brucea javanica was studied to identify nuclear factor kappaB (NF-kappaB) inhibitors exhibiting reactive oxygen species (ROS) intracellular amplification. MATERIAL AND METHODS: Eight compounds were evaluated for selective cytotoxicity using HT-29, HeLa, and HL-60 cells, and in a NF-kappaB assay. Active compounds were then tested using ROS and mitochondria transmembrane potential (MTP) assays. NF-kappaB and nuclear factor activated T-cell (NFAT) translocation were also assessed using their respective whole cell assays. RESULTS: Bruceajavanone B, Bruceantin, bruceine A, (-)-hydnocarpin, and chrysoeriol exhibited cytotoxic potential and NF-kappaB p65 inhibition. Chrysoeriol exhibited selective cytotoxicity against leukemia cells with greater potency and also showed an ability to up-regulate NFAT transcriptional pathways through the amplification of intracellular ROS, in the presence of H2O2, to a greater degree than Bruceantin and bruceine. CONCLUSION: Chrysoeriol selectively kills leukemic cells and potentiates the amplification of ROS levels. Therefore, chrysoeriol could serve as a potential chemotherapeutic modifier for leukemia chemotherapy since leukemia cells have a higher susceptibility to elevated ROS levels.

Bruceantin inhibits multiple myeloma cancer stem cell proliferation.[Pubmed:27434731]

Cancer Biol Ther. 2016 Sep;17(9):966-75.

Multiple myeloma (MM) continues to claim the lives of a majority of patients. MM cancer stem cells (CSCs) have been demonstrated to sustain tumor growth. Due to their ability to self-renew and to express detoxifying enzymes and efflux transporters, MM-CSCs are rendered highly resistant to conventional therapies. Therefore, managing MM-CSCs characteristics could have profound clinical implications. Bruceantin (BCT) is a natural product previously demonstrated to inhibit the growth of MM in RPMI 8226 cells-inoculated mouse xenograft models, and to cause regression in already established tumors. The objectives of the present study were to test the inhibitory effects of BCT on MM-CSCs growth derived from a human primary tumor, and to explore a mechanism of action underlying these effects. BCT exhibited potent antiproliferative activity in MM-CSCs starting at 25 nM. BCT induced cell cycle arrest, cell death and apoptosis in MM-CSCs as well as inhibited cell migration and angiogenesis in vitro. Using a qPCR screen, it was found that the gene expression of a number of Notch pathway members was altered. Pretreatment of MM-CSCs with the gamma-secretase inhibitor RO4929097, a Notch pathway inhibitor, reversed BCT-induced effects on MM-CSCs proliferation. In this study, BCT was shown to be an effective agent in controlling the proliferation, viability and migration of MM-CSCs as well as angiogenesis in vitro. The effect on MM-CSCs proliferation may be mediated by the Notch pathway. These results warrant further investigation of BCT in a broader set of human-derived MM-CSCs and with in vivo models representative of MM.

Quassinoids isolated from Brucea javanica inhibit pepper mottle virus in pepper.[Pubmed:27686478]

Virus Res. 2017 Jan 2;227:49-56.

A green fluorescent protein (GFP)-tagged pepper mottle virus (PepMoV) based leaf-disc method and systemic host method were developed to identify antiviral agents. Preliminary experiments using a PepMoV-GFP based leaf-disc method led to the isolation of five quassinoids, including brusatol (1), Bruceantin (2), brucein A (3), Bruceantinol (4), and brucein B (5), from the CH3OH extract of Brucea javanica. All isolated compounds exhibited inactivation effects in systemic host plants, and compounds 3 and 4 were potent, with a minimum inhibitory concentration of 10muM. Furthermore, compound 3 was found to have a protective effect at the tested concentration of 40muM.

Bruceantin(NSC165563) is first isolated from Brucea antidysenterica, a tree used in Ethiopia for the treatment of cancer, and activity was observed against B16 melanoma, colon 38, and L1210 and P388 leukemia in mice.

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