Bruceantin

Bruceantin was 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. Phase I and II clinical trials were then initiated, but no objective tumor regressions were observed and clinical development was terminated. Recently, the activity of bruceantin has been studied with a number of leukemia, lymphoma, and myeloma cell lines. 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...

PURPOSE: Bruceantin has been shown to induce cell differentiation in a number of leukemia and lymphoma cell lines. It also down-regulated c-MYC, suggesting a correlation of down-regulation with induction of cell differentiation or cell death. In the present study, we focused on multiple myeloma, using the RPMI 8226 cell line as a model. EXPERIMENTAL DESIGN: The effects of bruceantin on c-MYC levels and apoptosis were examined by immunoblotting, 4',6-diamidino-2-phenylindole staining, evaluation of caspase-like activity, and 3,3'-dihexyloxacarbocyanine iodide staining...

Employing the natural product quassinoid brusatol, we currently report cellular and molecular events leading to cell death or terminal differentiation in a panel of leukemic cells. Brusatol and bruceantin exerted significant cytotoxic effects with several leukemic cell lines, but not with K562 or normal lymphocytic cells. Cell lines that were less sensitive to the cytotoxic effects of brusatol responded primarily through induction of terminal differentiation. The differentiated phenotype in cell lines derived from acute or chronic myeloid leukemias (HL-60, K562, Kasumi-1, NB4, U937, BV173) was characterized for producing superoxide and non-specific esterase, and some with up-regulation of CD13 (cluster of differentiation) and down-regulation of CD15...

In an effort to discover new chemotherapeutic/chemopreventive agents from natural sources, brusatol (1) was found to induce HL-60 cellular differentiation, accompanied by strong antiproliferative and cytotoxic effects. A series of natural and semisynthetic quassinoids (1-48) was designed to effect both antiproliferative and differentiation-inducing properties. Compounds were assessed in vitro using the HL-60 promyelocytic cell model. Changes in activity due to structural modification of the core structure glaucarubolone (24) were consistent with activities reported in other cell systems...

The C-15 senecioyl side chain of brusatol was interchanged with fluorinated acyl groups, and the C-3 hydroxy group of bruceolide was esterified with fluorinated acyl chlorides. These fluorinated quassinoids 11, 12, 13, and 17 showed significant cytotoxic activity against eight human cancer cell lines including small and non-small cell lung, colon, CNS, ovarian and renal cancers, leukemia, and melanoma with 17 being about 100 times more potent than 11, 12, and 13. The activity of 17 was similar to that of bruceantin (1) in this in vitro cell line panel...

Ribosomal binding sites were investigated for the diverse group of antibiotics: anisomycin, anthelmycin, blasticidin S, bruceantin, carbomycin, chloramphenicol, griseoviridin, narciclasine, T2 toxin, tylosin and virginiamycin M1 all of which are considered to inhibit the peptidyl transferase reaction by different mechanisms. The drugs also exhibit differing degrees of specificity for bacterial, archaeal and eukaryotic ribosomes despite a high level of conservation of sequence and secondary structure at the peptidyl transferase centre of the 23 S-like rRNAs...

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Based on the fact that some known antineoplastic agents possess an ester moiety within their structure, the esters of helenalin, a sesquiterpene lactone, and of brusatol and bruceantin, quassinoids, were synthesized and tested for antileukemic activity in the P-388 screen. These agents gave different T/C% values dependent on the P-388 lymphocytic leukemia strain and the host strain of mice used. Later studies demonstrated that the agents caused different degrees of inhibition of nucleic acid and protein synthesis in the various P-388 strains...

The mechanism by which brusatol inhibits protein synthesis in rabbit reticulocytes has been investigated. When added to reticulocyte lysates, brusatol inhibits endogenous protein synthesis only after a lag of 2-4 min at 30 degrees C. During this period 80 S ribosomes accumulate. Brusatol is equally effective in inhibiting endogenous protein synthesis in lysates and poly(U)-directed polyphenylalanine synthesis with runoff ribosomes. In fractionated reticulocyte systems, brusatol does not inhibit formation of the ternary, 40 S, and 80 S initiation complexes, but does inhibit the reaction of puromycin with initiation complexes containing [35S]Met-tRNAf...

Fifteen adult patients with advanced solid tumors received bruceantin at doses of 1.6-6.0 mg/m2 iv for 30 minutes/week X 4, followed by a 2-week rest. The dose-limiting toxic effect was nausea and vomiting, which was more severe in patients with hepatic metastases or liver function abnormalities. Other sporadic toxic effects included fever, chills, malaise, alopecia, hypotension, thrombocytosis, and leukocytosis. Hematologic toxicity was insignificant. The recommended starting dose for phase II studies is 5 mg/m2/week X 4, every 6 weeks, with a reduction to 3 mg/m2 for patients with hepatic metastases...

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant...

KB (Eagle) cell culture has played a powerful role in discovery of antitumor agents from higher plants. Had KB alone been used as a preliminary screen, with in vivo screening limited to KB-active extracts, fractions, or compounds, KB activity of crude products would have led to discovery of vinblastine, vincristine, podophyllotoxin (from which the semisynthetics VM-26 and VP-16 were derived), and all but one of the antitumor agents now under development toward or in clinical evaluation, including bouvardin, bruceantin, camptothecin, ellipticine, homoharringtonine, maytansine, taxol, thalicarpine, and tripdiolide...

A phase II evaluation of bruceantin was carried out in 15 patients with refractory metastatic breast cancer. All patients had received extensive prior therapy including adriamycin, cytoxan, 5-FU, methotrexate, and a vinca alkaloid. Except for two patients with stable disease, no complete or partial response was observed. Drug toxicity, mainly nonhematologic, was severe, with nausea, vomiting, mild hypotension, and fever being the most frequently encountered.

A series of brusatol, bisbrusatol, and bruceantin esters were examined for their ability to inhibit protein synthesis in P-388 lymphocytic leukemia cells. Compounds which produced high T/C % values (170-272) resulted in ID50 of 5.4-15.5 microM for inhibition of whole cell protein synthesis, ID50 of 1.3-13 microM for inhibition of endogenous protein synthesis in cell homogenates, and ID50 of 1.9-6 microM for inhibition of polyuridine directed polyphenylalanine synthesis using "runoff" ribosomes and a "pH 5" enzyme preparation...

A series of esters of brusatol, bisbrusatol, and bruceantin were shown to have potent antileukemic activity. Antineoplastic activity was correlated with the ability of the compounds to suppress DNA and protein synthesis in P-388 lymphocytic leukemia cells. Compounds with high T/C% values successfully inhibited DNA polymerase activity and purine synthesis. The ability to inhibit protein synthesis during the elongation process also correlated positively with high antileukemic activity in this series of quassinoids...

A series of new bisbrusatolyl and brusatolyl esters and related compounds were synthesized and tested for in vivo antileukemia activity against a quassinoid sensitive strain of P-388 lymphocytic leukemia in BDF1 mice. The bisbrusatolyl malonate, succinate, glutarate, adipate, and sebacate were as active or more active than brusatol. The C-3 esters of brusatol and bruceantin were also found to be as active or more active than brusatol or bruceantin in general. The free hydroxyl groups at C-11 and C-12 as well as the enone double bond in ring A of both bisbrusatolyl and brusatolyl esters are required for antileukemic activity...

The quassinoids (brusatol, bruceantin, bisbrusatolyl esters, and bisbruceantinyl esters of succinic and malonic acids) were observed not to be universal protein synthesis inhibitors. Rather, they were selective for both the types of cancers, e.g., P-388 lymphocytic leukemia, Ehrlich and hepatoma carcinoma and L-1210 lymphoid leukemia, as well as types of normal tissues (e.g., lymphocytes), in which they demonstrated protein synthesis inhibition. The data suggest that the observed difference in the magnitude of protein synthesis inhibition of two P-388 lymphocytic leukemia cell lines by the quassinoids was at the ribosomal levels, whereas the observed difference in normal livers from various strains of mice involve differences in cell membrane transport of the quassinoids into the various tissues...

The Eastern Cooperative Oncology Group (ECOG) conducted a Phase II trial of Bruceantin in malignant melanoma. Twenty-two patients, thirteen without prior cytotoxic chemotherapy, were entered. All patients were evaluable for response and toxicity. Dose limiting toxicity was found to be hypotension during Bruceantin infusion. Other prominent side effects were nausea, vomiting, anorexia, fever, chills, and weakness. Only minor hematologic toxicity was encountered. Two partial responses, both in previously treated patients were observed (response rate -9%)...

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