glaucarubin and glaucarubolone

Quassinoids often exhibit antioxidant and antiproliferative activity. Emerging evidence suggests that these natural metabolites also display chemopreventive actions. In this study, we investigated the potential for the quassinoid glaucarubulone glucoside (Gg), isolated from the endemic Jamaican plant Castela macrophylla (Simaroubaceae), to display potent cytotoxicity and inhibit human cytochrome P450s (CYPs), particularly CYP1A enzymes, known to convert polyaromatic hydrocarbons into carcinogenic metabolites. Gg reduced the viability of MCF-7 breast adenocarcinoma cells (IC

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 Enzyme System; Cytotoxins; Female; Gene Expression; Glaucarubin; Humans; Jamaica; MCF-7 Cells; Plant Extracts; Quassins; Simaroubaceae

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. However, the following were novel SAR findings: (1) semisynthetic analogues with a hydroxylated ring at the beta-position of the ester side chain at C-15 were able to induce cellular differentiation at concentrations lower than those inducing cell growth arrest, and (2) quassinoids inhibiting DNA synthesis with greater efficacy than reducing cellular viability possessed alkyl substitutions at the alpha-position of the C-15 ester side chain. Analogues from this latter group and brusatol (1) and bruceantin (2) inhibited dimethylbenz(a)anthracene-induced preneoplastic lesion formation in a mouse mammary organ culture. The novel finding of 1 and glaucarubolone analogues as potent inducers of differentiation leads to potential novel applications in the field of cancer.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Differentiation; Cell Division; Cell Membrane; DNA; Drug Screening Assays, Antitumor; Female; Glaucarubin; Glycosylation; HL-60 Cells; Humans; Inhibitory Concentration 50; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Models, Biological; Molecular Structure; Nitroblue Tetrazolium; Organ Culture Techniques; Plants, Medicinal; Quassins; Rats; Simaroubaceae; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured

Growth of Crandall feline kidney cells permanently infected with feline immunodeficiency virus was inhibited by the anti-cancer quassinoid glaucarubolone whereas growth of uninfected cells was not inhibited. Similar results were obtained for human MOLT-4 cells infected with HIV-1. The results suggest that cell lines permanently infected with either the feline or the human lentivirus exhibit growth response characteristics to the quassinoids in common with other cell lines malignantly transformed. In addition the quassinoids may delay viral infection suggesting some commonality between the mechanism responsible for inhibition of the growth of the transformed phenotype and viral infection.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cats; Cell Division; Cell Transformation, Viral; Glaucarubin; HIV-1; Humans; Immunodeficiency Virus, Feline; Quassins

A plasma membrane-associated NADH oxidase of transformed cells was shown to be inhibited by nanomolar and subnanomolar concentrations of the antitumor quassinoid, glaucarubolone. The inhibition was seen with plasma membrane vesicles of HeLa cells at two log orders less glaucarubolone than with plasma membrane vesicles of rat liver. Assignment of a drug-binding site to the external surface of the HeLa cell plasma membrane was supported by findings where full activity of the glaucarubolone in the inhibition of NADH oxidase activity of isolated plasma membrane vesicles and of growth of HeLa cells was given on a molar glaucarubolone basis by an impermeant conjugate of glaucarubolone in which the glaucarubolone moiety was linked via the C-15 hydroxyl to amino polyethyleneglycol (ave Mr 5,000). The activity of the conjugate, and to a lesser extent, of free glaucarubolone was modulated by the redox environment of the cells and of the plasma membrane vesicles. Activity, both in the inhibition of NADH oxidase activity and in the inhibition of growth, was enhanced by oxidizing conditions in the presence of oxidized glutathione compared to reducing conditions in the presence of reduced glutathione.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Membrane; Glaucarubin; HeLa Cells; Humans; Liver; Molecular Weight; Multienzyme Complexes; NADH, NADPH Oxidoreductases; Oxidation-Reduction; Rats; Tumor Cells, Cultured

Several quassinoids, obtained by isolation and derivatization from Simaba multiflora and Soulamea soulameoides, were evaluated for growth inhibitory and insecticidal effects against the tobacco budworm (Heliothis virescens) and for antifeedant effects against H. virescens and the fall armyworm (Spodoptera frugiperda). The relative activity of the quassinoids as insect growth inhibitors generally paralleled their known relative potency as antileukemic and cytotoxic agents.

Topics: Animals; Antineoplastic Agents, Phytogenic; Chemical Phenomena; Chemistry; Diterpenes; Eating; Glaucarubin; Insecta; Insecticides; Larva; Phenanthrenes; Quassins

Topics: Avian Sarcoma Viruses; Cell Transformation, Viral; DNA; DNA Replication; Dose-Response Relationship, Drug; Glaucarubin; Lactones; Leucine; Phenanthrenes; Protein Biosynthesis; Quassins; RNA; Structure-Activity Relationship