Lumonadio Luyengi

Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase

For the discovery of new cancer chemopreventive agents, we have studied the potential of plant extracts to inhibit phorbol ester-induced ornithine decarboxylase (ODC) activity in cell culture. Four active rotenoids were obtained from the African plant Mundulea sericea (Leguminosae). These isolates were highly potent when evaluated for inhibition of chemically induced preneoplastic lesions in mammary organ culture and inhibition of papillomas in the two-stage mouse skin model, and they appear to function by a unique mechanism at the level of ODC messenger RNA expression. Based on our findings, rotenoids can be regarded as promising new chemopreventive or anticancer agents.

Angoline and Chelerythrine, Benzophenanthridine Alkaloids That Do Not Inhibit Protein Kinase C

Starting with an extract derived from the stem ofMacleaya cordata (Papaveraceae) that was active in the process of inhibiting phorbol 12,13-dibutyrate binding to partially purified protein kinase C (PKC), the benzophenanthridine alkaloid angoline was isolated and identified. This discovery appeared in context, as a related benzophenanthridine alkaloid, chelerythrine, has been reported to mediate a variety of biological activities, including potent and selective inhibition of protein kinase C (PKC). However, in our studies, angoline was not observed to function as a potent inhibitor of PKC. Moreover, we were unable to confirm the reported inhibitory activity of chelerythrine. In a comprehensive series of studies performed with various PKC isozymes derived from a variety of mammalian species, neither chelerythrine nor angoline inhibited activity with high potency. To the contrary, chelerythrine stimulated PKC activity in the cytosolic fractions of rat and mouse brain in concentrations up to 100 μm. In addition, chelerythrine and angoline did not inhibit [3H]phorbol 12,13-dibutyrate binding to the regulatory domain of PKC at concentrations up to 40 μg/ml, and no significant alteration of PKC-α, -β, or -γ translocation was observed with human leukemia (HL-60) cells in culture. Further, chelerythrine did not inhibit 12-O-tetradecanoylphorbol 13-acetate-induced ornithine decarboxylase activity with cultured mouse 308 cells, but angoline was active in this capacity with an IC50 value of 1.0 μg/ml. A relatively large number of biological responses have been reported in studies conducted with chelerythrine, and alteration of PKC activity has been considered as a potential mechanism of action. In light of the current report, mechanisms independent of PKC inhibition should be considered as responsible for these effects.

ROTENOIDS AND CHALCONES FROM MUNDULEA SERICEA THAT INHIBIT PHORBOL ESTER-INDUCED ORNITHINE DECARBOXYLASE ACTIVITY

Abstract Two novel rotenoids, (−)-13α-hydroxydeguelin and (−)-13α-hydroxytephrosin, and a new chalcone, munsericin, were isolated from the bark of Mundulea sericea , and their structures were elucidated by spectroscopic methods. Also obtained were the parent rotenoids, deguelin and tephrosin, and the known chalcone, 4-hydroxy-lonchocarpin. The rotenoids and chalcones exhibited potent inhibitory activity against phorbol ester-induced ornithine decarboxylase activity in cultured mouse 308 epidermal cells.

Antibacterial activity of diospyrin, isodiospyrin and bisisodiospyrin from the root of Diospyros piscatoria (Gurke) (Ebenaceae).

Two dimeric naphthoquinones, diospyrin and isodiospyrin, isolated from the root of Diospyros piscatoria (Gurke), a common ingredient in several folk medicines, have been shown to have a broad spectrum of antibacterial activity. The minimum inhibitory concentrations (MICs) of diospyrin against Streptococcus pyogenes ATCC 12344 and Streptococcus pneumoniae ATCC 33400 ranged from 1.56 to 50 µg/mL. While those against Salmonella choleraesuis serotype typhi (S. typhi), ATCC 6539 and Mycobacterium chelonae ATCC 19977 were between 25 and 100 µg/mL. Isodiospyrin was more active than its racemic isomer diospyrin. The MICs against Gram‐positive bacteria ranged from 0.78 to 50 µg/mL. While those against Pseudomonas aeruginosa ATCC 15443 and S. typhi ranged from 50 to 100 µg/mL. The MIC for M. chelonae was between 6.25 and 25 µg/mL. MICs were found to increase with the concentration of cells used for the inoculum. The MICs for Bacillus subtilis ATCC 6633 increased up to the highest concentration of cells tested. The same phenomenon was observed on M. chelonae, but with better effect in the latter. The kinetics of bacteria studies against both B. subtilis and M. chelonae increases with increasing concentration of isodiospyrin tested.

Constituents of Eugenia sandwicensis with potential cancer chemopreventive activity.

A triterpenoid, 3beta-cis-p-coumaroyloxy-2alpha,23-dihydroxyolean-12-en-28-oic acid (1), and two natural products, 3beta-trans-p-coumaroyloxy-2alpha,23-dihydroxyolean-12-en-28-oic acid (2) and 23-trans-p-coumaroyloxy-2alpha,3beta-dihydroxyolean-12-en-28-oic acid (3), were isolated from a chloroform-soluble extract of the stems of Eugenia sandwicensis, along with 10 known compounds. Of these compounds, 2 showed significant inhibitory activity (79.2% at 4 microg/ml) in a 7,12-dimethylbenz[a]anthracene-induced mouse mammary organ culture assay system of relevance to cancer chemoprevention. Gallic acid was isolated as an antioxidative constituent of an ethyl acetate-soluble extract of E. sandwicensis stems. Isolates 1-3 were characterized on the basis of spectral and chemical evidence.

Activity-guided isolation of constituents of Cerbera manghas with antiproliferative and antiestrogenic activities.

Two new cardenolides, (-)-14-hydroxy-3beta-(3-O-methyl-6-deoxy-alpha-L-rhamnosyl)-11a lpha, 12alpha-epoxy-(5beta,14beta,17betaH)-card-20 (22)-enolide (1), (-)-14-hydroxy-3beta-(3-O-methyl-6-deoxy-alpha-L-glucopyranosyl)-11al pha,12alpha-epoxy-(5beta,14beta,17betaH)-card -20(22)-enolide (2), and a known cardenolide, (-)-17beta-neriifolin (3), were isolated from the roots of Cerbera manghas as antiproliferative and antiestrogenic principles when evaluated against a human colon cancer cell line (Col2) and the Ishikawa cell line, respectively. Two known lignans, (-)-olivil (4) and (-)-cycloolivil (5), were also isolated but were inactive in the assay systems used.

Inhibitory effect of munetone, an isoflavonoid, on 12-O-tetradecanoylphorbol 13-acetate-induced ornithine decarboxylase activity

Starting with an extract derived from the bark of Mundulea sericea Willd. (Leguminosae) that was active in the process of inhibiting 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ornithine decarboxylase activity (ODC) in cultured mouse epidermal ME 308 cells, the isoflavonoid munetone was isolated and identified as an active principle (IC50 = 46 ng/ml). Topical application of munetone (0.04-5 micromol) to the skin of CD-1 mice 2 h prior to treatment with TPA (10 nmol) resulted in dose-dependent inhibition of epidermal ODC activity. In addition, munetone inhibited TPA-independent c-Myc-induced ODC activity with cultured BALB/c c-MycER cells, as well as 7,12-dimethylbenz[a]anthracene (DMBA)-induced preneoplastic lesion formation in a mouse mammary gland organ culture (MMOC) system. These data suggest the potential of munetone to serve as a cancer chemopreventive agent by virtue of blocking the process of tumor promotion.