Toxicity and Anticancer Potential of Karwinskia: A Review.

Karwinskia genus consists of shrubs and small trees. Four toxic compounds have been isolated from Karwinskia plants, which were typified as dimeric anthracenones and named T496, T514, T516, and T544. Moreover, several related compounds have been isolated and characterized. Here we review the toxicity of the fruit of Karwinskia plants when ingested (accidentally or experimentally), as well as the toxicity of its isolated compounds. Additionally, we analyze the probable antineoplastic effect of T514. Toxins cause damage mainly to nervous system, liver, lung, and kidney. The pathophysiological mechanism has not been fully understood but includes metabolic and structural alterations that can lead cells to apoptosis or necrosis. T514 has shown selective toxicity in vitro against human cancer cells. T514 causes selective and irreversible damage to peroxisomes; for this reason, it was renamed peroxisomicine A1 (PA1). Since a significant number of malignant cell types contain fewer peroxisomes than normal cells, tumor cells would be more easily destroyed by PA1 than healthy cells. Inhibition of topoisomerase II has also been suggested to play a role in the effect of PA1 on malignant cells. More research is needed, but the evidence obtained so far indicates that PA1 could be an effective anticancer agent.

Karwinaphthopyranones from the fruits of Karwinskia parvifolia and their cytotoxic activities.

The new 2-acetyl-8-methoxynaphthol (1) and five new "dimeric" napthopyranones, karwinaphthopyranones A1 and A2 (2 and 3) and karwinaphthopyranones B1-B3 (4-6), possessing a methoxy group at C-5', were isolated together with four other known compounds from the dried fruits of Karwinskia parvifolia. The structures of compounds 2-6 were determined by spectroscopic data interpretation. Cell culture assays showed that some of these compounds possess antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the micromolar range.

Antimicrobial activity of coupled hydroxyanthracenones isolated from plants of the genus Karwinskia.

The in vitro activity of some isolated hydroxyanthracenones belonging to the genus Karwinskia against four bacteria, six filamentous fungi and four yeast are reported. These hydroxyanthracenones were found to possess antimicrobial activity, particularly against Streptococcus pyogenes, Candida albicans, C. boidinii, C. glabrata and Cryptococcus neoformans; minimal inhibitory concentrations range between 16 and 2 microg/ml.

In vitro metabolism and toxicity assessment of toxin T-514 (Peroxisomicine A1) of Karwinskia humboldtiana in microsomes and primary cultured hepatocytes.

T-514 (Peroxisomicine A(1)) from Karwinskia humboldtiana is a dimeric hydroxyanthracenone with a highly selective cytotoxic effect on tumor cells. We evaluated the metabolism of this compound in two in vitro systems (liver microsomes and hepatocytes) and assessed the cytotoxicity of its metabolites on normal and tumor cells. Microsomes (12.5, 125 and 250 microg of protein/ml) and hepatocytes (1 x 10(6) cells/ml) were incubated with the toxin (25 microM) for 0.5, 1, 3, 6, 9, 12 and 24 h and the samples were examined using chromatographic analysis and UV spectra. Two metabolites (M1 and M2) were detected in the rat microsomes and one (M1) in the monkey microsomes. The retention times and UV spectra of the peaks were very similar to those of the toxin T-514. M1 was isolated and identified as a mixture of two isomers. The cytotoxicity of the metabolites was evaluated in Chang liver and Hep G2 cells but they did not show the selective cytotoxic effect on tumor cells seen in the original compound.

Production of reactive oxygen species by toxin T-514 of genus Karwinskia in vitro.

In the present study we have analyzed the production of reactive oxygen species by toxin T-514 of the genus Karwinskia in vitro (primary liver cell cultures and microsomes), as well as their possible role in its cytotoxicity. The role of catalase and superoxide dismutase (SOD) as defense mechanisms against oxidative stress was also studied. Freshly isolated hepatocytes or microsomes were exposed to T-514 in the presence or absence of catalase and SOD. Cytotoxicity was determined by methylthiazoltetrazolium (MTT) reduction. Oxidative stress was evaluated by the dichlorofluorescein diacetate (DCFDA) fluorescent probe and the reduction of ferricytochrome c. Exposure of hepatocytes to toxin T-514 for 2-, 4-, 6- and 24-h periods resulted in a time- and concentration-dependent increase in the suppression of mitochondrial metabolic activity. T-514 induced the production of reactive oxygen species in both hepatocytes and microsomes. Catalase and superoxide dismutase had a protective effect against the cytotoxicity of T-514 in hepatocytes and also inhibited the production of oxygen reactive species in microsomes. The results indicate that oxidative stress mediated by reactive intermediates may be a mechanism by which T-514 induces its cytotoxic effect.