Karwinskia parvifolia possesses the highest concentration levels of the anthracenone T-514 (PA1). Studies have demonstrated the induction of apoptosis by PA1 in cancer cell lines. The aim was to investigate the effects of PA1 on the apoptosis of the mouse liver in vivo and its underlying pathway. Sixty CD-1 mice were divided into three groups: untreated, vehicle, and treated with PA1. The animals were euthanized at 4, 8, 12, and 24 h post-treatment. To confirm the toxic effect of PA1 we determined the activity of catalase. Liver sections were prepared for morphological examination and for immunohistochemical evaluation of anti and pro-apoptotic markers. DNA fragmentation was detected by TUNEL assay and electrophoresis. Pre-apoptotic mitochondrial alterations and cytochrome c oxidase activity were analyzed by transmission electron microscopy. PA1 induced pre-apoptotic mitochondrial alterations, a high activity of the cytochrome oxidase, and apoptosis in hepatocytes. PA1 caused p53 over-expression and down regulation of PCNA. PA1 also increased the expression levels of the pro-apoptotic markers Bax and Bak, whereas the anti-apoptotic molecule Bcl-2 was decreased. PA1 induces apoptosis by activating the intrinsic mitochondrial apoptotic pathway. These results will be useful for studies regarding the use of PA1 as an antineoplastic agent.

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T-514 or Peroxisomicine A1 (PA1) is a toxin isolated from plants of genus Karwinskia . In vitro studies described selective toxicity of PA1 on malignant cell lines. A toxic effect of PA1 on TC-1 cells in vivo was reported. The objective was to evaluate the effect of PA1 over invasion of TC-1 cells to muscle fibers in vivo . TC-1 cells were implanted in 36 mice divided in two groups (n: 18): treated with PA1 or with vehicle, a control group was included. At 10 days, nine mice of each group were euthanized. TC-1 implant site was analyzed by light and electron microscopy, a morphometric study was also performed. Remaining mice were used to evaluate tumor growth and survival time. Results show tumor cells between muscle fibers, with diminution in diameter, change in the staining pattern, loss of continuity of external lamina, and sarcoplasm with tumor cells. Statistically difference was observed between treated group vs control group. PA1 decreased tumor growth and increased the survival time in treated mice. The degree of resistant activity, aggressiveness, and invasiveness of TC-1 cells described in present work; should be taken into account in studies that evaluate effectiveness of therapies using this cancer model.

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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.

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Peroxisomicines A1 (1) and A2 (2) are cytotoxic hydroxyanthracenones isolated from the fruits of Karwinskia parvifolia. Peroxisomicine A1 exhibits selective cytotoxicity against several tumor cell lines. In the present investigation three minor constituents were obtained from the same fruit extracts: peroxisomicine A3 (3) and isoperoxisomicines A1 (4) and A2 (5). Compounds 3 and 5 are novel and their structures were determined by spectroscopic methods and molecular modeling. Compounds 1-5 were significantly cytotoxic against hepatoma cell lines.

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Dimeric anthracenones obtained from the genus Karwinskia (Rhamnaceae) are characteristic compounds isolated from the plants of this species. Previous toxicity studies demonstrated Diast T-514 to be toxic to animals in experimental settings. Diast T-514 extracted and characterized from Karwinskia parvifolia, was studied in CD1 mice. The LD50 for this compound was determined. Animals were tested with Diast T-514 following enteral and parenteral administration. An LD50 dose by both oral and intraperitoneal administration showed selective damage to target organs.

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