Bullatacin, isolated from the fruit of Annona atemoya, is one of the most potentially effective antitumor annonaceous acetogenins. Bullatacin was studied here for its ability to inhibit the proliferation of 2.2.15 cells, hepatitis B virus (HBV) DNA transfected human hepatocarcinoma cell line. It was found that bullatacin induced cytotoxicity of 2.2.15 cells in a time- and dose-dependent manner. Fifty percent effective dose (ED50) on day 1 of exposure to bullatacin were 7.8 +/- 2.5 nM for 2.2.15 cells. [3H]-Thymidine incorporation assays showed almost the same results. Bullatacin-treatment also reduced concentrations of hepatitis B surface antigen (HBsAg) in the cultured medium released from 2.2.15 cells, coincident with the decrease in the cell proliferation. Analysis of mophological changes of bullatacin-treated 2.2.15 by inverted phase-contrast microscope and eletron microscopy revealed a possible model of action for bullatacin to inhibit proliferation of 2.2.15 cells by inducing apoptosis. Most of the bullatacin-induced cell death was found to be due to apoptosis, as determined by double staining with fluorescein-isothiocyanate (FITC)-labeled annexin V and propidium iodide (PI).
"The incubated cells were spread on the microscopic slides with a drop of diluted Giemsa stain. The slides were mounted with cover slips and observed under the phase contrast microscope (Nikon, Japan) for morphological changes as described by Chih et al (2001). 5 The numbers of cells showing apoptotic morphological changes were counted in each experimental group per 100 cells in ten different fields and the experiment was repeated for 5 times. "
"The resulting depletion of ATP and related nucleotides (all of which are precursors of DNA and RNA) has been demonstrated (Table I) in vitro in human leukemic cells (Fotopoulos, personal Communication); and the result is an upset of cell timing with subsequent apoptosis (programmed cell death) as demonstrated by DNA laddering in malignant B-cells (Geahlen, personal communication). Subsequent studies have confirmed that acetogenininduced cell death, indeed, involves apoptosis, and these studies are helping to define the molecular consequences such as caspase-3 activation and decreases in cyclic adenosine monophosphate and cyclic guanosine monophosphate levels  . The depletion of the nucleotide pool not only blocks replication of chromosomal, mitochondrial, and ribosomal nucleic acids in cancer cells but, as well, should block the replication of viral particles in viral-infected host cells and account for the previously observed antimalarial and antimicrobial effects . "
[Show abstract][Hide abstract] ABSTRACT: Summary The North American paw paw tree (Asiniina triloba (L.) Dunal, Annonaceae) contains complex mixtures of over 50 Annonaceous acetogenins. These are derivatives of long chain (C-32 or C34) fatty acids which are powerful inhibitors of mitochondrial (the PSST protein of complex I) and cytoplasmic (the plasma membrane NADH oxidase) production of adenosine triphosphate (ATP). A standardized extract of paw paw reduced tumor markers, reduced tumor sizes, and increased longevities among 94 cancer patients while causing minimal side effects. Ten case studies are presented. Inhibition of cellular energy (ATP), using the paw paw supplement, thus offers a novel, safe, and effective mechanism for the control of various types of clinical cancer.
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