acetogenins and Carcinoma--Hepatocellular

Multidrug-resistance (MDR) has been shown to play a critical role in the development of many diseases. In this study, we used metabolomic method to evaluate the MDR in hepatocellular carcinoma, and investigate regulatory of annonaceous acetogenins on MDR of hepatocellular carcinoma. Multivariate statistical analysis revealed that the MDR of SMMC 7721 together with changes in glutathione metabolism, arginine and proline metabolism, sphingolipid metabolism. Annonaceous acetogenins impact these metabolism pathways. Metabolic pathway analysis coupled with stoichiometry analysis can be an effective tool to understand MDR mechanism and to potentially find new MDR reversal agents.

Topics: Acetogenins; Annonaceae; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Liver Neoplasms; Metabolic Networks and Pathways; Metabolomics

The obtusallenes are a significant subset of C15-halogenated acetogenins that incorporate 12-membered cyclic ethers. We have recently reported the isolation from Laurencia marilzae of 12-epoxyobtusallene IV (1) and its related α,β-unsaturated carboxylate ester (2), both of special biogenetic relevance. Here we describe the final step of our study, the isolation of three new analogues (3-5), among these, the first bromopropargylic derivative (3) of this class of macrocyclic C15-acetogenins. The structures were elucidated by analysis of NMR and X-ray data. 12-Epoxyobtusallene IV (1), its new isomer 4, and known obtusallene IV (6) were evaluated for their apoptosis-inducing activities in a human hepatocarcinoma cell line.

Topics: Acetogenins; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Crystallography, X-Ray; Ethers, Cyclic; Humans; Hydrocarbons, Brominated; Laurencia; Molecular Conformation; Molecular Structure; Spain

To confirm the anticancer effect of total annonaceous acetogenins (TAAs) abstracted from Annona squamosa Linn. on human hepatocarcinoma.. The inhibitory effect of TAAs was demonstrated in H22-bearing mice. The potency of TAAs was confirmed as its 50% inhibiting concentration (IC50) on Bel-7402 cell under Sulfur Rhodamine B staining. Both underlying mechanisms were explored as cellular apoptosis and cell cycle under flow cytometry. Mitochondrial and recipient apoptotic pathways were differentiated as mitochondrial membrane potential under flow cytometry and caspases activities under fluorescence analysis.. The inhibitory rate of TAAs in mice was 50.98% at 4 mg/kg dose. The IC50 of TAAs on Bel-7402 was 20.06 µg/mL (15.13-26.61µg/mL). Effective mechanisms of TAAs were confirmed as both of arresting cell cycle at G1 phase and inducing apoptosis dose- and time-dependently. Mitochondrial and recipient pathways involved in apoptotic actions of TAAs.. TAAs is effective for hepatocarcinoma, via inhibiting proliferation and inducing apoptosis.

Topics: Acetogenins; Animals; Annona; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Caspases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Male; Membrane Potential, Mitochondrial; Mice; Organ Specificity; Spleen; Thymus Gland; Xenograft Model Antitumor Assays

Hepatocellular carcinoma (HCC) is the most common tumor in worldwide and chemotherapy resistant is a severe obstacle in HCC treatment. Annonaceous acetogenins was a nature compound from Uvaria accuminata and it has show the anti-tumor proliferation activity in many types cancer. In this study, we showed that annonaceous acetogenins is correlated with the drug resistance reversal in human hepatocellular carcinoma BEL-7402/5-FU and HepG2/ADM cell lines. We found that cell apoptosis was improved and cell cycle was arrested, further, multidrug-resistance proteins such as MDR1, MRP1, Topo-IIα, GST-π, cyclin D1, Survivin and bcl-2 are down-regulated, however, intracellular Rh-123 and caspase-3/8 was up-regulated by Annonaceous acetogenins treatment. We also found that there was a decreased activity of NF-κB and Akt in Annonaceous acetogenins treatment groups. Therefore, we demonstrate that Akt/NF-κB pathway was involved in Annonaceous acetogenins reverses drug resistance of human hepatocellular carcinoma cells.

Topics: Acetogenins; Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Hep G2 Cells; Humans; Liver Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction

The development of new anti-neoplastic drugs is a key issue for cancer chemotherapy due to the reality that, most likely, certain cancer cells are resistant to current chemotherapy. The past two decades have witnessed tremendous advances in our understanding of the pathogenesis of cancer. These advances have allowed identification new targets as oncogenes, tumor supressor genes and the possible implication of the mitochondria (Fulda et al. Nat Rev Drug Discov 9:447-464, 2010). Annonaceous Acetogenins (ACGs) have been described as the most potent inhibitors of the respiratory chain because of their interaction with mitochondrial Complex I (Degli Esposti and Ghelli Biochim Biophys Acta 1187:116-120, 1994; Zafra-Polo et al. Phytochemistry 42:253-271, 1996; Miyoshi et al. Biochim Biophys Acta 1365:443-452, 1998; Tormo et al. Arch Biochem Biophys 369:119-126, 1999; Motoyama et al. Bioorg Med Chem Lett 12:2089-2092, 2002). To explore a possible application of natural products from Annonaceous plants to cancer treatment, we have selected four bis-tetrahydrofuranic ACGs, three from Annona cherimolia (cherimolin-1, motrilin and laherradurin) and one from Rollinia mucosa (rollinianstatin-1) in order to fully describe their mechanisms responsible within the cell (Fig. 1). In this study, using a hepato-carcinoma cell line (HepG2) as a model, we showed that the bis-THF ACGs caused cell death through the induction of the apoptotic mitochondrial pathway. Their potency and behavior were compared with the classical mitochondrial respiratory chain Complex I inhibitor rotenone in every apoptotic pathway step.

Topics: Acetogenins; Apoptosis; Carcinoma, Hepatocellular; Electron Transport Complex I; Enzyme Inhibitors; Hep G2 Cells; Humans; Liver Neoplasms; Mitochondria; Mitochondrial Proteins; Neoplasm Proteins

Seeds of Annona squamosa L. have been used in the south of China as a folk remedy to treat "malignant sores" (cancer).. To investigate the chemical constituents and the anti-tumor activity of the standardized A. squamosa seeds extract in vitro and in vivo.. Annonaceous acetogenin profiles of the standardized extract were determined by using Fourier transform infrared (FT-IR) and high performance liquid chromatography (HPLC) techniques. The anti-tumor activity of the extract was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cytotoxicity in vitro and H(22) hepatoma cells transplantation tumor model in vivo.. The FT-IR spectroscopy showed the presence of annonaceous acetogenin compounds in the extract. Two major annonaceous acetogenins: 12, 15-cis-squamostatin-A and bullatacin were identified and quantified by HPLC. The seed extract showed significant anti-tumor activity against four human tumor cell lines, especially for MCF-7 (IC(50). 0.25 μg/ml) and Hep G2 (IC(50). 0.36 μg/ml) cells in vitro. The extract inhibited the growth of H(22) tumor cells in mice with a maximum inhibitory rate of 69.55% by oral administration.. A. squamosa seed extract showed significant anti-tumor activities against human hepatoma cells in vitro and in vivo, indicating a potential for developing the extract as a novel anti-liver cancer drug.

Topics: Acetogenins; Annona; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Furans; Hep G2 Cells; Humans; Phytotherapy; Plant Extracts; Seeds