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Biochimica Et Biophysica Acta Oct 2003Aplidine, a cyclic peptide, from the tunicate Aplidium albican, prevents the in vitro aggregation into beta-sheet containing fibrils of the prion peptide 106-126 when...
Aplidine, a cyclic peptide, from the tunicate Aplidium albican, prevents the in vitro aggregation into beta-sheet containing fibrils of the prion peptide 106-126 when co-incubated in a 1:1 molar ratio. The blocking of fibril formation induced by Aplidine has clear sequence specificity, being much stronger for the 106-126 prion peptide than for the beta-amyloid 25-35 peptide. In addition to the known ability of Aplidine to cross the plasmatic membrane, these results indicate that Aplidine is a potential leading compound for the development of therapeutic blockers of prion aggregation.
Topics: Animals; Depsipeptides; Microscopy, Electron; Peptide Fragments; Peptides, Cyclic; Prions; Protein Structure, Quaternary; Urochordata
PubMed: 14559120
DOI: 10.1016/j.bbadis.2003.08.003 -
British Journal of Cancer Aug 2003The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using...
The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent. Only in ALL-PO 20 nM Aplidin treatment caused a block of vascular endothelial growth factor (VEGF) secretion and downregulation of VEGF-mRNA, but Aplidin cytotoxicity does not seem to be related to VEGF inhibition since the sensitivity of ALL-PO cells to Aplidin is comparable to that observed for the other cells used. Aplidin induced a G(1) and a G(2) M block in ALL cell lines. In patient-derived leukaemia cells, Aplidin induced a strong cytotoxicity evidenced in a stroma-supported immunocytometric assay. Cells from children with genetic abnormalities such as t(9;22) and t(4;11) translocations, associated with an inferior treatment outcome, were sensitive to Aplidin to the same extent as that observed in other BCP-ALL cases. Aplidin exerted a strong cell killing effect (>88%) against primary culture cells from five relapsed ALL cases, at concentrations much lower than those reported to be achieved in plasma of patients receiving Aplidin at recommended doses. Taken together these data suggest that Aplidin could be a new anticancer drug to be investigated in ALL patients resistant to available therapy.
Topics: Adolescent; Antineoplastic Agents; Apoptosis; B-Lymphocytes; Caspase 3; Caspases; Cell Cycle; Child; Child, Preschool; Depsipeptides; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Endothelial Growth Factors; Female; Humans; Intercellular Signaling Peptides and Proteins; Karyotyping; Lymphokines; Male; Mass Spectrometry; Peptides, Cyclic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Messenger; RNA, Neoplasm; Stromal Cells; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 12915891
DOI: 10.1038/sj.bjc.6601130 -
The Journal of Biological Chemistry Jan 2003We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231...
We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a specific cellular stress response program, including sustained activation of the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK. Aplidin-induced apoptosis was only partially blocked by the general caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone and was also sensitive to AG1478 (an EGFR inhibitor), PP2 (an Src inhibitor), and SB203580 (an inhibitor of JNK and p38 MAPK) in MDA-MB-231 cells. Supporting a role for EGFR in Aplidin action, EGFR-deficient mouse embryo fibroblasts underwent apoptosis upon treatment more slowly than wild-type EGFR fibroblasts and also showed delayed JNK and reduced p38 MAPK activation. N-Acetylcysteine and ebselen (but not other antioxidants such as diphenyleneiodonium, Tiron, catalase, ascorbic acid, and vitamin E) reduced EGFR activation by Aplidin. N-Acetylcysteine and PP2 also partially inhibited JNK and p38 MAPK activation. The intracellular level of GSH affected Aplidin action; pretreatment of cells with GSH or N-acetylcysteine inhibited, whereas GSH depletion caused, hyperinduction of EGFR, Src, JNK, and p38 MAPK. Remarkably, Aplidin also induced apoptosis and activated EGFR, JNK, and p38 MAPK in two cell lines (A-498 and ACHN) derived from human renal cancer, a neoplasia that is highly refractory to chemotherapy. These data provide a molecular basis for the anticancer activity of Aplidin.
Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Division; Cell Survival; Cells, Cultured; Depsipeptides; Enzyme Activation; Enzyme Inhibitors; ErbB Receptors; Female; Fibroblasts; Flow Cytometry; Glutathione; Humans; JNK Mitogen-Activated Protein Kinases; Kidney Neoplasms; Mice; Mitogen-Activated Protein Kinases; Peptides, Cyclic; Phosphorylation; Proto-Oncogene Proteins pp60(c-src); Receptors, Platelet-Derived Growth Factor; Tumor Cells, Cultured; p38 Mitogen-Activated Protein Kinases
PubMed: 12414812
DOI: 10.1074/jbc.M201010200 -
British Journal of Cancer May 2002Aplidine, dehydrodidemnin B, is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans currently in phase II clinical trial. In human Molt-4...
Aplidine, dehydrodidemnin B, is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans currently in phase II clinical trial. In human Molt-4 leukaemia cells Aplidine was found to be cytotoxic at nanomolar concentrations and to induce both a G(1) arrest and a G(2) blockade. The drug-induced cell cycle perturbations and subsequent cell death do not appear to be related to macromolecular synthesis (protein, RNA, DNA) since the effects occur at concentrations (e.g. 10 nM) in which macromolecule synthesis was not markedly affected. Ten nM Aplidine for 1 h inhibited ornithine decarboxylase activity, with a subsequently strong decrease in putrescine levels. This finding has questionable relevance since addition of putrescine did not significantly reduce the cell cycle perturbations or the cytotoxicity of Aplidine. The cell cycle perturbations caused by Aplidine were also not due to an effect on the cyclin-dependent kinases. Although the mechanism of action of Aplidine is still unclear, the cell cycle phase perturbations and the rapid induction of apoptosis in Molt-4 cells appear to be due to a mechanism different from that of known anticancer drugs.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Depsipeptides; Humans; Leukemia; Peptides, Cyclic; Putrescine; Tumor Cells, Cultured
PubMed: 11986788
DOI: 10.1038/sj.bjc.6600265