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Cell cycle arrest and proapoptotic effects of the anticancer cyclodepsipeptide serratamolide (AT514) are independent of p53 status in breast cancer cells.

Abstract
In a search for new anticancer agents, we have identified serratamolide (AT514), a cyclodepsipeptide from Serratia marcescens 2170 that induces cell cycle arrest and apoptosis in various cancer cell lines. A cell viability assay showed that the concentrations that cause 50% inhibition (IC50) in human cancer cell lines range from 5.6 to 11.5 microM depending on the cell line. Flow cytometry analysis revealed that AT514 caused cell cycle arrest in G0/G1 or cell death, depending on the cell type and the length of time for which the cells were exposed to the drug. Subsequent studies revealed that AT514-induced cell death is caused by apoptosis, as indicated by caspases activation (8, 9, 2 and 3) and cleavage of poly (ADP-ribose) polymerase (PARP), release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, and the appearance of apoptotic bodies and DNA laddering. Alterations in protein levels of Bcl-2 family members might be involved in the mitochondrial disruption observed. AT514 induced p53 accumulation in wild-type p53 cells but cell death was observed in both deficient and wild-type p53 cells. Our results indicate that AT514 induces cell cycle arrest and apoptosis in breast cancer cells irrespectively of p53 status, suggesting that it might represent a potential new chemotherapeutic agent.
AuthorsVanessa Soto-Cerrato, Beatriz Montaner, Marc Martinell, Marta Vilaseca, Ernest Giralt, Ricardo Pérez-Tomás
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 71 Issue 1-2 Pg. 32-41 (Dec 19 2005) ISSN: 0006-2952 [Print] England
PMID16298346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Depsipeptides
  • Tumor Suppressor Protein p53
  • serratamolide
  • Caspases
Topics
  • Antineoplastic Agents (isolation & purification, pharmacology)
  • Apoptosis (drug effects)
  • Breast Neoplasms (enzymology, metabolism, pathology)
  • Caspases (metabolism)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Depsipeptides (isolation & purification, pharmacology)
  • Enzyme Activation
  • Humans
  • Intracellular Membranes (metabolism)
  • Mitochondria (drug effects)
  • Tumor Suppressor Protein p53 (metabolism)

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