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.
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Authors | Vanessa Soto-Cerrato, Beatriz Montaner, Marc Martinell, Marta Vilaseca, Ernest Giralt, Ricardo Pérez-Tomás |
Journal | Biochemical pharmacology
(Biochem Pharmacol)
Vol. 71
Issue 1-2
Pg. 32-41
(Dec 19 2005)
ISSN: 0006-2952 [Print] England |
PMID | 16298346
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Depsipeptides
- Tumor Suppressor Protein p53
- serratamolide
- Caspases
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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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