Curcumin induces apoptosis-independent death in oesophageal cancer cells.
O'Sullivan-Coyne, G O'Sullivan, G C O'Donovan, T R Piwocka, K McKenna, S L
O'Sullivan-Coyne, G
O'Sullivan, G C
O'Donovan, T R
Piwocka, K
McKenna, S L
Advisors
Editors
Other Contributors
Date
2012-01-31T16:39:15Z
Date Submitted
Keywords
Other Subjects
Subject Mesh
Antineoplastic Agents/*pharmacology
Apoptosis/*drug effects
Autophagy/drug effects
Caspase 3/metabolism
Cell Cycle/drug effects
Cell Line, Tumor
Cell Survival/drug effects
Curcumin/*pharmacology
Cyclin B/metabolism
Cyclin B1
Esophageal Neoplasms/*drug therapy/pathology
Humans
Mitotic Index
Proteasome Endopeptidase Complex/physiology
Ubiquitin/metabolism
Apoptosis/*drug effects
Autophagy/drug effects
Caspase 3/metabolism
Cell Cycle/drug effects
Cell Line, Tumor
Cell Survival/drug effects
Curcumin/*pharmacology
Cyclin B/metabolism
Cyclin B1
Esophageal Neoplasms/*drug therapy/pathology
Humans
Mitotic Index
Proteasome Endopeptidase Complex/physiology
Ubiquitin/metabolism
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
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Abstract
BACKGROUND: Oesophageal cancer incidence is increasing and survival rates remain extremely poor. Natural agents with potential for chemoprevention include the phytochemical curcumin (diferuloylmethane). We have examined the effects of curcumin on a panel of oesophageal cancer cell lines. METHODS: MTT (3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assays and propidium iodide staining were used to assess viability and DNA content, respectively. Mitotic catastrophe (MC), apoptosis and autophagy were defined by both morphological criteria and markers such as MPM-2, caspase 3 cleavage and monodansylcadaverine (MDC) staining. Cyclin B and poly-ubiquitinated proteins were assessed by western blotting. RESULTS: Curcumin treatment reduces viability of all cell lines within 24 h of treatment in a 5-50 muM range. Cytotoxicity is associated with accumulation in G2/M cell-cycle phases and distinct chromatin morphology, consistent with MC. Caspase-3 activation was detected in two out of four cell lines, but was a minor event. The addition of a caspase inhibitor zVAD had a marginal or no effect on cell viability, indicating predominance of a non-apoptotic form of cell death. In two cell lines, features of both MC and autophagy were apparent. Curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin-proteasome system. This effect on a key cell-cycle checkpoint regulator may be responsible for the mitotic disturbances and consequent cytotoxicity of this drug. CONCLUSION: Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of oesophageal cancer.
Language
eng
ISSN
1532-1827 (Electronic)
0007-0920 (Linking)
0007-0920 (Linking)
eISSN
ISBN
DOI
10.1038/sj.bjc.6605308
PMID
19809435