Molecular Diagnostics

BJC Open article

British Journal of Cancer (2009) 101, 1585–1595. doi:10.1038/sj.bjc.6605308 www.bjcancer.com
Published online 6 October 2009

Curcumin induces apoptosis-independent death in oesophageal cancer cells

G O'Sullivan-Coyne1, G C O'Sullivan1, T R O'Donovan1, K Piwocka2 and S L McKenna1

  1. 1Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork and Mercy University Hospital, Cork, Ireland
  2. 2Nencki Institute of Experimental Biology, Warsaw, Poland

Correspondence: Dr SL McKenna Sharon, E-mail: s.mckenna@ucc.ie

Received 1 June 2009; Revised 10 August 2009; Accepted 17 August 2009
Advance online publication 6 October 2009

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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 24h of treatment in a 5–50μM 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.

Keywords:

curcumin; apoptosis; mitotic catastrophe; autophagy; oesophageal cancer