Biochemical and Biophysical Research Communications
Chlorimipramine: A novel anticancer agent with a mitochondrial target☆
Section snippets
Materials and methods
Chemicals. All chemicals and other materials used were of the highest quality available and were from: The Sigma Chemical, Fancy Road Poole, UK; Nalgene, Nalge (Europe), Hereford, UK; Calbiochem, Beeston, Nottingham, UK; Fisher Scientific, Loughborough, UK or Molecular Probes, Invitrogen, Paisley, UK.
Glioma cell culture. Glioma cell lines used were derived from primary cultures of human biopsy material taken at craniotomy in the neurosurgical theatres of King’s College London and Atkinson
Chlorimipramine causes changes in glioma cell morphology
The microscopical examination of glioma and glial cells showed a time-dependent change in glioma cell morphology (rounding up of the cells) after 1 h exposure to CIMP, with many cells detaching from the tissue culture plate following 2 h exposure to CIMP (Fig. 1). Foetal astrocytes exposed to CIMP showed no changes in morphology and did not become detached from the tissue culture plate.
Chlorimipramine decreases glioma cell viability
The MTT assay demonstrated a concentration-dependent decrease in IPBB-98, IPDDC-98 and NP785-96 cell viability
Discussion
Approximately 95% of a cell’s oxygen utilisation is by the mitochondrial complex IV [27]. Thus, the decrease in oxygen uptake measured in glioma cells in the presence of CIMP suggests a blockade of mitochondrial electron transport. Using the specific mitochondrial enzyme assays on mitochondria isolated from brain, heart, liver, and kidney it is clear that CIMP inhibits both mitochondrial complex I and complex III activities. However, 1 μM antimycin a caused total inhibition of complex III
Acknowledgment
We thank the Samantha Dickson Research Trust (see http://www.sdrt.co.uk.) for financial support for the work described in this document and for the chlorimipramine clinical trial in human glioma.
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Chlorimipramine is now being assessed for its anti-cancer activity in the clinic.
- 1
Present address: School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK.
- 2
Present address: MRC Applied Neuroscience Group, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK.