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In vitro influence of Amitriptyline on glioma cell oxygen<br />
comsumption and viability using oxygen electrode assay<br />
and Vi-Cell TM automated trypan blue dye exclusion assay<br />
S. Higgins and G. J. Pilkington<br />
Cellular & Molecular Neuro-Oncology Group, School of Pharmacy & Biomedical Sciences,<br />
Institute of Biomedical & Biomolecular Sciences, University of Portsmouth, White Swan<br />
Road, Portsmouth PO1 2DT<br />
Introduction: We have previously reported that the tricyclic antidepressant<br />
Clomipramine exerts a pro-apoptotic effect on neoplastic glial cells in vitro. This<br />
effect is mediated via the mitochondria where cytochrome C liberation and activation<br />
of caspases precedes apoptosis. There is increasing evidence in our laboratories,<br />
however, that additional tricyclics - Amitriptyline and its metabolic product,<br />
Nortriptyline - may play a similar role.<br />
Methods: The influence of Amitriptyline & Nortriptyline at a range of concentrations<br />
on oxygen consumption in a) non-neoplastic human astrocytes (CC-2565 Cambrex<br />
Biosciences), b) a short-term cultured of biopsy-derived human glioblastoma<br />
multiforme (UPMC) and c) an established human anaplastic astrocytoma cell line<br />
(IPSB-18) was studied using a Hansatech, Clark-type Oxytherm TM & Oxygraph TM<br />
multiple series oxygen electrode apparatus. Cell viability was then studied under<br />
similar experimental conditions using the trypan blue dye exclusion test in a<br />
Vi-Cell TM XR Cell viability analyzer.<br />
Results: The influence of Amitriptyline was more pronounced than that of its<br />
metabolic product, Nortriptyline, both in reduction of oxygen consumption and cell<br />
viability and both were concentration-dependent. The order of the level of sensitivity<br />
84p13<br />
between different type of cell culture to both agents was UPMC>IPSB-18>CC-2565.<br />
Discussion: The high level of resistance of CC-2565 supports a specific anti-neoplastic<br />
role for the tricyclics in the management of primary malignant brain tumours.<br />
However, although Amitriptyline crosses the blood-brain barrier and specifically<br />
kills tumour cells, the lower efficacy of Nortriptyline (which results from conversion<br />
of Amitryptyline in the liver) may suggest that local administration of Amitriptyline<br />
to the brain may confer better therapeutic potential.
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