Evaluation of the effects of swainsonine, captopril, tangeretin and nobiletin on the biological behaviour of brain tumour cells in vitro

Although intrinsic tumours of the brain seldom metastasize to distant sites , their diffuse. infiltrative-invasive growth within the brain generally pr ecludes successful surgical and adjuvant therapy. Hence, attention has now focused on novel therapeutic approaches to combat brain tumours that includ e the use of anti-invasive and anti-proliferative agents, The effect of fou r anti-invasive agents, swainsonine (a locoweed alkaloid), captopril tan an ti-hypertensive drug, tangeretin and nobiletin (both citrus flavonoids), we re investigated on various parameters of brain tumour invasion such as matr ix metalloproteinase (MMP) secretion, migration, invasion and adhesion. A s tandard cytotoxicity assay was used to optimize working concentrations of t he drugs on seven human brain tumour-derived cell lines of various histolog ical type and grade of malignancy. A qualitative assessment by gelatin zymo graphy revealed that the effect of these agents varied between the seven ce ll lines such that the low grade pilocytic astrocytoma was unaffected by th ree of the agents. IN contrast, downregulation of the two gelatinases. MMP- 2 and MMP-9 was seen in the grade 3 astrocytoma irrespective of which agent was used. Generally, swainsonine was the least effective whereas the citru s flavonoids, particularly nobiletin, showed the greatest downregulation of secretion of the MMPs. Furthermore, captopril and nobiletin were most effi cient at inhibiting invasion, migration and adhesion in four representative cell lines (an ependymoma, a grade II oligoastrocytoma, an anaplastic astr ocytoma and a glioblastoma multiforme), Yet again, the effects of the four agents varied between the four cell lines. Nobiletin was, nevertheless, the most effective agent used in these assays, In conclusion, the differential effects seen on the various parameters studied by these putative anti-inva sive agents may be the result of interference with MMPs and other mechanism s underlying the invasive phenotype. From these pilot studies, it is possib le that these agents, especially the citrus flavonoids, could be of future therapeutic value. However, further work is needed to validate this in a la rger study.