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

Abstract

Although intrinsic tumours of the brain seldom metastasize to distant sites, their diffuse, infiltrative-invasive growth within the brain generally precludes successful surgical and adjuvant therapy. Hence, attention has now focused on novel therapeutic approaches to combat brain tumours that include the use of anti-invasive and anti-proliferative agents. The effect of four anti-invasive agents, swainsonine (a locoweed alkaloid), captopril (an anti-hypertensive drug), tangeretin and nobiletin (both citrus flavonoids), were investigated on various parameters of brain tumour invasion such as matrix metalloproteinase (MMP) secretion, migration, invasion and adhesion. A standard cytotoxicity assay was used to optimize working concentrations of the drugs on seven human brain tumour-derived cell lines of various histological type and grade of malignancy. A qualitative assessment by gelatin zymography revealed that the effect of these agents varied between the seven cell lines such that the low grade pilocytic astrocytoma was unaffected by three 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 citrus flavonoids, particularly nobiletin, showed the greatest downregulation of secretion of the MMPs. Furthermore, captopril and nobiletin were most efficient at inhibiting invasion, migration and adhesion in four representative cell lines (an ependymoma, a grade II oligoastrocytoma, an anaplastic astrocytoma 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-invasive agents may be the result of interference with MMPs and other mechanisms underlying the invasive phenotype. From these pilot studies, it is possible that these agents, especially the citrus flavonoids, could be of future therapeutic value. However, further work is needed to validate this in a larger study.

<i>Citrus</i> Flavonoids and Human Cancers

“…In human MCF-7/6 breast carcinoma cells, tangeretin treatment effectively inhibited the metastasis by down-regulating MMP-2 and MMP-9 in breast cancer [94]. In melanoma, the invasion of B16F10 cells was inhibited by the treatment of tangeretin [111]. Moreover, wound healing assay showed that tangeretin exerted inhibitory effects on SKOV3 cell migration.…”

Nobiletin, a Citrus Flavonoid, Down-Regulates Matrix Metalloproteinase-7 (matrilysin) Expression in HT-29 Human Colorectal Cancer Cells

“…36) Of importance, other groups have found that NOB suppressed MMP-9 expression in interleukin-1-treated rabbit synovial fibroblasts, 20) as well as in phorbol ester-stimulated HT-1080 21) and in some brain tumor cell lines that showed a constitutive expression of MMP-9. 22) In addition, inhibition of MMP-9 production by NOB in Fig. 3.…”

“…Moreover, thecatenin/TCF complex is known to cooperate with AP-1 for maximum expression. 14) While there are a large number of reports regarding MMP-9 suppressants, including catechins, 15) curcumin, 16) 1,25-dihydroxyvitamin D 3 , 17) peroxisome proliferator-activated receptor (PPAR) activators, 18) inhibitors of cyclooxygenase (COX) and phospholipase A 2 , 19) and nobiletin (NOB), [20][21][22][23] those for MMP-7 are limited (e.g., retinoic acid, 24) butyrate, 25) and PPAR agonist troglitazone 26) ). In the present study, we investigated the expression of MMPs in human colorectal cancer cell lines and found a high level of MMP-7 mRNA in HT-29 cells.…”

BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion

“…The upregulation in glioma cells of specific members of the MMP family, such as MMP2 and MMP9 (reviewed in [12,21,22]), and the decrease of glioma invasion through inhibition of these enzymes [23][24][25][26][27] have encouraged the design of adjuvant therapies based on targeting MMP activity. However, clinical trials of MMP inhibitors have proven disappointing due to lack of effect or damaging side-effects [28][29][30].…”