The mechanism of tamoxifen action on glioma cell lines

Abstract

Tamoxifen, a member of the selective estrogen receptor modulator (SERM) family, is widely used in the treatment of estrogen-receptor (ER) positive breast cancer. It has been shown in previous studies that Tamoxifen exerts an antiproliferative effect in patients harbouring glioma.
Glioma brain tumours differ from most other cancers by their diffusive invasion of the surrounding normal tissue and frequent recurrence following all forms of therapy. It is this invasive nature that ultimately contributes to their poor 6-12 month prognosis.
Because of their profound devastating effect much research is currently being carried out to investigate gliomas and it seems that the chemosensitivity of gliomas, i.e. the analysis of glioma response to a specific drug, is a focal point of developing treatment, and more recently an idea of prevention.
Tamoxifen is considered to exert its anitproliferative effect in ER-positive neoplasms through blocking the estrogen receptor, thus, inhibiting gene transcription and cellular proliferation. In vitro studies have shown that Tamoxifen can inhibit the growth of a brain tumour cell lines, but whether the mechanism involves oestrogen blockade remains a matter of some debate.
As well as its effect in blocking estrogen receptors, Tamoxifen is also known to exert antiproliferative effects via non-receptor mediated mechanisms including the blockage of Protein Kinase C and inhibition of the MAPK family among a vast array
of cellular signalling pathways.
This study employed three different glioma cell lines to investigate the antiproliferative effect of Tamoxifen. The results of this study have demonstrated that Tamoxifen induces cell death in a dose-dependent manner in all three cell lines. Moreover, cells pre-treated with 50 nM of 17-estradiol for 1 week prior to treatment with Tamoxifen demonstrated no significant increase in cell death.
Previous work in the University laboratory (unpublished) has indicated that Tamoxifen can affect MAPK activity. A known MAPK inhibitor, Aloe Emodin (AE) in combination with Tamoxifen was investigated to examine whether combination of
the two agents would enhance the anti-proliferative capability of Tamoxifen. The results of this study have shown that a combination of Tamoxifen and AE caused no apparent increase in Tamox ifen- induced cell death.
In addition to Tamoxifen toxicity, the expression of ER for each cell line was investigated to determine if the mechanism of action of Tamoxifen is by an estrogendependent or —independent pathway. None of the three glioma cell lines in this study
demonstrated positive expression of ERa by immunofluorescence. Based on these results alone, it would suggest that the mechanism of Tamox ifen- induced glioma cell death is likely to be independent of the ER pathway.
In conclusion, the results suggest a potential use of a combination of Tamoxifen and AE, due to AE's relatively low toxicity to normal cells, and the association of Tamoxifen with high toxicity. Potentially, in combination, a lower dosage of Tamoxifen could be administered, representing a lowered risk of associated toxicity and this in turn may improve quality of life of glioma patients.