Journal Article

Tamoxifen inhibits the growth of head and neck cancer cells and sensitizes these cells to cisplatin induced-apoptosis: role of TGF-β1

Mahvash Tavassoli, Jila Soltaninia, Joanna Rudnicka, Dorothy Mashanyare, Newell Johnson and Joop Gäken

in Carcinogenesis

Volume 23, issue 10, pages 1569-1576
Published in print October 2002 | ISSN: 0143-3334
Published online October 2002 | e-ISSN: 1460-2180 | DOI:
Tamoxifen inhibits the growth of head and neck cancer cells and sensitizes these cells to cisplatin induced-apoptosis: role of TGF-β1

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A number of studies have shown that tamoxifen increases the sensitivity of several types of solid tumours to cisplatin without increasing the associated side effects. The cellular mechanisms responsible for this increased sensitivity are currently unknown. In this study we have investigated whether tamoxifen alone or in combination with cisplatin could induce apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines. We have shown that tamoxifen treatment resulted in G1 arrest in two cell lines, HN5 and HN6. Tamoxifen induced growth suppression was independent of p53 status but resulted in up-regulation of cyclin dependent kinase inhibitors (CDKIs) p21/Waf-1, p27/Kip1 and p15/INK4a. Furthermore, tamoxifen treatment resulted in an increased level of hypophosphorylated active RB. Cisplatin induced p53 independent apoptosis in both head and neck cancer cell lines. There was a significant sensitizing effect of tamoxifen on cisplatin-induced apoptosis in HN5 and HN6 cells, with the combined treatment being more effective in inducing apoptosis. Addition of tamoxifen did not result in significant inhibition of PKC activity in HN5 and HN6 cells. However, tamoxifen treatment resulted in increased secretion of TGF-β1 by HN5 and HN6 cells. An anti-TGF-β blocking antibody prevented both the blockade of cellular proliferation and the increased expression of CDKIs associated with tamoxifen treatment of HN5 and HN6 cells. These results show that tamoxifen alone induces a transient G1 arrest that greatly sensitizes the cells to apoptosis induced by cisplatin. We have shown that the mechanism for this p53-independent G1 arrest and apoptosis is at least partly due to the activation of TGF-β1 resulting in the induction of p15/INK4b, p27/Kip-1, p21/Waf-1 and RB hypophosphorylation. These in vitro results suggest that combination of tamoxifen and cisplatin might be a more effective treatment for head and neck cancers than single modality therapy.

Keywords: CDKIs, cyclin dependent kinase inhibitors; CDP, calmodulin-dependent cAMP phosphodiesterase; ERs, oestrogen receptors; HNSCC, head and neck squamous cell carcinoma; KIP, kinase inhibitor protein; PKC, protein kinase C; TAM, tamoxifen; TGF-β1, transforming growth factor β1.

Journal Article.  5362 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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