Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis.

C Ferlini,G Scambia,P Benedetti Panici,G Isola,E Bombardelli,S Mancuso,P Filippini,A Riva,M Distefano,A Fattorossi

doi:10.1038/bjc.1997.156

Abstract

The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.

Highlights

Our results showed that this synergism occurred in the ER-negative MCF-7 ADRr, CEMVBLr and MDA-MB 231 cell lines, since a consistent increase in docetaxel activity was found in association with TAM, thereby suggesting a possible new approach for improving the therapeutic validity of the taxane family of anti-tumour drugs
Cell count analysis showed that half maximal growth-inhibitory concentration (IC50) was reached in the presence of docetaxel at 0.8 nm, 700 nm and 580 nm on MDA-MB 231, MCF-7 ADRr and CEM-VBLr cell lines respectively
MDAMB 231 cells were sensitive to docetaxel as, in contrast to the other two cell lines used here, they do not express the classical MDR phenotype, the major resistance factor for taxanes (Bhalla et al, 1994)