Inhibitory Effects of 5-Fluorouracil on the Growth of 4-Hydroxytamoxifen-Resistant and Sensitive Breast Cancer Cells

Abstract

Cancer is one of the leading causes of death worldwide, accounting for about 10 million deaths a year, or nearly one in six deaths. The most common types of cancer are breast, colorectal, lung, and prostate cancers. Prolonged application of hormone drugs leads to the development of resistance. The development of agents with high activity against resistant cells is a challenge. It is important to create novel targeted compounds and search for active molecules among those previously developed. The study aimed to evaluate the sensitivity of 4-hydroxytamoxifen-resistant cells to 5-fluorouracil (5-FU) and analyse the signalling pathways that are regulated by 5-FU in breast cancer cells. Antiproliferative activity of compounds was assessed by the MTT assay, and immunoblotting was used to evaluate the expression of proteins in breast cancer cells. Activity of 5-FU was evaluated on parental MCF7 cells and a cell subline with resistance to 4-hydroxytamoxifen (HT), named MCF7/HT. The MCF7/HT cells showed high sensitivity to 5-FU. Expression of oestrogen receptor α (ERα, a key driver of breast cancer growth) in MCF7 and MCF7/HT cells was not sensitive to 5-FU treatment. In both parental and resistant cells, 5-FU induced changes in the activity of several signalling proteins. 5-FU activated AKT, extracellular signal-regulated kinase 1/2 (ERK 1/2) and upregulated cyclin D1 expression. The data suggest that 5-FU should be further investigated as a chemotherapeutic for hormone-resistant cancers; the combination of 5-FU with novel apoptosis inducer LCTA-3344 is considered effective to inhibit the growth of breast cancer cells, including those that are hormone-resistant.

Keywords

• 4-hydroxytamoxifen
• 5-fluorouracil
• breast cancer
• resistance
• oestrogen receptor alpha