Abstract
Bisphosphonates (BPs) are antiresorptive drugs that act as effective inhibitors of cancer cell proliferation. However, not all bisphosphonates are equally effective against breast cancer cells in vitro. The present study investigated the extent to which three BPs decrease the viability of MCF-7 human breast cancer cells, stimulate cell apoptosis and inhibit cell migration by modulating proteins in the mevalonate pathway. The three BPs exerted direct anticancer effects against MCF-7 cells in a dose- and time-dependent manner, with pamidronate demonstrating the highest efficacy. In addition, the BPs inhibited colony formation ability. The activity of BPs against MCF-7 cells was inhibited by the mevalonate product geranylgeranyl pyrophosphate, which was potentiated by doxorubicin. It was also identified that BPs modulated Ras-related C3 botulinum toxin substrate 1, Ras homolog gene family member A and cell division control protein 42 homolog gene expression. Consistent with the observed growth inhibitory effects, BPs also inhibited the cell cycle by promoting G1 phase arrest and the downregulation of cyclin D1 and upregulation of p21. Additionally, BPs were revealed to induce reactive oxygen species expression, caspase-3 activity and increase the mitochondrial transmembrane potential, which was associated with apoptosis. BP-induced cancer cell apoptosis was detected by acridine orange/ethidium bromide staining and flow cytometry analysis, and was identified to be associated with the induction of caspase-3 and cytochrome c protein expression. Furthermore, BPs significantly decreased cancer cell migration in a dose-dependent manner and reduced matrix metallopeptidase-9 protein expression. In summary, the current study demonstrated that BPs exhibited a direct anticancer effect and an antimigratory effect on MCF-7 cells. These findings suggest that BPs may be developed as a therapeutic option for breast cancer and may serve as sensitizing chemotherapeutic agents.