Inhibition of breast cancer cell proliferation in repeated and non-repeated treatment with zoledronic acid

The study was performed on 4 breast cancer cell lines (BRC-230, SkBr3, MCF-7 and MDA-MB-231). Non-repeated treatment (single exposure of 168？hrs’ duration) with zoledronic acid was compared with repeated treatment (separate exposures, each of 48？hrs’ duration, for a total of 168？hrs) at different dosages. A dose–response profile was generated using sulforhodamine B assay. Apoptosis was evaluated by TUNEL assay and biomolecular characteristics were analyzed by western blot.Zoledronic acid produced a dose-dependent inhibition of proliferation in all cell lines. Anti-proliferative activity was enhanced with the repeated treatment, proving to be statistically significant in the triple-negative lines. In these lines repeated treatment showed a cytocidal effect, with apoptotic cell death caused by caspase 3, 8 and 9 activation and decreased RAS and pMAPK expression. Apoptosis was not observed in estrogen receptor-positive line: p21 overexpression suggested a slowing down of cell cycle. A decrease in RAS and pMAPK expression was seen in HER2-overexpressing line after treatment.The study suggests that zoledronic acid has an antitumor activity in breast cancer cell lines. Its mechanism of action involves the decrease of RAS and RHO, as in osteoclasts. Repeated treatment enhances antitumor activity compared to non-repeated treatment. Repeated treatment has a killing effect on triple-negative lines due to apoptosis activation. Further research is warranted especially in the treatment of triple-negative breast cancer.Breast cancer is the most commonly diagnosed cancer in women in developed countries and over 50% of patients have bone involvement at relapse [1-4]. Bone metastasis is a major epidemiological and clinical problem in women with breast cancer, causing pain and other serious complications such as pathologic fracture, spinal cord compression and hypercalcemia with poor quality of life and prognosis [5,6].The skeleton is characterized by a dynamic balance between osteoc