Abstract
BackgroundZoledronic acid is used to treat bone metastases and has been shown to reduce skeletal-related events and exert antitumor activity. The present in vitro study investigates the mechanism of action of Zoledronic Acid on breast cancer cell lines with different hormonal and HER2 patterns. Furthermore, we investigated the efficacy of repeated versus non-repeated treatments.MethodsThe 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.ResultsZoledronic 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.ConclusionsThe 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.
Highlights
Zoledronic acid is used to treat bone metastases and has been shown to reduce skeletal-related events and exert antitumor activity
Triple negative cell lines The non-repeated schedules (NRS) treatment induced, in MDA-MB-231 cells, a IC50 mean value of 29 μM compared to 23 μM for RS, with a decrease of 26% compared to standard treatment, (p =0.042) (Figure 2)
BRC-230 cells were more sensitive to Zol for both schedules, and the IC50 decrease was 14% greater with RS compared to NRS (p =0.003)
Summary
Zoledronic acid is used to treat bone metastases and has been shown to reduce skeletal-related events and exert antitumor activity. The present in vitro study investigates the mechanism of action of Zoledronic Acid on breast cancer cell lines with different hormonal and HER2 patterns. Bone metastasis is a major epidemiological and clinical problem in women with breast cancer, causing pain and other serious complications such as pathologic fracture, The skeleton is characterized by a dynamic balance between osteoclast (induced bone resorption) and osteoblast (stimulated bone formation) bone remodeling, which maintains physiological bone turnover. Bisphosphonates are potent antiresorptive drugs in widespread use that are well suited to the treatment of metabolic bone disease. These drugs bind avidly to hydroxyapatite crystals at sites of active bone metabolism, achieving therapeutic concentrations. Bisphosphonates are released during bone resorption and are internalized by osteoclasts, leading to inhibition of bone resorption itself and induction of osteoclast apoptosis [10]
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