Bladder cancer is a common malignancy of the urinary tract, with bone metastasis being a serious complication in advanced stages, often associated with poor prognosis. Chemotherapy and bisphosphonates are commonly used to treat bone metastases in bladder cancer, but their side effects are considerable. Studies have shown that histone deacetylase inhibitors (HDAC inhibitors) can induce cancer cell apoptosis, inhibit cell proliferation, and prevent cancer cell invasion and metastasis, demonstrating broad potential for application in various cancer treatments. However, the potential of HDAC inhibitors in treating osteolytic bone metastasis has not been fully explored. This study aims to investigate the effects of HDAC inhibitors on bladder cancer bone metastasis and explore therapeutic strategies when combined with chemotherapy or bisphosphonates.

Western blotting and real-time RT-PCR were used to analyze the expression of specific proteins and their corresponding mRNAs. Resazurin and colony formation assays were employed to measure cell proliferation and survival rates, respectively. RAW264.7 cells, as osteoclast precursors, were used for in vitro osteoclast differentiation. Enzyme-Linked Immunosorbent Assay (ELISA) was used to analyze CCL2 expression, and flow cytometry was performed to assess cell apoptosis.

The combination of HDAC inhibitors with cisplatin chemotherapy optimized the treatment effect on bone metastasis. HDAC inhibitors reduced CCL2 gene transcription through epigenetic modifications, thereby inhibiting the osteolytic activity of bladder cancer cells. In vitro experiments also demonstrated that HDAC inhibitors enhanced the inhibitory effects of bisphosphonate—specifically zoledronic acid—on osteoclast differentiation.

This study found that the HDAC inhibitor butyrate can reduce osteoclast activity and bone metastasis in bladder cancer when combined with cisplatin or zoledronic acid treatments.