In vitro antitumor effect of sodium butyrate and zoledronic acid combined with traditional chemotherapeutic drugs: A paradigm of synergistic molecular targeting in the treatment of Ewing sarcoma

Abstract

Histone deacetylase inhibitors and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, particularly when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been systematically evaluated in Ewing sarcoma. The in vitro effects on cellular proliferation, viability and survival were investigated in two Ewing sarcoma cell lines, SK-ES-1 and RD-ES. The cell lines were treated with sodium butyrate, a histone deacetylase inhibitor and zoledronic acid, a bisphosphonate, alone, together or in combination with chemotherapeutic drugs recommended for clinical treatment of Ewing sarcoma. The data demonstrated that the combination of sodium butyrate and zoledronic acid had a synergistic cytotoxic effect at 72 h following treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between sodium butyrate or zoledronic acid and the traditional antineoplastic drugs (doxorubicin, etoposide and vincristine) demonstrated a synergistic cytotoxic effect at 72 h in SK-ES-1 and RD-ES cells, except for the combinations of sodium butyrate with vincristine and of zoledronic acid with doxorubicin, which showed only an additive effect in RD-ES cell lines as compared to each agent alone. These acute effects observed in both Ewing sarcoma cell lines were confirmed by the clonogenic assay. The present data suggest that combining histone deacetylase inhibitors and bisphosphonates with traditional chemotherapeutic drugs is a promising therapeutic strategy for the treatment of Ewing sarcoma, and provides a basis for further studies in this field.

Synergistic suppression of human breast cancer cells by combination of plumbagin and zoledronic acid In vitro

“…Therefore, researchers have sought new strategies that combine ZA with other chemotherapeutic agents or nutraceuticals, including paclitaxel, doxorubicin, cisplatin, camellia sinensis and gemcitabine, to treat osteosarcoma, breast cancer and multiple myeloma [15][16][17] . Synergistic effects have been shown to affect various types of tumor cells, regardless of the uncertain cytotoxicity of individual drug treatments [18][19][20] .…”

Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma

“…Each plate was placed in the same position on the light table by aligning it with the center of the preview exposed light window. For analysis of the clonogenic assay images, optimized digital colony counts were performed with ImageJ software (version 1.37 for Windows) as described by dos Santos et al [69]. Drug effects were expressed as surviving fraction of the colonies (SF; according to the formula below) and area occupied by colonies.…”

Crosstalk between bone niche and immune system: Osteoimmunology signaling as a potential target for cancer treatment

“…Similarly, ZOL in combination with serine/threonine phosphatase inhibitors increased efficacy and apoptosis in hor- mone refractory prostate cancer cell lines [57]. Also, its synergistic effect with chemotherapeutics has been recently studied in Ewing sarcoma [58]. Moreover, ZOL seems to reduce the persistence of DTCs in the bone marrow of patients with early breast cancer [59,60]; hence, some investigators have suggested that it could be used in adjuvant setting, in order to prevent bone metastases from solid tumors [61].…”