In vitro toxicity of bisphosphonates on human neuroblastoma cell lines

Abstract

Neuroblastoma is the commonest extracranial solid tumor of childhood and frequently metastasizes to the bone. Bisphosphonates are standard treatment of osteolytic lesions by bone metastasis. Since recent studies suggested direct antitumor effects of bisphosphonates, we screened the toxicity of different bisphosphonates on neuroblastoma cell lines. The nitrogen-containing bisphosphonate pamidronate was significantly more toxic on a panel of eight neuroblastoma cell lines than the non-nitrogen-containing bisphosphonates, clodronate and tiludronate. After 72 h, GI₅₀ concentrations (inhibiting cell growth by 50% compared to untreated controls) for pamidronate ranged from 12.8 to >500 μM. CHLA-90 and SH-SY5Y were the most sensitive cell lines. In CHLA-90, zoledronate was the most cytotoxic bisphosphonate, followed by alendronate, pamidronate and ibandronate. In SH-SY5Y, alendronate was the most cytotoxic bisphosphonate, followed by ibandronate, pamidronate and zoledronate. The GI₅₀ values after 72 h were 34.1 (SH-SY5Y) and 3.97 μM (CHLA-90) for zoledronate, and 22.4 (SH-SY5Y) and 9.55 μM (CHLA-90) for alendronate. Neuroblastoma cells treated with bisphosphonates showed signs of differentiation and finally underwent apoptosis. The observed GI₅₀ concentrations suggest that local nitrogen-containing bisphosphonate concentrations at the bone interface can directly target neuroblastoma cell penetration into the bone matrix. In summary, these observations warrant the investigation of adjuvant bisphosphonate treatment in controlled clinical trials.