title: Zoledronate induces autophagic cell death in human umbilical vein endothelial cells via Beclin-1 dependent pathway activation.
abstract: Zoledronate has been reported to exhibit pro‑apoptotic and anti-angiogenic effects in endothelial cells, which partially contributes to bisphosphonate‑associated osteonecrosis of the jaw (BP‑ONJ). Zoledronate can also induce autophagic cell death. The present study hypothesized that Zoledronate may activate autophagy to exert pro‑apoptotic effects in endothelial cells and aimed to investigate the effect of Zoledronate on human umbilical vein endothelial cells (HUVECs) and explore the underlying mechanisms. The current study demonstrated that Zoledronate induced autophagy in HUVECs in a dose‑dependent manner, as demonstrated by increased levels of microtubule‑associated proteins 1A/1B light chain 3B‑II (LC3B‑II) and Beclin‑1, and decreased levels of sequestome 1 (SQSTM1). In addition, treatment with chloroquine further increased LC3B‑II and increased SQSTM1 levels, indicating that Zoledronate induces autophagy by increasing autophagic activity. Flow cytometry and Hoechst 33258 staining revealed that inhibition of autophagy with 3-methyladenine markedly attenuated Zoledronate‑induced apoptosis. Furthermore, genetic knockdown of Beclin‑1 significantly inhibited autophagy and apoptosis induced by Zoledronate. The present study therefore demonstrated that Zoledronate may promote Beclin‑1‑mediated autophagy to induce endothelial cell apoptosis, and suggests that blocking autophagy may represent a novel approach for the prevention of BP‑ONJ in patients receiving Zoledronate.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D000077211:Zoledronic Acid
chemical_list: D000071186:Beclin-1; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid