title: Reactive oxygen species and autophagy associated apoptosis and limitation of clonogenic survival induced by zoledronic acid in salivary adenoid cystic carcinoma cell line SACC-83.
abstract: Salivary adenoid cystic carcinoma is an epithelial tumor in the head and neck region. Despite its slow growth, patients with salivary adenoid cystic carcinoma exhibit poor long term survival because of a high rate of distant metastasis. Lung and bone are common distant metastasis sites. Zoledronic acid, a third generation bisphosphonate, has been used for tumor-induced osteolysis due to bone metastasis and has direct antitumor activity in several human neoplasms. Here, we observed that zoledronic acid inhibited salivary adenoid cystic carcinoma cell line SACC-83 xenograft tumor growth in nude mice. In vitro, zoledronic acid induced apoptosis and reduced clonogenic survival in SACC-83. Flow cytometry and western blotting indicated that the cell cycle was arrested at G0/G1. Zoledronic acid treatment upregulated reactive oxygen species as well as the autophagy marker protein LC-3B. Reactive oxygen species scavenger N-acetylcysteine and autophagy antagonist 3-methyladenine decreased zoledronic acid-induced apoptosis and increased clonogenic survival. Silencing of the autophagy related gene Beclin-1 also decreased zoledronic acid-induced apoptosis and inhibition of clonogenic formation. In addition, isobolographic analysis revealed synergistic effects on apoptosis when zoledronic acid and paclitaxel/cisplatin were combined. Taken together, our results suggest that zoledronic acid induced apoptosis and reduced clonogenic survival via upregulation of reactive oxygen species and autophagy in the SACC-83 cell line. Thus, zoledronic acid should be considered a promising drug for the treatment of salivary adenoid cystic carcinoma.
authors: Central Laboratory, Peking University School and Hospital of Stomatology, Haidian District, Beijing, PR China.
authors: Xi-Yuan
authors: XY
authors: Ge
authors: Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Haidian District, Beijing, PR China.
authors: Lin-Qian
authors: LQ
authors: Yang
authors: Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Haidian District, Beijing, PR China.
authors: Yang
authors: Y
authors: Jiang
authors: Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Haidian District, Beijing, PR China.
authors: Wen-Wen
authors: WW
authors: Yang
authors: Central Laboratory, Peking University School and Hospital of Stomatology, Haidian District, Beijing, PR China.
authors: Jia
authors: J
authors: Fu
authors: Central Laboratory, Peking University School and Hospital of Stomatology, Haidian District, Beijing, PR China; Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Haidian District, Beijing, PR China.
authors: Sheng-Lin
authors: SL
authors: Li
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004164:Diphosphonates / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D017382:Reactive Oxygen Species; D000077211:Zoledronic Acid; D017239:Paclitaxel; D002945:Cisplatin