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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. [ABSTRACT FROM AUTHOR]

Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8. We also show that epiregulin can be delivered via exosomes and was enriched in exosomes derived from epiregulin-overexpressing SACC cells. Furthermore, treating immunodeficient mice with these epiregulin-enriched exosomes greatly enhanced SACC metastasis to lung. These epiregulin-enriched exosomes significantly enhanced angiogenesis in the neighboring tumor microenvironment and increased vascular permeability in the pre-metastatic lung microenvironment in vivo . Therefore, epiregulin, as well as epiregulin-containing exosomes, may be a novel target for controlling SACC lung metastasis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.