Cancer stem‑like cells (CSCs; also referred to as tumor‑initiating cells) play crucial roles in tumor progression and aggressiveness. Recent studies have demonstrated the antitumor activity of zoledronic acid (ZA), a third‑generation bisphosphonate, in various types of human cancer. However, its effect on oral CSCs and the underlying mechanism remain obscure. The present study demonstrated that ZA suppresses the growth and stemness properties of oral/oropharyngeal squamous cell carcinoma (OSCC) cells. ZA inhibited the malignant characteristics of OSCC cells, such as anchorage‑independent growth and epithelial thickening in organotypic raft cultures. Moreover, ZA treatment resulted in suppression of self‑renewal capacity, a key feature of CSCs. ZA also inhibited important CSC properties, such as migration and chemo‑radioresistance. Mechanistically, ZA exposure significantly decreased chemokine (C‑C motif) ligand 3 (CCL3) expression in OSCC cells. It was further demonstrated that CCL3 signaling via its receptor is crucial for supporting the CSC phenotype in OSCC cells. Moreover, an antagonist of the CCL3 receptor reversed the effect of CCL3 on CSC properties, and exogenous CCL3 rescued the suppressaed CSC phenotype in ZA‑treated OSCC cells. These results demonstrated that ZA suppresses the CSC phenotype in OSCC cells by reducing CCL3 expression, suggesting that ZA may be an effective therapeutic agent for oral cancer by targeting CSCs.
Keywords: zoledronic acid; oral/oropharyngeal squamous cell carcinoma; cancer stem cells; chemokine (C‑C motif) ligand 3.