Naltrexone Has Variable and Schedule-Dependent Effects on Oral Squamous Cell Carcinoma Cells

Oral squamous cell carcinoma (OSCC) is marked by profound differences in survival between the localized and disseminated disease, estimated to result in a 70% and less than a 40% five-year survival rate with surgical and/or radiation approaches (in localized cases) and chemotherapy (in metastatic cases), respectively. Given the suboptimal efficacy of current management options, new therapeutic approaches are needed to supplement existing chemotherapies and improve outcomes. One emerging therapeutic option is naltrexone (NTX), an opioid antagonist that has shown promising outcomes at low doses in other forms of cancer. This study sought to determine the effectiveness of intermittent dosing of naltrexone on oral cancer cell survival, either as a single agent or in combination with traditional chemotherapy. Two human OSCC lines (locally invasive SCC-25 and metastatic Detroit 562) were cultured. Cells were exposed to 1 µM and 10 µM NTX alone, using intermittent (5 h once, 5 h daily, 5 h every other day) or constant 72 h exposure. Cells were exposed to combination therapy with cisplatin or docetaxel under three NTX regimens (5 h, 24 h, and continuous). Cell viability was determined using Sulphorhodamine B (SRB) assay and Cell Counting Kit-8 (CCK-8). Differences across treatments were assessed using ANOVA (p < 0.05). The effect of low-dose NTX alone, across varying treatment regimens, did not yield significant, consistent changes in OSCC cell survival. Combination with cytotoxic drugs reduced cell viability more efficiently than chemotherapy alone at select doses, particularly through intermittent short-term pretreatment schedules, but the full dose response demonstrated antagonism between NTX and chemotherapy, independent of the dosing schedule. These results contrast with previous findings in other cancers, and, thus, further study and optimization will be needed to determine the clinical benefit and reproducibility of these findings.