Harnessing Cerium Oxide Nanoparticles Combined with Tolfenamic Acid to Sensitize Head and Neck Cancer to Radiation

Purpose: Radiotherapy is an important strategy for cancer treatment, but the resistance of tumor cells to radiation remains a challenge. Survivin is overexpressed in most human cancers, including head and neck cancer, and is regulated by members of the Specificity Protein (Sp) family of transcription factors, which results in resistance of cancer to radiation therapy.1 Tolfenamic acid, a non-steroidal anti-inflammatory drug induces the production of reactive oxygen species, causes DNA damage, and inhibits the expression of Sp, which enhances tumor cell death.2 Our data demonstrate that the pro-oxidant activity of cerium oxide nanoparticles (CONPs) drives radiation-induced radical production selectively in a variety of cancer cell lines resulting in radiation sensitization. We report the effects of Tolfenamic Acid combined with CONPs on Survivin and Sp expression and the potential efficacy of this combined therapy to enhance therapeutic outcomes in head and neck cancer patients (HNC).

Methodology: To investigate the effects of Tolfenamic Acid combined with CONPs on HNC cell viability, UM-SCC-1, human HNC squamous cell carcinoma (HNSCC) cells were exposed to 10 GY radiation in the presence or absence of 100uM of Tolfenamic Acid alone, 100uM of CONP alone, or Tolfenamic Acid (100uM) combined with CONPs (100uM). Over the course of 120 hours, cell viability was measured by the quantification of ATP present, which signals the presence of metabolically active cells. We next measured the expression of Survivin protein and Sp using western blot analysis.

Results: In a time-dependent manner, 10 GY radiation resulted in a 53% (P = 0.055) reduction in UM-SCC-1 cell viability at time 120 hours as compared to control (no treatment). With the addition of Tolfenamic Acid to the irradiated cells, a 73% (P = 0.001) reduction in cell viability was observed. The addition of CONP alone to the irradiated cells resulted in a 20% (P= 0.01) reduction in cell viability. However, when UM-SCC-1 cells were exposed to radiation in the presence of Tolfenamic Acid combined with CONPS, a 85.7% reduction (P = 0.05) in cell viability was observed at 120 hours as compared to radiation alone. The most significant reduction in protein expression of Survivin and Sp was measured in UM-SCC-1 cells exposed to radiation in the presence of Tolfenamic Acid combined with CONPs.

Conclusions: These data suggest that Tolfenamic Acid combined with CONPs has the potential to increase the response of HNSCC to radiation therapy. Additional studies are warranted to determine the underlying synergistic effects of Tolfenamic Acid combined with CONPs to enhance HNSCC response to radiation therapy.

References: Frassanito, M et al. “Survivin overexpression in head and neck squamous cell carcinomas as a new therapeutic target.” Oncology Reports, 41(2019);2615-2624.
Basha, R et al. “Therapeutic applications of NSAIDS in cancer: special emphasis on tolfenamic acid.” Frontiers in Bioscience, 3(2011);797-805.