Glucocorticoids reduce chemotherapeutic effectiveness on OSCC cells via glucose-dependent mechanisms.

Synthetic corticosteroids are routinely administered during the treatment of several diseases, including malignancies. However, recent evidence suggests that corticosteroids may have tumor-promoting effects, particularly in epithelial neoplasms. Our aim was to assess the role of the recently characterized cancer-associated glucocorticoid (GC) system in the resistance to chemotherapy of oral malignant keratinocytes. Human malignant oral keratinocyte cell lines H314/H357/H400/BICR16/BICR56 were tested with: two chemotherapeutic agents, doxorubicin (DOXO) and 5-fluorouracil (5-FU), as well as hydrocortisone (HC), adrenocorticotropic hormone (ACTH), 5-pregnen-3-beta-ol-20-one-16-alfa-carbonitrile (PCN), and two glucose uptake inhibitors, Fasentin and WZB. Both DOXO and 5-FU induced apoptosis in a dose-dependent and time-dependent manner. HC administration (100 nM) reduced the effectiveness of both chemotherapeutic agents to a variable extent in all 5 oral squamous cell carcinoma cell lines. ACTH also reduced the effectiveness of DOXO on 2 cell lines tested (H357 and BICR56). The glucose uptake inhibitors Fasentin and WZB were able to partially block the increased resistance to the cytotoxic drugs induced by HC. In summary, we have demonstrated, for the first time, the importance of cortisol on oral cancer cells ability to proliferate and combat the effectiveness of chemotherapeutic agents. This effect appears to be glucose dependent.