Celentano, Antonio (2017) Effect of glucocorticoids on the anti-cancer activity of chemotherapeutic agents in oral squamous cell carcinoma (OSCC) cells. [Tesi di dottorato]

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Glucocorticoid hormones, such as hydrocortisone, are produced in the adrenal cortex and exert pleiotropic effects in peripheral tissues by regulating the expression of up to 10% of genes that are associated with broad spectrum of metabolic processes. In addition to the adrenal‐derived steroids, it is now recognised that peripheral tissues, such as the epidermis, may also act as steroidogenic organs. Recently has been shown that oral keratinocytes regulate the local concentration of active steroids as well as synthesize hydrocortisone de novo following stimulation with adrenocorticotropin hormone (ACTH). Synthetic corticosteroids are routinely administered during the treatment of several diseases, including pre-malignant and malignant conditions, particularly to alleviate side effects of chemotherapy. However, recent evidence suggests that corticosteroids may have tumour-promoting effects, particularly in epithelial neoplasms. The aim of this thesis was to assess the influence of the recently characterized tumor-associated glucocorticoid (GC) system on both cell proliferation and migration, and on the efficacy of chemotherapeutic agents in the treatment of oral squamous cell carcinoma (OSCC). The chemotherapeutic agents used in the present study were 5-fluorouracil (5-FU), an established drug for OSCC treatment and doxorubicin (DOXO), a potential candidate for the treatment of OSCC.Five different human malignant oral keratinocyte cell lines were selected: H314 / H357 / H400 / BICR16 / BICR56. The cell lines were treated with 5μM DOXO, 5 μg/mL 5-FU, 0,5 μg/mL Hydrocortisone (HC), 10 nM Adrenocorticotropic hormone (ACTH), 10 μM 5-pregnen-3-beta-ol- 20-one-16-alfa-carbonitrile (PCN) (a Glucocorticoid Receptor antagonist), 25 μM Fasentin (a novel inhibitor of glucose uptake that interacts with GLUT1), and 10 μM WZB-117 (an inhibitor of basal glucose transport; specific GLUT1 inhibitor). The cell lines were tested with both high (4.5 g/L) and low (1g/L) glucose mediums. Moreover in vitro wound healing assays were performed using the H357 human carcinoma cell line to assess cell migration. The literature review performed showed, in contrast to previous thought, how increased levels of autocrine, paracrine, and exogenous cortisol are important to tumor progression, as well as the expression of enzymes regulating the levels of tumor-derived cortisol. In the experimental part of the project we have clearly demonstrated, for the first time, the importance of cortisol on oral cancer cells ability to survive, migrate, and interestingly combat the effectiveness of chemotherapeutic agents. This effect would appear to be glucose dependent. Finally, Doxorubicin shows promise for the treatment of oral cancer. In conclusion, glucocorticoids promote oral carcinoma cell proliferation and migration implying an increase in cell invasiveness. This has important implications on the pharmacological use of glucocorticoids, as topical and systemic preparations, for the treatment of a wide variety of oral conditions and in combination with chemotherapy.

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