Celentano, Antonio
(2017)
Effect of glucocorticoids on the anti-cancer activity of chemotherapeutic agents in oral squamous cell carcinoma (OSCC) cells.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
Effect of glucocorticoids on the anti-cancer activity of chemotherapeutic agents in oral squamous cell carcinoma (OSCC) cells |
| Autori: |
| Autore | Email |
|---|
| Celentano, Antonio | antony.celentano@gmail.com |
|
| Data: |
Gennaio 2017 |
| Numero di pagine: |
260 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
Neuroscienze e Scienze Riproduttive ed Odontostomatologiche |
| Scuola di dottorato: |
Medicina clinica e sperimentale |
| Dottorato: |
Medicina clinica e sperimentale |
| Ciclo di dottorato: |
29 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Marone, Gianni | marone@unina.it |
|
| Tutor: |
| nome | email |
|---|
| Mignogna, Michele Davide | [non definito] |
|
| Data: |
Gennaio 2017 |
| Numero di pagine: |
260 |
| Parole chiave: |
glucocorticoids, oral cancer, doxorubicin |
| Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/28 - Malattie odontostomatologiche |
[error in script]
[error in script]
| Depositato il: |
28 Apr 2017 12:21 |
| Ultima modifica: |
13 Mar 2018 10:28 |
| URI: |
http://www.fedoa.unina.it/id/eprint/11473 |
| DOI: |
10.6093/UNINA/FEDOA/11473 |
Abstract
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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