Cyclooxygenase-2 Overexpression in Non-Melanoma Skin Cancer: Molecular Pathways Involved as Targets for Prevention and Treatment

GONZÁLEZ MAGLIO, DANIEL H.; PAZ, MARIELA L.; CELA, ELIANA M.; LEONI, JULIANA

Skin Cancers. Risk factors, prevention and therapy

Intech

Año: 2011; p. 175 - 196

Non melanoma skin cancer (a group of malignancies that involve keratinocytes) is the most frequent tumor in humans. Many cellular pathways are involved in the development of malignant phenotype in keratinocytes, depending on the kind of stimulus. Carcinogenic stimulus include not only ultraviolet radiation (primary UVB) but also chemical compounds such as 7,12-dimethyl benzanthracene (DMBA) or Benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE) and viral infections. Many genes are activated during the cellular response to these stimulus, some of them involved in cell cycle (cyclin D1b and D2) and apoptosis (p53, p21, Bax, etc.), determining the fate of the affected cells: death or survival. Many other activated genes are also related to the immune system, promoting local inflammation and, in cases like UVB exposure, systemic immunosuppression. Cyclooxygenase-2 (COX-2) and one of its downstream products, prostaglandin E2 (PGE2), have been closely associated to skin cancer development. There are epidemiological evidences of the over-expression of this enzyme in human non-melanoma skin cancer (as in other solid tumors). Additionally, many investigators have demonstrated the role of PGE2 in photoimmunosuppression and also as a growth factor for transformed keratinocytes, among other effects.The effect of COX-2 pathway inhibition on skin tumor generation and development has been extensively studied. One approach to this study consists of direct inhibition of the enzyme activity, performed with non-steroidal anti-inflammatory drugs (NSAID), both COX-2 specific (like celecoxib and rofecoxib) and non-specific (like naproxen and indometacin). Many experimental data from animal and in vitro models suggest that this direct inhibition could be a possible treatment for non-melanoma skin cancer. This enzymatic activity specific inhibition is not the only approach investigated. Another line of evidence has shown that many natural compounds, derived from fruits, vegetables andplants (such as green tea or blueberries), are capable of inhibiting the whole COX-2 cellular pathway, which includes different cellular kinases. In this way, the level of the active enzyme is decreased resulting in an attractive new kind of potential chemotherapy for this kind of cancer.The aim of this chapter, which will be written as a review paper, is to perform an extensive discussion of the literature about the relationship between COX-2 and non-melanoma skin cancer. The review will include:1.The molecular basis of this relationship, discussing the proven and the possible pathways involved in the development of a malignant cell phenotype, which leads to a solid tumor establishment and growth.2.The molecular targets to inhibit the tumor generation and/or progression described in research models (both in vivo and in vitro) and its application for human non-melanoma skin cancer treatment.