Insights on the role of adenosine and adenosine receptors on melanoma: New therapeutic strategies

• Type: Chapter or Part of a Book
• Date: 2014

Authors

Soares, AS (Author) Other; Sousa, JB (Author) Other; Diniz, C (Author) FFUP; Fresco, P (Author) FFUP

Book

Title: Adenosine Receptors: Pharmacology, Functions and Therapeutic Aspects

Pages: 77-114

ISBN: 9781634634717; 9781634634540

Indexing

Scopus - 0 Citations

Other information

Authenticus ID: P-00K-4E6

Abstract (EN): The role of adenosine and adenosine receptors in tumourigenesis has been largely investigated. Studies suggest a contradictory role of adenosine in viability of normal and cancer cells, ascribed to the stimulation of adenosine receptors subtypes, named A1, A2A, A2B, and A3, which couple to different signal transduction pathways and can be co-expressed in the same cell. Several studies have suggested a crucial role for A3 adenosine receptors on cancer cells' cytotoxicity, improving, by opposition, normal cells proliferation. This dual effect, coupled with the fact that these receptors are overexpressed in several tumours and expressed at low levels in normal tissues, suggested A3 agonists as promising cancer therapeutic strategies. However, time has proved this to be an oversimplified view. In fact, activation of adenosine A3 receptors can lead both to malignant cell proliferation and death, depending on agonist's concentration. Moreover, A3 agonists can mediate cytotoxicity independently of adenosine A3 receptor activation. Melanoma is considered one of the most aggressive malignant tumours, due to its high metastatic potential and resistance to current treatment modalities. Patients with metastatic melanoma present poor prognosis, with an overall survival of 8-18 months. Melanoma incidence is increasing faster than any other solid tumour accounting for a global annual incidence of about 160 thousands new cases. This chapter intends to integrate our research work and the current knowledge concerning the role of adenosine/adenosine receptors in the complex interplay of proliferation, cell death mechanisms and metastatic progression of melanoma. Our group has shown adenosine receptor subtypes expression, on different metastatic melanoma cell lines. Their activation did not affect cell proliferation of human A375 and mouse K1735-M2 cells. However, proliferation of human C32 cells was increased, after activation of A3 adenosine receptor, by micromolar concentrations of adenosine or nanomolar concentrations of the selective A3 agonist, Cl-IB-MECA. By opposition, Cl-IB-MECA, at micromolar concentrations, caused marked cytotoxicity, through A3-independent mechanisms. A major role for adenosine A3 receptors in C32 cell proliferation induced by an adenosine metabolite, inosine, through PLC-PKC-MEK1/2-ERK1/2 pathway activation was demonstrated. Inosine also enhanced proliferation of A375 cells and stimulated metastatic processes evaluated in both cell lines (migration, adhesion, invasion and colony-formation), through adenosine A3 receptor activation. The combination Cl-IB-MECA and paclitaxel was investigated and found to induce multiple mechanisms of cell death and inhibit metastatic processes. This combination emerges, therefore, as a promising new therapeutic strategy for human metastatic melanoma, potentially overcoming chemotherapy multiresistance and improving patient prognosis.

Language: English

Type (Professor's evaluation): Scientific