TARGETED CANCER THERAPY THROUGH INHIBITION OF PURINERGIC RECEPTORS: THE ROLE OF A1 RECEPTOR ANTAGONISTS
Keywords:
Purinergic Receptors, A1 Adenosine Receptor, Cancer Therapy, Targeted Therapy, A1 Antagonists, Tumor Microenvironment, Adenosine Signaling, Immunosuppression.Abstract
The tumor microenvironment (TME) plays a crucial role in cancer progression, immune evasion, and therapeutic resistance. Purinergic signaling, mediated by extracellular nucleotides (ATP, ADP, AMP) and nucleosides (adenosine), has emerged as a critical regulatory system within the TME. Adenosine, in particular, accumulates to high levels in tumors and predominantly exerts immunosuppressive and pro-tumorigenic effects through its interaction with four G protein-coupled receptor subtypes: A1, A2A, A2B, and A3. While the roles of A2A and A2B receptors in cancer are increasingly well-documented, the contribution of the A1 adenosine receptor (A1R) is more complex and context-dependent. This review explores the multifaceted roles of A1R in cancer biology, including its expression in various cancer types, its impact on tumor cell proliferation, survival, angiogenesis, and immune modulation. We delve into the therapeutic potential of targeting A1R using specific antagonists, summarizing preclinical evidence that suggests A1R blockade can inhibit tumor growth and modulate the TME. Furthermore, we discuss the underlying mechanisms of action, the challenges associated with A1R-targeted therapies, including receptor subtype selectivity and potential side effects, and future directions for developing A1R antagonists as novel anti-cancer agents, potentially in combination with existing treatments. The strategic inhibition of A1R signaling presents a promising avenue for innovative targeted cancer therapies.
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