title: Multilevel pharmacological manipulation of adenosine-prostaglandin E₂/cAMP nexus in the tumor microenvironment: a 'two hit' therapeutic opportunity.
abstract: Novel trends in cancer treatment research are focused on targeting the tumor microenvironment, thereby developing chemo-immunotherapeutic strategies which not only directly kill tumor cells, but also trigger the anti-tumor immune effector responses. Ectonucleotidases (CD39 and CD73)-generated extracellular adenosine and cyclooxygenase-2 (COX2)-derived prostaglandin E₂ (PGE₂) are amongst the tumor microenvironmental factors that have emerged as attractive targets in this regard. Both comprise a pivotal axis in tumor progression and immune escape via autocrine and paracrine activation of a common intracellular signaling pathway, the cAMP-protein kinase A (PKA) pathway, in cancer and immune cells. In this review, we venture a potential and realistic strategy that this adenosine-PGE₂/cAMP nexus is targetable at different levels, thereby pointing out a 'two hit' chemo-immunotherapeutic proposition: direct killing of tumor cells on one hand, and the rescuing of endogenous anti-tumor immune response on the other. The reviewed experimental, preclinical and clinical data provide the proof of concept that 'two hit' multilevel pharmacological manipulation of adenosine-E₂/cAMP nexus is achievable within the tumor microenvironment.
authors.affiliation: Department of Pharmacology & Toxicology, University of Veterinary and Animal Sciences, Lahore, Pakistan.
authors.forename: Muzammal
authors.initials: M
authors.lastname: Hussain
authors.forename: Aqeel
authors.initials: A
authors.lastname: Javeed
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
authors.forename: Hou
authors.initials: H
authors.lastname: Yuzhu
authors.forename: Muhammad Mahmood
authors.initials: MM
authors.lastname: Mukhtar
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine; D015232:Dinoprostone