Specific A3 adenosine receptor (A3AR) agonist, 2‑chloro‑N6‑(3‑iodobenzyl)‑5'‑N‑methylcarboxamidoadenosine (2‑Cl‑IB‑MECA), demonstrates anti‑proliferative effects on various types of tumor. In the present study, the cytotoxicity of 2‑Cl‑IB‑MECA was analyzed in a panel of tumor and non‑tumor cell lines and its anticancer mechanisms in JoPaca‑1 pancreatic and Hep‑3B hepatocellular carcinoma cell lines were also investigated. Initially, decreased tumor cell proliferation, cell accumulation in the G1 phase and inhibition of DNA and RNA synthesis was found. Furthermore, western blot analysis showed decreased protein expression level of β‑catenin, patched1 (Ptch1) and glioma‑associated oncogene homolog zinc finger protein 1 (Gli1), which are components of the Wnt/β‑catenin and Sonic hedgehog/Ptch/Gli transduction pathways. In concordance with these findings, the protein expression levels of cyclin D1 and c‑Myc were reduced. Using a luciferase assay, it was revealed for the first time a decrease in β‑catenin transcriptional activity, as an early event following 2‑Cl‑IB‑MECA treatment. In addition, the protein expression levels of multidrug resistance‑associated protein 1 and P‑glycoprotein (P‑gp) were reduced and the P‑gp xenobiotic efflux function was also reduced. Next, the enhancing effects of 2‑Cl‑IB‑MECA on the cytotoxicity of conventional chemotherapy was investigated. It was found that 2‑Cl‑IB‑MECA enhanced carboplatin and doxorubicin cytotoxic effects in the JoPaca‑1 and Hep‑3B cell lines, and a greater synergy was found in the highly tumorigenic JoPaca‑1 cell line. This provides a novel in vitro rationale for the utilization of 2‑Cl‑IB‑MECA in combination with chemotherapeutic agents, not only for hepatocellular carcinoma, but also for pancreatic cancer. Other currently used conventional chemotherapeutics, fluorouracil and gemcitabine, showed synergy only when combined with high doses of 2‑Cl‑IB‑MECA. Notably, experiments with A3AR‑specific antagonist, N‑[9‑Chloro‑2‑(2‑furanyl)(1,2,4)‑triazolo(1,5‑c)quinazolin‑5‑yl]benzene acetamide, revealed that 2‑Cl‑IB‑MECA had antitumor effects via both A3AR‑dependent and ‑independent pathways. In conclusion, the present study identified novel antitumor mechanisms of 2‑Cl‑IB‑MECA in pancreatic and hepatocellular carcinoma in vitro that further underscores the importance of A3AR agonists in cancer therapy.

• Klíčová slova
• 2‑Cl‑IB‑MECA, adenosine A3 receptor, chemosensitivity, hepatocellular carcinoma, multidrug resistance, pancreatic carcinoma,
• MeSH
• adenosin analogy a deriváty   MeSH
• buněčné linie MeSH
• léková rezistence MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory jater * farmakoterapie   MeSH
• nádory slinivky břišní * genetika   MeSH
• proliferace buněk MeSH
• protein Gli1 genetika   metabolismus   MeSH
• proteiny hedgehog MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide MeSH Prohlížeč
• adenosin MeSH
• protein Gli1 MeSH
• proteiny hedgehog MeSH

A key objective in immuno-oncology is to reactivate the dormant immune system and increase tumour immunogenicity. Adenosine is an omnipresent purine that is formed in response to stress stimuli in order to restore physiological balance, mainly via anti-inflammatory, tissue-protective, and anti-nociceptive mechanisms. Adenosine overproduction occurs in all stages of tumorigenesis, from the initial inflammation/local tissue damage to the precancerous niche and the developed tumour, making the adenosinergic pathway an attractive but challenging therapeutic target. Many current efforts in immuno-oncology are focused on restoring immunosurveillance, largely by blocking adenosine-producing enzymes in the tumour microenvironment (TME) and adenosine receptors on immune cells either alone or combined with chemotherapy and/or immunotherapy. However, the effects of adenosinergic immunotherapy are not restricted to immune cells; other cells in the TME including cancer and stromal cells are also affected. Here we summarise recent advancements in the understanding of the tumour adenosinergic system and highlight the impact of current and prospective immunomodulatory therapies on other cell types within the TME, focusing on adenosine receptors in tumour cells. In addition, we evaluate the structure- and context-related limitations of targeting this pathway and highlight avenues that could possibly be exploited in future adenosinergic therapies.

• Klíčová slova
• adenosine, adenosine receptors, adenosinergic therapy, adverse effects, cancer, immuno-oncology, immunosurveillance, tumour microenvironment,
• MeSH
• adenosin biosyntéza   genetika   imunologie   terapeutické užití   MeSH
• cílená molekulární terapie * MeSH
• imunoterapie trendy   MeSH
• karcinogeneze účinky léků   imunologie   MeSH
• lidé MeSH
• nádorové mikroprostředí účinky léků   imunologie   MeSH
• nádory genetika   imunologie   terapie   MeSH
• purinergní receptory P1 imunologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• adenosin MeSH
• purinergní receptory P1 MeSH