adenosine-kinase and Neoplasms

The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5'-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.

Topics: Adenosine; Adenosine Deaminase; Adenosine Kinase; Adenosine Monophosphate; Humans; Inosine; Neoplasms; Tumor Microenvironment

Long-term accumulation of adenosine (Ado) in tumor tissues helps to establish the immunosuppressive tumor microenvironment and to promote tumor development. Regulation of Ado metabolism is particularly pivotal for blocking Ado-mediated immunosuppression. The activity of adenosine kinase (ADK) for catalyzing the phosphorylation of Ado plays an essential role in regulating Ado metabolism. Specifically, accumulated Ado in the tumor microenvironment occupies the active site of ADK, inhibiting the phosphorylation of Ado. Phosphate can protect ADK from inactivation and restore the activity of ADK. Herein, calcium phosphate-reinforced iron-based metal-organic frameworks (CaP@Fe-MOFs) are designed to reduce Ado accumulation and to inhibit Ado-mediated immunosuppressive response in the tumor microenvironment. CaP@Fe-MOFs are found to regulate the Ado metabolism by promoting ADK-mediated phosphorylation and relieving the hypoxic tumor microenvironment. Moreover, CaP@Fe-MOFs can enhance the antitumor immune response via Ado regulation, including the increase of T lymphocytes and dendritic cells and the decrease of regulatory T lymphocytes. Finally, CaP@Fe-MOFs are used for cancer treatment in mice, alleviating the Ado-mediated immunosuppressive response and achieving tumor suppression. This study may offer a general strategy for blocking the Ado-mediated immunosuppression in the tumor microenvironment and further for enhancing the immunotherapy efficacy in vivo.

Topics: Adenosine; Adenosine Kinase; Animals; Calcium Phosphates; Catalytic Domain; Cell Line, Tumor; Humans; Immunity; Immunosuppression Therapy; Immunosuppressive Agents; Metal-Organic Frameworks; Mice; Neoplasms; Phosphorylation; T-Lymphocytes, Regulatory; Transplantation, Heterologous; Tumor Microenvironment

To predict the response of cells to chemotherapeutic agents based on gene expression profiles, we performed a chemoinformatic study of a set of standard anticancer agents assayed for activity against a panel of 60 human tumor-derived cell lines from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI).. Mechanistically-relevant gene:drug activity associations were identified in the scientific literature. The correlations between expression levels of drug target genes and the activity of the drugs against the NCI's 60 cell line panel were calculated across and within each tumor tissue type, using published drug activity and gene expression data.. Compared to other mechanistically-relevant gene-drug associations, that of triciribine phosphate (TCN-P) and adenosine kinase (ADK) was exceptionally strong--overall and within tumor tissue types-across the 60 cell lines profiled for chemosensitivity (1) and gene expression (2).. The results suggest ADK expression may be useful for stratifying TCN-P-responsive vs. non-responsive tumors. Based on TCN-P's mechanism of action and the observed TCN-P:ADK association, we contend that catalytic drug activation provides a rational, mechanistic basis for personalizing cancer treatment based on tumor-specific differences in the expression of drug-activating enzymes.

Topics: Acenaphthenes; Adenosine Kinase; Antineoplastic Agents; Biotransformation; Catalysis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Medical Informatics; Neoplasms; Oligonucleotides; Ribonucleotides