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      Inhibition of tumor cell growth by adenine is mediated by apoptosis induction and cell cycle S phase arrest

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          Abstract

          Gekko swinhonis has a long standing history in Chinese traditional medicine recognized for its application in treating patients with terminal cancer.In order to discover novel anticancer drugs with high anti-tumor efficacy and low toxicity to normal cells, we aim to investigate the anti-tumor components from Gekko swinhonis. Four nucleosides from the extracted samples were enriched, namely adenosine, guanosine, thymidine and inosine. We evaluated the antitumor effect of the four nucleosides and found that adenosine possessed the strongest anti-tumor effect. Besides, adenine could inhibit the growth of Bel-7402 and Hela cells in a dose and time dependent manner, but not normal human cervical keratinocytes. Bel-7402 and Hela cells had undergone apoptosis 48 hours after treatment as evidenced by morphologic changes under TEM, while adenine blocked cell cycle of tumor cells at S phase and subsequently causing cell cycle exit and promoting apoptosis. Moreover, the pharmacokinetics of adenine was stable in cell culture medium for up to 72 hours. Combining its potency with stability, we conclude adenine makes a promising candidate for an anti-tumor drug.

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          Adenosine induces apoptosis in the human gastric cancer cells via an intrinsic pathway relevant to activation of AMP-activated protein kinase.

          M Saitoh, Tomoyuki Nishizaki, TAKEHIRA YAMAMURA … (2004)
          Extracellular adenosine significantly reduced cell viability in a dose (0.1-20mM)- and treatment time (24-72h)-dependent manner in GT3-TKB cells, a human gastric cancer cell line. Nuclei of cells were reactive to Hoechst 33342, a marker of apoptosis, and an anti-single-stranded DNA. Adenosine-induced GT3-TKB cell death was significantly inhibited by dipyridamole, an inhibitor of adenosine transporter, and 5'-amino-5'-deoxyadenosine, an inhibitor of adenosine kinase, but the effect was not affected by theophylline, a broad inhibitor of adenosine receptors, 8-cyclopentyltheophylline, an inhibitor of A(1) adenosine receptors or 3,7-dimethyl-1-propargylxanthine, an inhibitor of A(2a) adenosine receptors. Adenosine had no effect on mitochondrial membrane potentials. The effect of adenosine on GT3-TKB cell death was not inhibited by a pancaspase inhibitor or inhibitors of caspase-1,-3,-4,-8, and -9. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of AMP-activated protein kinase (AMPK), significantly reduced GT3-TKB cell viability, but the AICAR action was not reinforced in the presence of adenosine. The results of the present study, thus, suggest that extracellular adenosine induces apoptosis in GT3-TKB cells by its uptake into cells and conversion to AMP followed by activation of AMPK, regardless of caspase activation linked to the mitochondria and the endoplasmic reticulum.
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            Older and new purine nucleoside analogs for patients with acute leukemias.

            Pawel Robak, Tadeusz Robak (2013)
            Purine nucleoside analogs (PNAs) compose a class of cytotoxic drugs that have played an important role in the treatment of hematological neoplasms, especially lymphoid and myeloid malignancies. All PNA drugs have a chemical structure similar to adenosine or guanosine, and they have similar mechanisms of action. They have many intracellular targets: they act as antimetabolites, competing with natural nucleosides during DNA or RNA synthesis, and as inhibitors of key cell enzymes. In contrast to other antineoplastic drugs, PNAs act cytotoxically, both in the mitotic and quiescent cell cycle phases. In the last few years, three PNAs have been approved for the treatment of lymphoid malignancies and other hematological disorders: 2-chlorodeoxyadenosine (2-CdA), fludarabine and pentostatin. 2-CdA and fludarabine are also active in the treatment of acute myeloid leukemia (AML). These drugs, in combination with cytarabine and other agents, are commonly used as salvage regimens in relapsed or refractory AML. Moreover, the addition of 2-CdA to the standard induction regimen is associated with an increased rate of complete remission and improved survival of adult patients with AML. More recently three novel PNAs have been synthesized and introduced into clinical trials: clofarabine, nelarabine and forodesine. Clofarabine is the most promising PNA in current clinical trials in pediatric and adult patients with acute leukemias. Nelarabine is more cytotoxic in T-lineage than in B-lineage leukemias. Clofarabine and nelarabine have been approved for the treatment of refractory patients with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. Clofarabine is also an active drug in AML treatment when administered either alone or in combination regimens as front-line treatment and in relapsed or refractory patients. Unlike other PNA, forodesine is not incorporated into DNA but displays a highly selective purine nucleoside phosphorylase inhibitory action. Forodesine is undergoing clinical trials for the treatment of T-cell malignancies, including T-cell ALL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PNAs, as well as their emerging role in lymphoid and myeloid acute leukemias.
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              Adenine nucleotide translocase family: four isoforms for apoptosis modulation in cancer.

              C Pertuiset, C Brenner, K Subramaniam … (2011)
              Mitochondria have important functions in mammalian cells as the energy powerhouse and integrators of the mitochondrial pathway of apoptosis. The adenine nucleotide translocase (ANT) is a family of proteins involved in cell death pathways that perform distinctly opposite functions to regulate cell fate decisions. On the one hand, ANT catalyzes the adenosine triphosphate export from the mitochondrial matrix to the intermembrane space with the concomitant import of ADP from the intermembrane space to the matrix. On the other hand, during periods of stress, ANT could function as a lethal pore and trigger the process of mitochondrial membrane permeabilization, which leads irreversibly to cell death. In human, ANT is encoded by four homologous genes, whose expression is not only tissue specific, but also varies according to the pathophysiological state of the cell. Recent evidence revealed a differential role of the ANT isoforms in apoptosis and a deregulation of their expression in cancer. In this review, we introduce the current knowledge of ANT in apoptosis and cancer cells and propose a novel classification of ANT isoforms.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 7 November 2017
                Publication date (Electronic): 9 October 2017
                Volume: 8
                Issue: 55
                Pages: 94286-94296
                Affiliations
                1 School of Clinical Medicine, Weifang Medical University, Weifang 261053, China
                2 Department of Medical Imaging, Weifang Medical University, Weifang 261053, China
                3 School of Bioscience and Technology, Weifang Medical University, Weifang 261053, China
                4 Medical Imaging Center, Affiliated Hospital of Weifang Medical University, Weifang 261031, China
                Author notes
                Correspondence to: Shizhuang Zhang, zhangsz0102@ 123456163.com
                Article
                Publisher ID: 21690
                DOI: 10.18632/oncotarget.21690
                PMC ID: 5706874
                SO-VID: 13a26615-8790-4f1f-b839-8cb3cfa9e1e5
                Copyright © Copyright: © 2017 Han et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 22 June 2017
                Date accepted : 21 September 2017
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: adenine,adenosine,cell cycle,apoptosis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: adenine, adenosine, cell cycle, apoptosis

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