Protezione Anti Tumorale – Attività Ematopoietica e Mielo Protettiva
Cell. 2011 Apr 29;145(3):435-46. doi: 10.1016/j.cell.2011.03.044.
Nucleotide deficiency promotes genomic instability in early stages of cancer development.
Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B.
Source
Department of Genetics, The Life Sciences Institute, Edmond J. Safra Campus, The Hebrew University, Jerusalem, Israel.
Abstract
Chromosomal instability in early cancer stages is caused by stress on DNA replication. The molecular basis for replication perturbation in this context is currently unknown. We studied the replication dynamics in cells in which a regulator of S phase entry and cell proliferation, the Rb-E2F pathway, is aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 or cyclin E oncogenes significantly decreased the cellular nucleotide levels in the newly transformed cells. Exogenously supplied nucleosides rescued the replication stress and DNA damage and dramatically decreased oncogene-induced transformation. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor c-myc, increased the nucleotide pool and also rescued the replication-induced DNA damage. Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability.
Copyright © 2011 Elsevier Inc. All rights reserved.
Comment in
Does metabolite deficiency mark oncogenic cell cycles? [Cell. 2011]
Does metabolite deficiency mark oncogenic cell cycles?Venkitaraman AR. Cell. 2011 Apr 29; 145(3):337-8. PMID:21529715[PubMed – indexed for MEDLINE] PMCID:PMC3740329
Curr Top Med Chem. 2003;3(4):463-9.
Pharmacology and therapeutic applications of A3 receptor subtype.
Fishman P, Bar-Yehuda S.
Source
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Rabin Medical Center, Petach-Tikva, Israel. pnina@canfite.co.il
Abstract
The present study summarizes the biological effects elicit upon A(3) adenosine receptor (A(3)AR) activation in normal and tumor cells. Anti-inflamatory response is mediated upon A(3)AR activation in neutrophils, eosinophils and macrophages via direct effect on cell degranulation or the production of anti-inflamatory cytokines. In basophils, which highly express A(3)AR, degranulation and mediator release upon receptor activation lead to pro-inflammatory effects resulting in bronchospasm and asthma. In other normal cells such as cardiomyocytes, neuronal cells and bone marrow cells A(1)AR activation induces cytoprotective effects in vitro. In vivo, A(3)AR agonists act as cardio- and neuroprotective agents and attenuate ischemic damage. Furthermore, agonists to A(3)AR induce granulocyte colony stimulating factor (G-CSF) production and myeloprotective effect in chemotherapy treated mice. Interestingly, A(3)AR agonists inhibit tumor cell growth both in vitro and in vivo through a cytostatic effect mediated via the de-regulation of the Wnt signaling pathway. The variety of activities elicit by A(3)AR agonists suggest their potential use as therapeutic agents in inflammation, brain/cardiac ischemia and cancer. Antagonists to A(3)AR may be implemented to the therapy of asthma and additional allergic conditions.
PMID:12570762[PubMed – indexed for MEDLINE]
J Cell Physiol. 2000 Jun;183(3):393-8.
Adenosine acts as a chemoprotective agent by stimulating G-CSF production: a role for A1 and A3 adenosine receptors.
Fishman P, Bar-Yehuda S, Farbstein T, Barer F, Ohana G.
Source
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Tel-Aviv University, Rabin Medical Center, Petach-Tikva, Israel. pnina@mor-research.com
Abstract
Adenosine, a ubiquitous nucleoside, is released into the extracellular environment from metabolically active or stressed cells. It binds to cells through specific A1, A(2A), A(2B), and A3 G-protein-associated cell-surface receptors, thus acting as a signal-transduction molecule by regulating the levels of adenylyl cyclase and phospholipase C. In this study, we showed that adenosine stimulates the proliferation of murine bone marrow cells in vitro. Pharmacological studies, using antagonists to the adenosine receptors, revealed that this activity was mediated through the binding of adenosine to its A1 and A3 receptors. This result was further corroborated by showing that the two selective A1 and A3 receptor agonists, N-cyclopentyladenosine (CPA) and 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-be ta-D-ribofuranuronamide (IB-MECA) respectively, induced bone marrow cell proliferation in a manner similar to adenosine. Adenosine’s interaction with its A1 and A3 receptors induced G-CSF production, which led to its stimulatory effect on bone marrow cells.
These results were confirmed in vivo when we demonstrated that low-dose adenosine (0.25 mg/kg) acted as a chemoprotective agent. When administered after chemotherapy, it restored the number of leukocytes and neutrophils to normal levels, compared with the decline in these parameters after chemotherapy alone.
It is suggested that low-dose adenosine, already in clinical use, may also be applied as a chemoprotective agent.
Copyright 2000 Wiley-Liss, Inc.PMID:10797314[PubMed – indexed for MEDLINE]
J Cell Physiol. 2001 Jan;186(1):19-23.
Differential effect of adenosine on tumor and normal cell growth: focus on the A3 adenosine receptor.
Ohana G, Bar-Yehuda S, Barer F, Fishman P.
Source
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Tel-Aviv University, Petach-Tikva, Israel.
Abstract
Adenosine is an ubiquitous nucleoside present in all body cells. It is released from metabolically active or stressed cells and subsequently acts as a regulatory molecule through binding to specific A1, A2A, A2B and A3 cell surface receptors.
The synthesis of agonists and antagonists to the adenosine receptors and their cloning enabled the exploration of their physiological functions. As nearly all cells express specific adenosine receptors, adenosine serves as a physiological regulator and acts as a cardioprotector, neuroprotector, chemoprotector, and as an immunomodulator.
At the cellular level, activation of the receptors by adenosine initiates signal transduction mechanisms through G-protein associated receptors.
Adenosine’s unique characteristic is to differentially modulate normal and transformed cell growth, depending upon its extracellular concentration, the expression of adenosine cell surface receptors, and the physiological state of the target cell.
Stimulation of cell proliferation following incubation with adenosine has been demonstrated in a variety of normal cells in the range of low micromolar concentrations, including mesangial and thymocyte cells, Swiss mouse 3T3 fibroblasts, and bone marrow cells.
Induction of apoptosis in tumor or normal cells was shown at higher adenosine concentrations (>100 microM) such as in leukemia HL-60, lymphoma U-937, A431 epidermoid cells, and GH3 tumor pituitary cell lines.
It was further noted that the A3 adenosine receptor (A3AR) plays a key role in the inhibitory and stimulatory growth activities of adenosine. Modulation of the A3AR was found to affect cell growth either positively or negatively depending on the concentration of the agonist, similar to the effect described for adenosine.
At nanomolar concentrations, the A3AR agonists possess dual activity, i.e., antiproliferative activity toward tumor cells and stimulatory effect on bone marrow cells. In vivo, these agonists exerted anti-cancer effects, and when given in combination with chemotherapy, they enhanced the chemotherapeutic index and acted as chemoprotective agents.
Taken together, activation of the A3AR, by minute concentrations of its natural ligand or synthetic agonists, may serve as a new approach for cancer therapy.
PMID:11147810[PubMed – indexed for MEDLINE]
Eur J Cancer. 2000 Jul;36(11):1452-8.
Adenosine acts as an inhibitor of lymphoma cell growth: a major role for the A3 adenosine receptor.
Fishman P, Bar-Yehuda S, Ohana G, Pathak S, Wasserman L, Barer F, Multani AS.
Source
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Tel-Aviv University, Rabin Medical Center, Petach-Tikva, Israel. pnina@mor-reseach.com
Abstract
In this study, we demonstrated several mechanisms exploring the inhibitory effect of low-dose adenosine on lymphoma cell growth. Adenosine, a purine nucleoside present in plasma and other extracellular fluids, acts as a regulatory molecule, by binding to G-protein associated cell-surface receptors, A1, A2 and A3. Recently we showed that low-dose adenosine released by muscle cells, inhibits tumour cell growth and thus attributes to the rarity of muscle metastases. In the present work, a cytostatic effect of adenosine on the proliferation of the Nb2-11C rat lymphoma cell line was demonstrated. This effect was mediated through the induction of cell cycle arrest in the G0/G1 phase and by decreasing the telomeric signal in these cells. Adenosine was found to exert its antiproliferative effect mainly through binding to its A3 receptor.
The cytostatic anticancer activity, mediated through the A3 adenosine receptor, turns it into a potential target for the development of anticancer therapies.
PMID:10899660[PubMed – indexed for MEDLINE]
Exp Hematol. 2002 Dec;30(12):1390-8.
Agonists to the A3 adenosine receptor induce G-CSF production via NF-kappaB activation: a new class of myeloprotective agents.
Bar-Yehuda S, Madi L, Barak D, Mittelman M, Ardon E, Ochaion A, Cohn S, Fishman P.
Source
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Rabin Medical Center, Petach-Tikva, 49100 Israel.
Abstract
OBJECTIVE:
The aim of this study was to evaluate the effect of CF101, a synthetic agonist to the A3 adenosine receptor (A3AR), on the production of granulocyte colony-stimulating factor (G-CSF). The ability of CF101 to act as a myeloprotective agent in chemotherapy-treated mice was tested.
METHODS:
CF101 was administered orally to naïve mice and its effect was studied on blood cell counts (coulter counter), serum G-CSF level (ELISA), bone marrow colony-forming cells (soft agar culture), and splenocytes’ ability to produce ex vivo G-CSF. Protein extract was prepared from splenocytes and Western blot analysis was carried out to evaluate expression level of key proteins. In an additional set of experiments, CF101 was administered to mice 48 hours after cyclophosphamide treatment and blood cell counts as well as serum G-CSF levels were monitored.
RESULTS:
Oral administration of CF101 to naïve mice led to the elevation of serum G-CSF levels, an increase in absolute neutrophil counts (ANC), and bone marrow colony-forming cells. Splenocytes derived from these mice produced higher G-CSF level than controls. The molecular mechanisms underlying the events prior to G-CSF production included the upregulation of NF-kappaB and the upstream kinases phosphoinositide 3-kinase (PI3K), protein kinase B/Akt (PKB/Akt), and IKK. Accelerated recovery of white blood cells and neutrophil counts were observed in cyclophosphamide-treated mice following CF101 administration.
CONCLUSION:
CF101 induced upregulation of the PI3K/NF-kappaB pathway leading to G-CSF production, resulting in myeloprotective effect in cyclophosphamide-treated mice.
PMID:12482500[PubMed – indexed for MEDLINE]
Med Res Rev. 2013 Mar;33(2):235-335. doi: 10.1002/med.20254. Epub 2011 Nov 16.
The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry, and in silico approaches.
Cheong SL, Federico S, Venkatesan G, Mandel AL, Shao YM, Moro S, Spalluto G, Pastorin G.
Source
Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Singapore 117543,
Singapore.
Abstract
Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A(1), A(2A), A(2B), and A(3).
Among these G protein-coupled receptors, the A(3) subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer. In this review, we focused on the pharmacology and the therapeutic implications of the human (h)A(3) adenosine receptor (AR), together with an overview on the progress of hA(3) AR agonists, antagonists, allosteric modulators, and radioligands, as well as on the recent advances pertaining to the computational approaches (e.g., quantitative structure-activity relationships, homology modeling, molecular docking, and molecular dynamics simulations) applied to the modeling of hA(3) AR and drug design.
2011 Wiley Periodicals, Inc.
PMID:22095687[PubMed – indexed for MEDLINE]
Anticancer Drugs. 2002 Jun;13(5):437-43.
A3 adenosine receptor as a target for cancer therapy.
Fishman P, Bar-Yehuda S, Madi L, Cohn I.
Source
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Tel-Aviv University, Rabin Medical Center, Petach Tikva 49100, Israel. pfishman@post.tau.ac.il
Abstract
Targeting the A3 adenosine receptor (A3AR) by adenosine or a synthetic agonist to this receptor (IB-MECA and Cl-IB-MECA) results in a differential effect on tumor and on normal cells. Both the adenosine and the agonists inhibit the growth of various tumor cell types such as melanoma, colon or prostate carcinoma and lymphoma.
This effect is specific and is exerted on tumor cells only.
Moreover, exposure of peripheral blood mononuclear cells to adenosine or the agonists leads to the induction of granulocyte colony stimulating factor (G-CSF) production. When given orally to mice, the agonists suppress the growth of melanoma, colon and prostate carcinoma in these animals, while inducing a myeloprotective effect via the induction of G-CSF production. The de-regulation of the Wnt signaling pathway was found to be involved in the anticancer effect. Receptor activation induces inhibition of adenylyl cyclase with a subsequent decrease in the level of protein kinase A and protein kinase B/Akt leading to activation of glycogen synthase kinase-3beta, a key element in the Wnt pathway. The oral bioavailability of the synthetic A3AR agonists, and their induced systemic anticancer and myeloprotective effect, renders them potentially useful in three different modes of treatment: as a stand-alone anticancer treatment, in combination with chemotherapy to enhance its therapeutic index and myelprotection. It is evident that use of the A3AR agonist for increasing the therapeutic index of chemotherapy may also invariably give rise to myeloprotection and vice versa.
The A3AR agonists are thus a promising new class of agents for cancer therapy.
PMID:12045454[PubMed – indexed for MEDLINE]
Exp Cell Res. 2001 Oct 1;269(2):230-6.
The A3 adenosine receptor as a new target for cancer therapy and chemoprotection.
Fishman P, Bar-Yehuda S, Barer F, Madi L, Multani AS, Pathak S.
Source
Laboratory of Clinical and Tumor Immunology, Rabin Medical Center, Petach-Tikva, 49100, Israel. pfishman@post.tau.ac.il
Abstract
Adenosine, a purine nucleoside, acts as a regulatory molecule, by binding to specific G-protein-coupled A(1), A(2A), A(2B), and A(3) cell surface receptors. We have recently demonstrated that adenosine induces a differential effect on tumor and normal cells.
While inhibiting in vitro tumor cell growth, it stimulates bone marrow cell proliferation.
This dual activity was mediated through the A3 adenosine receptor. This study showed that a synthetic agonist to the A3 adenosine receptor, 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5′-N-methyl-uronamide (Cl-IB-MECA), at nanomolar concentrations, inhibited tumor cell growth through a cytostatic pathway, i.e., induced an increase number of cells in the G0/G1 phase of the cell cycle and decreased the telomeric signal. Interestingly, Cl-IB-MECA stimulates murine bone marrow cell proliferation through the induction of granulocyte-colony-stimulating factor. Oral administration of Cl-IB-MECA to melanoma-bearing mice suppressed the development of melanoma lung metastases (60.8 +/- 6.5% inhibition). In combination with cyclophosphamide, a synergistic anti-tumor effect was achieved (78.5 +/- 9.1% inhibition). Furthermore, Cl-IB-MECA prevented the cyclophosphamide-induced myelotoxic effects by increasing the number of white blood cells and the percentage of neutrophils, demonstrating its efficacy as a chemoprotective agent. We conclude that A3 adenosine receptor agonist, Cl-IB-MECA, exhibits systemic anticancer and chemoprotective effects.
Copyright 2001 Academic Press.PMID:11570815[PubMed – indexed for MEDLINE]
Expert Opin Ther Pat. 2012 Apr;22(4):369-90.
Therapeutic potential of A2 and A3 adenosine receptor: a review of novel patented ligands.
Federico S, Spalluto G.
Source
Università degli Studi di Trieste, Dipartimento di Scienze Chimiche e Farmaceutiche, Italy. sfederico@units.it
Abstract
INTRODUCTION:
Adenosine exerts its effects by interacting with G-protein coupled receptors (GPCR) namely A(1), A(2A), A(2B) and A(3), respectively. These are involved in several diseases, for example and most importantly, Parkinson’s disease, ischemia and inflammation. There is high interest in the development of potent and selective ligands for these adenosine receptor (AR) subtypes, primarily for their therapeutic potential but also as pharmacological tools in receptor studies.
AREAS COVERED:
This paper concentrates on reviewing the therapeutic potential of A(2) and A(3) ARs, which represent the most interesting subtypes of recent years. A general description of each receptor is reported with novel agonist and antagonist structures, patented in 2008 – 2011. PubMed and Free Patents Online databases were principally used to collect all the material.
EXPERT OPINION:
In the past years, by modulating A(2) and A(3)ARs, several new possible therapeutic applications were discovered. For this reason, research concerning AR ligands is still of great interest. In particular, few potent and selective A(2B) agonists and antagonists are actually reported and a clear SAR (structure-activity relationship) profile lacks for this AR subtype. At the A(3)AR, allosteric modulation may prevent problems related to the high difference between rat and human orthosteric sites and simplify the preclinical studies on A(3)AR.
PMID:22435652[PubMed – indexed for MEDLINE]
Anticancer Res. 2003 May-Jun;23(3A):2077-83.
Targeting the A3 adenosine receptor for cancer therapy: inhibition of prostate carcinoma cell growth by A3AR agonist.
Fishman P, Bar-Yehuda S, Ardon E, Rath-Wolfson L, Barrer F, Ochaion A, Madi L.
Source
Can-Fite Biopharma Ltd, Kiryat-Matalon, Laboratory of Clinical and Tumor Immunology, Felsenstein Medical Research Center, Tel-Aviv University Sackler Faculty of Medicine, Rabin Medical Center, Petach-Tikva, Israel. pfishman@post.tau.ac.il
Abstract
BACKGROUND:
Agonists to A3 adenosine receptor (A3AR) were shown to inhibit the growth of various tumor cell types. The present study demonstrates that a synthetic A3AR agonist, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purine- 9-yl]-N-methyl-beta-D-ribofura-nuronamide (IB-MECA), inhibits the growth of androgen-independent PC-3 prostate human carcinoma cells and illustrates the molecular mechanism involved.
MATERIALS AND METHODS:
PC-3 prostate carcinoma cells were used. Cell growth was examined in vitro by the thymidine incorporation assay and in vivo by inoculating the tumor cells subcutaneously into nude mice and monitoring tumor size. The protein expression level in cells and tumor extracts was tested by Western blot analysis.
RESULTS:
A decrease in the protein expression level of A3AR and the downstream effector PKAc was observed. Consequently, the GSK-3 beta protein level increased, resulting in the destabilization of beta-catenin and the subsequent suppression of cyclin D1 and c-myc expression. IB-MECA treatment also induced down-modulation of the expression of NF-kappa B/p65, known to regulate the transcription of cyclin D1 and c-Myc. This chain of events occurred both in vitro and in vivo and suggests the use of the above-mentioned signaling proteins as markers to predict tumor cell response to A3AR activation.
CONCLUSION:
Taken together, we demonstrated that A3AR activation deregulates the Wnt and the NF-kappa B signaling pathways resulting in the inhibition of prostate carcinoma cell growth.
PMID:12894581[PubMed – indexed for MEDLINE]
Br J Cancer. 2003 Oct 20;89(8):1552-8.
Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101.
Ohana G, Bar-Yehuda S, Arich A, Madi L, Dreznick Z, Rath-Wolfson L, Silberman D, Slosman G, Fishman P.
Source
Department of Surgery A/B, Rabin Medical Center, Campus Golda, Sackler Faculty of Medicine Tel-Aviv University, Petach-Tikva 49100, Israel.
Abstract
Adenosine is a purine nucleoside that acts as a regulatory molecule by binding to specific G-protein-coupled A1, A(2A), A(2B), and A3 cell surface receptors. We have recently demonstrated that adenosine inhibits tumour cell growth and concomitantly stimulates bone marrow cell proliferation via activation of the A3 adenosine receptor (A3AR). In the present study, we show that a synthetic agonist to the A3AR, CF101, at the low nanomolar concentration range, inhibits HCT-116 human colon carcinoma cell growth. This effect was reversed by the selective A3AR antagonist MRS1523, demonstrating the specificity of the response. CF101 (given orally) was efficacious in inhibiting the development of primary tumours in xenograft and syngeneic models in which mice were inoculated subcutaneously with human HCT-116 or murine CT-26 colon carcinoma cells, respectively. Moreover, CF101 suppressed (50%, P<0.01) colon cancer liver metastases in syngeneic mice inoculated to the spleen with CT-26 cells. The mechanism of action entailed upregulation of interleukin-12 production in the CF101-treated groups and potentiation of NK cell activity. In the HCT-116 xenograft model in which a combined therapy of CF101 and 5-fluorouracyl (5-FU) was examined, an additive antitumour effect was demonstrated. Moreover, CF101 prevented the 5-FU-induced myelotoxicity, resulting in normal values of white blood cell and neutrophil counts. We conclude that the A3AR agonist CF101, a small orally bioavailable molecule, exerts systemic anticancer, antimetastatic, and myeloprotective effects in colon carcinoma-bearing mice, and may serve as an adjuvant treatment to enhance the chemotherapeutic index and prevent myelotoxicity.
PMID:14562031[PubMed – indexed for MEDLINE] PMCID:PMC2394357
Neoplasia. 2001 Mar-Apr;3(2):125-31.
Resistance of muscle to tumor metastases: a role for a3 adenosine receptor agonists.
Bar-Yehuda S, Barer F, Volfsson L, Fishman P.
Source
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Rabin Medical Center, Petach Tikva, Israel.
Abstract
Tumor metastases are extremely rare in striated muscles. Lately, we have found that muscle cell conditioned medium (MCM) inhibits the proliferation of various tumor cells while maintaining the growth of normal murine bone marrow cells. This dual activity was confirmed in vivo when the MCM was administered orally, i.e., it inhibited the development of tumor growth in mice and prevented the myelotoxic effects of chemotherapy. Adenosine was found to be one of the active components of MCM, inhibiting tumor cell growth while maintaining bone marrow cell proliferation in vitro. Adenosine is known to act as an important regulatory molecule through its binding to specific G-protein-associated A1, A(2a), A(2b) and A3 cell surface receptors. In distinction from MCM, adenosine did not suppress tumor development in mice and was not active as a chemoprotective agent when administered orally or intravenously. Thus, the in vivo activity of MCM could not be attributed to adenosine. In this study, MCM from which adenosine was enzymatically removed still retained its dual activity that was also found to be mediated through the A3 adenosine receptor (A3AR). This result led to the conclusion that natural agonists to A3AR were responsible for the activity of MCM. We further tested synthetic agonist to the A3AR and demonstrated that it possessed the same in vitro and in vivo activity profile as MCM. Taken together, muscle cells, in addition to adenosine, secrete natural agonists to A3AR. These agonists are stable nondegradable molecules and may contribute to the systemic anticancer and chemoprotective activity exerted by MCM. This group of molecules may account for the rarity of tumor metastases in muscle.
PMID:11420748[PubMed – indexed for MEDLINE] PMCID:PMC1505413
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9105-10.
Cyclic adenosine monophosphate differentiated beta-endorphin neurons promote immune function and prevent prostate cancer growth.
Sarkar DK, Boyadjieva NI, Chen CP, Ortigüela M, Reuhl K, Clement EM, Kuhn P, Marano J.
Source
Endocrine Program and Neurotoxicology Laboratories, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA. sarkar@aesop.rutgers.edu
Abstract
Pituitary adenylate cyclase-activating peptide (PACAP), a cAMP-activating agent, is highly expressed in the hypothalamus during the period when many neuroendocrine cells become differentiated from the neural stem cells (NSCs). Activation of the cAMP system in rat hypothalamic NSCs differentiated these cells into beta-endorphin (BEP)-producing neurons in culture. When these in vitro differentiated neurons were transplanted into the paraventricular nucleus (PVN) of the hypothalamus of an adult rat, they integrated well with the surrounding cells and produced BEP and its precursor gene product, proopiomelanocortin (POMC). Animals with BEP cell transplants demonstrated remarkable protection against carcinogen induction of prostate cancer. Unlike carcinogen-treated animals with control cell transplants, rats with BEP cell transplants showed rare development of glandular hyperplasia, prostatic intraepithelial neoplasia (PIN), or well differentiated adenocarcinoma with invasion after N-methyl-N-nitrosourea (MNU) and testosterone treatments. Rats with the BEP neuron transplants showed increased natural killer (NK) cell cytolytic function in the spleens and peripheral blood mononuclear cells (PBMCs), elevated levels of antiinflammatory cytokine IFN-gamma, and decreased levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in plasma. These results identified a critical role for cAMP in the differentiation of BEP neurons and revealed a previously undescribed role of these neurons in combating the growth and progression of neoplastic conditions like prostate cancer, possibly by increasing the innate immune function and reducing the inflammatory milieu.
PMID:18562281[PubMed – indexed for MEDLINE] PMCID:PMC2449372
Cancer Res. 2012 Feb 15;72(4):836-40.
Regulation of cancer progression by β-endorphin neuron.
Sarkar DK, Murugan S, Zhang C, Boyadjieva N.
Source
Rutgers Endocrine Program, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA. Sarkar@aesop.rutgers.edu
Abstract
It is becoming increasingly clear that stressful life events can affect cancer growth and metastasis by modulating nervous, endocrine, and immune systems. The purpose of this review is to briefly describe the process by which stress may potentiate carcinogenesis and how reducing body stress may prevent cancer growth and progression. The opioid peptide β-endorphin plays a critical role in bringing the stress axis to a state of homeostasis. We have recently shown that enhancement of endogenous levels of β-endorphin in the hypothalamus via β-endorphin neuron transplantation suppresses stress response, promotes immune function, and reduces the incidence of cancer in rat models of prostate and breast cancers. The cancer-preventive effect of β-endorphin is mediated through the suppression of sympathetic neuronal function, which results in increased peripheral natural killer cell and macrophage activities, elevated levels of anti-inflammatory cytokines, and reduced levels of inflammatory cytokines. β-endorphin inhibition of tumor progression also involves alteration in the tumor microenvironment, possibly because of suppression of catecholamine and inflammatory cytokine production, which are known to alter DNA repair, cell-matrix attachments, angiogenic process, and epithelial-mesenchymal transition. Thus, β-endorphin cell therapy may offer some therapeutic value in cancer prevention.
PMID:22287549[PubMed – indexed for MEDLINE] PMCID:PMC3288320
Eur J Pharmacol. 2009 Aug 15;616(1-3):7-15.
Adenosine: an endogenous modulator of innate immune system with therapeutic potential.
Kumar V, Sharma A.
Source
Department of Microbiology, Panjab University, Chandigarh-160014, India. vij_tox@yahoo.com
Abstract
Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. Once adenosine is released in the extracellular environment, it binds to different types of adenosine (i.e. adenosine A(1), A(2A), A(2B) and A(3) receptors) receptors expressed on various innate immune cells [Neutrophils, macrophages, mast cells, dendritic cells and natural killer cells]. Thus, depending on the type of adenosine receptor to which it binds, adenosine modulates innate immune response during various inflammatory conditions [i.e. chronic (cancer, asthma) as well as acute (sepsis, acute lung injury) inflammatory diseases]. This review summarizes the effect of adenosine on innate immunity and the use of adenosine receptor specific agonists or antagonists in various immunologic disorders (asthma, cancer, HIV-1 infection) as future immunomodulatory therapeutics.
PMID:19464286[PubMed – indexed for MEDLINE]
J Urol. 2013 Jan;189(1):321-8.
A3 adenosine receptor mediates apoptosis in in vitro RCC4-VHL human renal cancer cells by up-regulating AMID expression.
Nagaya H, Gotoh A, Kanno T, Nishizaki T.
Source
Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences and Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Japan.
Abstract
PURPOSE:
Accumulating studies have shown that extracellular adenosine induces apoptosis in various cancer cells via diverse signaling pathways. We sought to understand adenosine induced apoptosis in human renal cancer cells and the underlying pathway.
MATERIALS AND METHODS:
RCC4-VHL (European Collection of Animal Cell Cultures, Salisbury, United Kingdom), ACHN (Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohuku University, Aoba-ku, Sendai, Japan) and 786-O (ATCC®) human renal cancer cells were cultured. MTT assay, TUNEL staining, reverse transcriptase-polymerase chain reaction and Western blot were done in cells untransfected and transfected with siRNA silencing the A(3) adenosine receptor targeted gene or the AMID targeted gene.
RESULTS:
Adenosine induced apoptosis in all cell types used in a concentration (1 to 10 mM) dependent manner. A similar effect was obtained with the A(3) adenosine receptor agonist 2-Cl-IB-MECA. Adenosine induced RCC4-VHL cell death was inhibited by the A(3) adenosine receptor inhibitor MRS1191 or by knocking down A(3) adenosine receptor or AMID. Adenosine up-regulated the expression of AMID mRNA and protein in RCC4-VHL cells, which was suppressed by A(3) adenosine receptor knockdown. Moreover, adenosine promoted AMID translocation from cytosol to nucleus.
CONCLUSIONS:
Adenosine induces RCC4-VHL cell apoptosis by up-regulating AMID expression and accumulating AMID in the nucleus via A(3) adenosine receptor.
Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.PMID:23174235[PubMed – indexed for MEDLINE]
J Cancer Res Clin Oncol. 2011 Oct;137(10):1511-23. Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway.
Aghaei M, Panjehpour M, Karami-Tehrani F, Salami S.
Source
Department of Clinical Biochemistry, Cancer Research Laboratory, School of Medical Science, Tarbiat Modares University, P.O. Box: 14115-331, Tehran, Iran.
Abstract
PURPOSE:
A3 adenosine receptor has shown several physiological and pathological activities, including cell proliferation and apoptosis in various cancer cell lines. This study is designed to investigate molecular mechanism and apoptotic pathway of A3 adenosine receptor in DU-145, PC3 and LNcap-FGC10 human prostate cancer cells.
METHODS:
The expression level of A3 adenosine receptor was examined using real-time RT-PCR. cAMP concentration was also measured. MTT viability, cell counting and BrdU incorporation tests were used to study the cell proliferation effect of IB-MECA. Cell cycle analysis, Annexin V-FITC staining, Hoechst 33258 staining, mitochondrial membrane potential (ΔΨM), caspase-3 activity, Bcl-2 and Bax protein expression were used to detect apoptosis.
RESULT:
A3 adenosine receptors mRNAs were detected at different levels. IB-MECA inhibited forskolin-stimulated cAMP. IB-MECA at (1 μM) suppressed cell proliferation and induced G1 cell cycle arrest. Indeed, IB-MECA down-regulated the expression of CDK4, cyclin D1 and up-regulated p53 expression. IB-MECA at (10-100 μM) induced apoptosis. The activity of caspase-3 was also increased. Expression of Bcl-2 was decreased in response to IB-MECA, while the expression of Bax protein was increased. The results showed a significant loss of ΔΨM, in a dose-dependent manner.
CONCLUSION:
This study introduces a possible mechanism through A3 adenosine receptor activation. IB-MECA inhibited prostate cancer cells proliferation and induced G1 cell cycle arrest through p53, Cdk4/cyclinD1 pathway. Apoptosis determined by characteristic morphological changes and increased in sub-G1 population. Loss of MMP, activation of caspase-3 and down-regulation of Bcl-2 expression indicated mitochondrial signaling pathway that involved in the apoptosis.
PMID:21830157[PubMed – indexed for MEDLINE]
Prostate. 2012 Mar;72(4):361-75. Adenosine induces cell-cycle arrest and apoptosis in androgen-dependent and -independent prostate cancer cell lines, LNcap-FGC-10, DU-145, and PC3.
Aghaei M, Karami-Tehrani F, Panjehpour M, Salami S, Fallahian F.
Source
Department of Clinical Biochemistry, Cancer Research Laboratory, School of Medical Science, Tarbiat Modares University, Tehran, Iran.
Abstract
BACKGROUND:
Adenosine has been shown to inhibit cell growth and induce apoptosis in the several cancer cells via intrinsic and extrinsic pathway. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis in the DU-145, PC3, and LNcap-FGC10 human prostate cancer cells.
METHODS:
To observe cell viability and proliferation, MTT assay, cell counting, and BrdU assay were carried out in DU-145, PC3, and LNcap-FGC10 cells. Apoptosis was assessed with the analysis of cell cycle, Hoechst 33258 staining, propidium iodide and annexin-V staining, reactive oxygen species (ROS) formation, mitochondrial membrane potential (ΔΨM) measurement, caspase-3 activity assay, Bcl-2 and Bax protein expression. Moreover, the expression of adenosine receptors and the effects of adenosine receptor (A(1) , A(2a) , and A(3) ) antagonists were examined.
RESULT:
Adenosine significantly reduced cell proliferation in a dose-dependent manner in DU-145, PC3, and LNcap-FGC10 cell lines. Adenosine induced arrest in the cell-cycle progression in G0/G1 phase through Cdk4/cyclinD1-mediated pathway. Adenosine induced apoptosis, which was determined by morphological changes and increased sub-G1 population. Furthermore, increase of ROS, loss of MMP, activation of caspase-3, and down-regulation of Bcl-2 expression was observed. A(1) , A(2a) , A(2b) , and A(3) adenosine receptors mRNA are expressed in the cell lines. Moreover, adenosine-induced apoptosis was inhibited by MRS1220, A(3) adenosine receptor antagonist.
CONCLUSION:
Our results suggest that adenosine induced apoptosis in prostate cancer cells via the mitochondrial pathway and is related to the adenosine receptors. These data might suggest that adenosine could be used as an agent for the treatment of prostate cancer.
Copyright © 2011 Wiley Periodicals, Inc.
PMID:21656837[PubMed – indexed for MEDLINE]
Tumour Biol. 2013 Apr;34(2):1085-95.
Adenosine induces cell cycle arrest and apoptosis via cyclinD1/Cdk4 and Bcl-2/Bax pathways in human ovarian cancer cell line OVCAR-3.
Shirali S, Aghaei M, Shabani M, Fathi M, Sohrabi M, Moeinifard M.
Source
Department of Laboratory Sciences, Chalous Branch, Islamic Azad University, Chalous, Iran.
Abstract
Adenosine is a regulatory molecule with widespread physiological effects in almost every cells and acts as a potent regulator of cell growth.
Adenosine has been shown to inhibit cell growth and induce apoptosis in the several cancer cells via caspase activation and Bcl-2/Bax pathway.
The present study was designed to understand the mechanism underlying adenosine-induced apoptosis in the OVCAR-3 human ovarian cancer cells. MTT viability, BrdU and cell counting assays were used to study the cell proliferation effect of adenosine in presence of adenosine deaminase inhibitor and the nucleoside transporter inhibitor. Cell cycle analysis, propidium iodide and annexin V staining, caspase-3 activity assay, cyclinD1, Cdk4, Bcl-2 and Bax protein expressions were assessed to detect apoptosis. Adenosine significantly inhibited cell proliferation in a concentration-dependent manner in OVCAR-3 cell line. Adenosine induced cell cycle arrest in G0/G1 phase via Cdk4/cyclinD1-mediated pathway. Adenosine induced apoptosis, which was determined by Annexin V-FITC staining and increased sub-G1 population. Moreover, down-regulation of Bcl-2 protein expression, up-regulation of Bax protein expression and activation of caspase-3 were observed in response to adenosine treatment.
The results of this study suggest that extracellular adenosine induced G1 cell cycle arrest and apoptosis in ovarian cancer cells via cyclinD1/ Cdk4 and Bcl-2/Bax pathways and caspase-3 activation.
These data might suggest that adenosine could be used as an agent for the treatment of ovarian cancer.
PMID:23345014[PubMed – indexed for MEDLINE]
Cancer Lett. 2012 Aug 1;321(1):65-72.
Intracellularly transported adenosine induces apoptosis in [corrected] MCF-7 human breast cancer cells by accumulating AMID in the nucleus.
Tsuchiya A, Kanno T, Saito M, Miyoshi Y, Gotoh A, Nakano T, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Japan.
Erratum in
Cancer Lett. 2012 Nov 28;324(2):231.
Abstract
Extracellular adenosine induced apoptosis of MCF-7 human breast cancer cells in a concentration (10μM-10mM)- and treatment time (24-72h)-dependent manner, and the effect was inhibited by the adenosine transporter inhibitor dipyridamole, but not an inhibitor of adenosine kinase, an inhibitor of AMP-activated protein kinase, or inhibitors for A(1), A(2a), A(2b), and A(3) adenosine receptors. No significant activation of caspase-7, -8, or -9 was obtained with adenosine. Adenosine promoted translocation of apoptosis-inducing factor (AIF)-homologous mitochondrion-associated inducer of death (AMID) from the cytosol into the nucleus, although the total amount of AMID was not affected. Adenosine-induced MCF-7 cell death was abrogated by knocking-down AMID.
The results of the present study indicate that intracellularly transported adenosine induces MCF-7 cell apoptosis by accumulating AMID in the nucleus in a caspase-independent manner.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
PMID:22388174[PubMed – indexed for MEDLINE]
Cell Physiol Biochem. 2012;30(1):61-74.
AMP converted from intracellularly transported adenosine upregulates p53 expression to induce malignant pleural mesothelioma cell apoptosis.
Nogi Y, Kanno T, Nakano T, Fujita Y, Tabata C, Fukuoka K, Gotoh A, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Japan.
Abstract
BACKGROUND/AIMS:
The present study investigated adenosine-induced apoptosis in human malignant pleural mesothelioma cells.
METHODS:
MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out using malignant pleural mesothelioma cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells, and p53 or A(3) adenosine receptor was knocked-down by transfecting each siRNA into cells.
RESULTS:
Adenosine induced apoptosis in all the malignant pleural mesothelioma cells used here, independently of caspase activation. The adenosine effect was prevented by the adenosine transporter inhibitor dipyridamole, the adenosine kinase inhibitor ABT-702, or the A(3) adenosine receptor inhibitor MRS1191. Adenosine upregulated expression of the p53 mRNA and protein, that is abolished by ABT-702, but not by knocking-down A(3) adenosine receptor. Adenosine-induced apoptosis in NCI-H28 cells was significantly inhibited by knocking-down p53 and in part by knocking-down A(3) adenosine receptor.
CONCLUSION:
The results of the present study show that AMP converted from intracellularly transported adenosine upregulates p53 expression to induce caspase-independent apoptosis in malignant pleural mesothelioma cells and that A(3) adenosine receptor also participates partially in the apoptosis by the different mechanism.
Copyright © 2012 S. Karger AG, Basel.PMID:22759956[PubMed – indexed for MEDLINE]
Cell Physiol Biochem. 2011;28(4):761-70.
Adenosine promotes GATA-2-regulated p53 gene transcription to induce HepG2 cell apoptosis.
Yaguchi T, Nakano T, Gotoh A, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan.
Abstract
BACKGROUND/AIMS:
In our earlier study, adenosine induced apoptosis in HepG2 human hepatoma cells by tuning of apoptosis-mediator gene transcription. The present study aimed at understanding the regulatory mechanism underlying the apoptosis-mediator gene transcription under the control of adenosine.
METHODS:
For HepG2 cells with and without knocking-down p53 or GATA-2, cell viability, mitochondrial membrane potentials, caspase activity, and transcriptional activity were monitored, and Western blotting, RT-PCR, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP) assay were carried out.
RESULTS:
Extracellular adenosine upregulated expression of the p53 mRNA and protein in HepG2 human hepatoma cells. Adenosine induced apoptosis, disrupted mitochondrial membrane potentials, and activated caspase-3, -8 and -9 in HepG2 cells, and those effects were inhibited by silencing the p53-targetd gene. In the assay of transcriptional activity using full-length p53 gene promoter and 5′ deletion mutants combined with the luciferase reporter vector, adenosine enhanced transcriptional activity for full-length p53 gene promoter, that was prevented by deleting from -240 to -146 bp on the promoter. In the EMSA using a (32)P-labeled DNA probe to detect binding to the putative GATA-2 biding site on the p53 gene promoter, adenosine produced (32)P-positive signals in nuclear extracts from HepG2 cells. In the Western blot analysis, adenosine increased presence of GATA-2 in nuclear extracts. In the ChIP assay, adenosine increased PCR products for the p53 gene promoter in chromosomal extracts from HepG2 cells, immunoprecipitated using an anti-GATA-2 antibody. Adenosine-induced upregulation of the p53 mRNA expression was suppressed by knocking-down GATA-2.
CONCLUSION:
The results of the present study show that p53 is a transcriptional target of GATA-2 and that adenosine upregulates GATA-2-regulated p53 expression, thereby activating caspase-3, -8, and -9 to induce HepG2 cell apoptosis.
Copyright © 2011 S. Karger AG, Basel.PMID:22178888PubMed – indexed for MEDLINE]
J Cell Biochem. 2012 May;113(5):1766-75.
A(2a) adenosine receptor mediates HepG2 cell apoptosis by downregulating Bcl-X(L) expression and upregulating Bid expression.
Tamura K, Kanno T, Fujita Y, Gotoh A, Nakano T, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
Abstract
Extracellular adenosine induced apoptosis in HepG2 cells, a human hepatoma cell line, by tuning apoptosis-mediator gene transcription.
The present study aimed at identifying the responsible adenosine receptor and clarifying the signaling pathway underlying adenosine-induced HepG2 cell apoptosis. Adenosine and CGS21680, an A(2a) adenosine receptor agonist, induced HepG2 cell apoptosis, and the effect was inhibited by DMPX, an A(2a) adenosine receptor antagonist, or by knocking-down A(2a) adenosine receptors. Adenosine reduced expression of Bcl-X(L) mRNA and protein but otherwise increased expression of the Bid mRNA and protein in HepG2 cells, and those effects were also prevented by knocking-down A(2a) adenosine receptors. Adenosine caused disruption of mitochondrial membrane potentials and stimulated cytochrome c efflux from the mitochondria in HepG2 cells. Adenosine activated caspases-3 and -9 in HepG2 cells, which was significantly inhibited by knocking-down A(2a) adenosine receptors. The results of the present study indicate that extracellular adenosine downregulates Bcl-X(L) expression and upregulates Bid expression, thereby disrupting mitochondrial membrane potentials to allow cytochrome c efflux from the mitochondria, and then causing activation of caspase-9 and the effector caspase-3, as mediated via A(2a) adenosine receptors.
Copyright © 2011 Wiley Periodicals, Inc.PMID:22213163[PubMed – indexed for MEDLINE]
J Gastroenterol. 2009;44(1):56-65.
Extracellular adenosine induces apoptosis in Caco-2 human colonic cancer cells by activating caspase-9/-3 via A(2a) adenosine receptors.
Yasuda Y, Saito M, Yamamura T, Yaguchi T, Nishizaki T.
Source
Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, 663-8501,
Japan.
Abstract
BACKGROUND:
Extracellular adenosine has been shown to induce apoptosis in a variety of cells via an intrinsic pathway linked to adenosine uptake into cells and the ensuing signaling cascades and an extrinsic pathway linked to adenosine receptors. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis of Caco-2 human colonic cancer cells.
METHODS:
To observe cell viability, an MTT assay was carried out in Caco-2 cells untransfected or transfected with the A(2a) adenosine receptor pcDNA3.1. Apoptotic cell death was assessed with flow cytometry using propidium iodide and annexin V and internucleosomal DNA fragmentation analysis. Activities of caspase-3, -8, and -9 were measured using a caspase fluorometric assay kit. Mitochondrial membrane potentials were monitored using a DePsipher kit. Expression of adenosine receptors was examined with the reverse transcription-polymerase chain reaction (RT-PCR) method.
RESULTS:
Extracellular adenosine induced Caco-2 cell apoptosis in a concentration-dependent (1-20 mM) and treatment time-dependent (24-72 h) manner. The adenosine effect was inhibited by DMPX, an inhibitor of A(2a) adenosine receptors and SQ22536, an inhibitor of adenylate cyclase. CGS21680, an agonist of A(2a) adenosine receptors, and forskolin, an adenylate cyclase activator, mimicked the adenosine action. Caco-2 cell death was still induced by overexpressing A(2a) adenosine receptors, and adenosine further promoted the cell death. Adenosine disrupted mitochondrial membrane potentials and activated caspase-9 and -3, but not caspase-8.
CONCLUSIONS:
Extracellular adenosine induces apoptosis in Caco-2 cells by activating caspase-9 and the downstream effector caspase caspase-3 in association with mitochondrial damage via A(2a) adenosine receptors.
PMID:19159073[PubMed – indexed for MEDLINE]
Cancer Lett. 2009 Aug 28;281(2):128-33.
Caspase-8 in cancer biology and therapy.
Fulda S.
Source
University Children’s Hospital, Ulm, Germany. simone.fulda@uniklinik-ulm.de
Abstract
Caspase-8 belongs to the caspase family of proteases and plays a key role in the regulation of programmed cell death (apoptosis) during normal development as well as in adult life. Since signaling via the death receptor (extrinsic) pathway critically depends on caspase-8, the disturbance of caspase-8 expression or function may contribute to human diseases. For example, caspase-8 is inactivated in a variety of human cancers, which may promote tumor progression as well as resistance to current treatment approaches. Therefore, caspase-8 presents a promising target to restore defective apoptosis programs in cancers in order to overcome resistance.
PMID:19111387[PubMed – indexed for MEDLINE]
Cell Physiol Biochem. 2012;30(1):210-20.
A3 adenosine receptor-mediated p53-dependent apoptosis in Lu-65 human lung cancer cells.
Otsuki T, Kanno T, Fujita Y, Tabata C, Fukuoka K, Nakano T, Gotoh A, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
Abstract
BACKGROUND/AIMS:
A(3) adenosine receptor mediates apoptosis in cancer cells via diverse signaling pathways. The present study examined A(3) adenosine receptor-mediated apoptosis in Lu-65 cells, a human giant cell lung carcinoma cell line.
METHODS:
MTT assay, TUNEL staining, real-time RT-PCR, Western blotting, and assay of caspase-3, -8, and -9 activities were carried out in Lu-65 cells, and A(3) adenosine receptor or p53 was knocked-down by transfecting each siRNA into cells.
RESULTS:
Extracellular adenosine induces Lu-65 cell apoptosis in a concentration (0.01-10 mM)-dependent manner, and the effect was inhibited by the A(3) adenosine receptor inhibitor MRS1191 or by knocking-down A(3) adenosine receptor or p53. Like adenosine, the A(3) adenosine receptor agonist 2-Cl-IB-MECA also induced Lu-65 cell apoptosis. Adenosine upregulated expression of p53 and Noxa mRNAs and activated caspase-3 and -9, but not caspase-8. Those adenosine effects were still inhibited by knocking-down A(3) adenosine receptor or p53.
CONCLUSION:
The results of the present study show that adenosine upregulates p53 expression via A(3) adenosine receptor, to promote p53-dependent Noxa gene transcription, causing activation of caspase-9 and the effector caspase-3 to induce Lu-65 cell apoptosis.
Copyright © 2012 S. Karger AG, Basel.
PMID:22759968[PubMed – indexed for MEDLINE]
Cell Physiol Biochem. 2012;30(3):666-77.
Adenosine induces apoptosis in SBC-3 human lung cancer cells through A(3) adenosine receptor-dependent AMID upregulation.
Kanno T, Nakano T, Fujita Y, Gotoh A, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
Abstract
BACKGROUND/AIMS:
We have shown that A(3) adenosine receptor mediates apoptosis in human lung cancer cells such as A549 cells, an epithelial adenocarcinoma cell line, and Lu-65 cells, a giant cell cancer cell line, via each different signaling pathway. AMID, a pro-apoptotic protein, induces caspase-independent apoptosis by accumulating in the nucleus. The present study investigated AMID-dependent apoptosis through A(3) adenosine receptor in SBC-3 cells, a human small cell lung cancer cell line.
METHODS:
MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, and Western blotting were carried out in SBC-3 cells transfected with and without the siRNA to silence the A(3) adenosine receptor-targeted gene or the AMID-targeted gene.
RESULTS:
Adenosine induced SBC-3 cell apoptosis in a concentration (0.01-10 mM) and treatment time (24-72 h)-dependent manner, and a similar effect was obtained with the A(3) adenosine receptor agonist 2-Cl-IB-MECA. Adenosine-induced SBC-3 cell death was inhibited by the A(3) adenosine receptor inhibitor MRS1191, knocking-down A(3) adenosine receptor, or knocking-down AMID. Adenosine upregulated expression of the AMID mRNA and protein in SBC-3 cells, that is suppressed by knocking-down A(3) adenosine receptor. In addition, adenosine increased nuclear AMID localization in concert with decreased cytosolic AMID localization.
CONCLUSION:
The results of the present study show that adenosine induces SBC-3 cell apoptosis by upregulating AMID expression and promoting AMID translocation into the nucleus via A(3) adenosine receptor.
Copyright © 2012 S. Karger AG, Basel.
PMID:22854535[PubMed – indexed for MEDLINE]
Cell Physiol Biochem. 2012;29(5-6):687-96.
Apoptosis-related gene transcription in human A549 lung cancer cells via A(3) adenosine receptor.
Kamiya H, Kanno T, Fujita Y, Gotoh A, Nakano T, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan.
Abstract
BACKGROUND/AIMS:
Extracellular adenosine induces apoptosis in a variety of cancer cells via diverse signaling pathways. The present study investigated the mechanism underlying adenosine-induced apoptosis in A549 human lung cancer cells.
METHODS:
MTT assay, TUNEL staining, flow cytometry using propidium iodide and annexin V-FITC, real-time RTPCR, Western blotting, monitoring of mitochondrial membrane potentials, and assay of caspase-3, -8, and -9 activities were carried out in A549 cells, and the siRNA to silence the A(3) adenosine receptor-targeted gene was constructed.
RESULTS:
Extracellular adenosine induces A549 cell apoptosis in a concentration (0.01-10 mM)-dependent manner, and the effect was inhibited by the A3 adenosine receptor inhibitor MRS1191 or knocking-down A(3) adenosine receptor. Like adenosine, the A(3) adenosine receptor agonist 2-Cl-IB-MECA also induced A549 cell apoptosis. Adenosine increased expression of mRNAs for Puma, Bax, and Bad, disrupted mitochondrial membrane potentials, and activated caspase-3 and -9 in A549 cells, and those adenosine effects were also suppressed by knocking-down A3 adenosine receptor.
CONCLUSION:
Adenosine induces A549 cell apoptosis by upregulating expression of Bax, Bad, and Puma, to disrupt mitochondrial membrane potentials and to activate caspase-9 followed by the effector caspase-3, via A(3) adenosine receptor.
Copyright © 2012 S. Karger AG, Basel.PMID:22613969[PubMed – indexed for MEDLINE]
Cell Physiol Biochem. 2012;30(5):1159-68.
A(3) adenosine receptor mediates apoptosis in 5637 human bladder cancer cells by G(q) protein/PKC-dependent AIF upregulation.
Kanno T, Gotoh A, Fujita Y, Nakano T, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Japan.
Abstract
BACKGROUND/AIMS:
A(3) adenosine receptor mediates apoptosis in a variety of cancer cells via diverse signaling pathways.
The present study was conducted to assess A(3) adenosine receptor-mediated apoptosis in human bladder cancer cell lines and to understand the underlying mechanism.
METHODS:
Human bladder cancer cell lines such as 253J, 5637, KK-47, TCCSUP, T24, and UMUC-3 cells were cultured. The siRNA to silence the A(3) adenosine receptor-targeted gene was constructed and transfected into cells. MTT assay, TUNEL staining, Western blotting, and real-time RT-PCR were carried out.
RESULTS:
For all the investigated cell types adenosine induced apoptosis in a concentration (0.01-10 mM)- and treatment time (24-48 h)-dependent manner. Adenosine-induced 5637 cell death was significantly inhibited by the A(3) adenosine receptor inhibitor MRS1191 or knocking-down A(3) adenosine receptor, and the A(3) adenosine receptor agonist 2-Cl-IB-MECA mimicked the adenosine effect. The adenosine effect was prevented by GF109203X, an inhibitor of protein kinase C (PKC), but it was not affected by forskolin, an activator of adenylate cyclase. Adenosine-induced 5637 cell death, alternatively, was not inhibited by the pan-caspase inhibitor Z-VAD. Adenosine upregulated expression of apoptosis-inducing factor (AIF), that is suppressed by knocking-down A(3) adenosine receptor, and accumulated AIF in the nucleus.
CONCLUSION:
The results of the present study show that adenosine induces 5637 cell apoptosis by upregulating AIF expression via an A(3) adenosine receptor-mediated G(q) protein/PKC pathway.
Copyright © 2012 S. Karger AG, Basel.PMID:23171836[PubMed – in process]
Cell Physiol Biochem. 2010;26(2):125-34.
Higher concentrations of extracellular ATP suppress proliferation of Caco-2 human colonic cancer cells via an unknown receptor involving PKC inhibition.
Yaguchi T, Saito M, Yasuda Y, Kanno T, Nakano T, Nishizaki T.
Source
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
Abstract
BACKGROUND/AIMS:
Adenosine 5′-triphosphate (ATP) mediates a variety of signal transductions via ATP receptors such as P2X and P2Y receptors. The present study aimed at understanding the mechanism underlying extracellular ATP-induced suppression of Caco-2 human colonic cancer cell proliferation.
METHODS:
Caco-2 cells were cultured. To examine cell viability and cell cycling, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, fluorescent cytochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and flow cytometry were carried out. To see mRNA expression of ATP receptors, reverse transcription-polymerase chain reaction (RT-PCR) was performed. To examine PKC activity and mitogen-activated protein (MAP) kinase activity, in situ PKC assay and Western blotting using an anti-extracellular signal-regulated kinase 1 (ERK1)-antibody and an anti-phospho-ERK antibody were carried out.
RESULTS:
Extracellular ATP or the unhydrolyzed ATP analogue 5′-adenylyimido-diphosphate (AMP-PNP) reduced Caco-2 cell viability in a concentration (10 microM-10 mM)-dependent manner at 48-h treatment, and the effect was not affected by caspase inhibitors. Caco-2 cells were little reactive to propidium iodide and Hoechst 33342 or little positive to TUNEL after 48-h treatment with ATP (1 mM). In the flow cytometry, 48-h treatment with ATP (1 mM) arrested cell cycling at the S phase in Caco-2 cells. P(2) purinoceptor agonists reduced Caco-2 cell viability with the order of potency: 2-methylthio ATP>UTP>beta, gamma-methylene ATP, and the ATP effect was partially inhibited by suramin, a non-selective inhibitor of P(2) purinoceptors. The PKC inhibitor GF109203X or the MAP kinase kinase inhibitor PD98059 reduced Caco-2 cell viability to an extent similar to that achieved by ATP (1 mM), and no further reduction was obtained with co-treatment with ATP. ATP and its ATP analogues such as AMP-PNP and ATPgammaS, at higher concentrations (1-10 mM), inhibited PKC activation in Caco-2 cells in a fashion that mimics the effect of GF109203X, but PD98059 exhibited no effect on PKC activation. The inhibitory effect of ATP on PKC activation was not found with SK-N-SH cells, a human neuroblastoma cell line, but the cells expressed all the mRNAs for P2X and P2Y receptors that Caco-2 cells did. ATP (10 mM) or GF109203X inhibited activation of ERK, a MAP kinase, in Caco-2 cells.
CONCLUSION:
Extracellular ATP, at higher concentrations, suppresses Caco-2 cell proliferation at the S phase of cell cycling by inhibiting PKC, possibly as mediated via an unknown ATP receptor, followed by MAP kinase.
Copyright 2010 S. Karger AG, Basel.PMID: 20798496 [PubMed – indexed for MEDLINE]
FEBS J. 2006 Aug;273(16):3756-67.
Adenine nucleotides inhibit proliferation of the human lung adenocarcinoma cell line LXF-289 by activation of nuclear factor kappaB1 and mitogen-activated protein kinase pathways.
Schäfer R, Hartig R, Sedehizade F, Welte T, Reiser G.
Source
Institut für Neurobiochemie, Otto-von-Guericke-Universität, Medizinische Fakultät, Magdeburg,
Germany.
Abstract
Extracellular nucleotides have a profound role in the regulation of the proliferation of diseased tissue.
We studied how extracellular nucleotides regulate the proliferation of LXF-289 cells, the adenocarcinoma-derived cell line from human lung bronchial tumor. ATP and ADP strongly inhibited LXF-289 cell proliferation. The nucleotide potency profile was ATP = ADP = ATPgammaS > > UTP, UDP, whereas alpha,beta-methylene-ATP, beta,gamma-methylene-ATP, 2′,3′-O-(4-benzoylbenzoyl)-ATP, AMP and UMP were inactive. The nucleotide potency profile and the total blockade of the ATP-mediated inhibitory effect by the phospholipase C inhibitor U-73122 clearly show that P2Y receptors, but not P2X receptors, control LXF-289 cell proliferation. Treatment of proliferating LXF-289 cells with 100 microm ATP or ADP induced significant reduction of cell number and massive accumulation of cells in the S phase. Arrest in S phase is also indicated by the enhancement of the antiproliferative effect of ATP by coapplication of the cytostatic drugs cisplatin, paclitaxel and etoposide. Inhibition of LXF-289 cell proliferation by ATP was completely reversed by inhibitors of extracellular signal related kinase-activating kinase/extracellular signal related kinase 1/2 (PD98059, U0126), p38 mitogen-activated protein kinase (SB203508), phosphatidylinositol-3-kinase (wortmannin), and nuclear factor kappaB1 (SN50). Western blot analysis revealed transient activation of p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, and nuclear factor kappaB1 and possibly new formation of p50 from its precursor p105. ATP-induced attenuation of LXF-289 cell proliferation was accompanied by transient translocation of p50 nuclear factor kappaB1 and extracellular signal-related kinase 1/2 to the nucleus in a similar time period. In summary, inhibition of LXF-289 cell proliferation is mediated via P2Y receptors by activation of multiple mitogen-activated protein kinase pathways and nuclear factor kappaB1, arresting the cells in the S phase.
PMID:16911524[PubMed – indexed for MEDLINE]
J Hepatol. 2010 Aug;53(2):348-56.
Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.
Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A.
Source
2nd Department of Internal Medicine, Athens University Medical School, Athens, Greece. gepapath@med.uoa.gr
Abstract
BACKGROUND & AIMS:
Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues.
METHODS:
We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for> or = 24 months.
RESULTS:
Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32-108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466).
CONCLUSIONS:
Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC.
Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.PMID:20483498[PubMed – indexed for MEDLINE]
Virol J. 2011 Feb 15;8:72
Long-term nucleos(t)ide analogues therapy for adults with chronic hepatitis B reduces the risk of long-term complications: a meta-analysis.
Zhang QQ, An X, Liu YH, Li SY, Zhong Q, Wang J, Hu HD, Zhang DZ, Ren H, Hu P.
Source
Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
Abstract
BACKGROUND:
The effect of antiviral therapy in chronic hepatitis B (CHB) on reducing the risk of long-term complications (LTCs) remains unclear so far. To study whether long-term nucleos(t)ide analogues therapy can reduce the risk of long-term complications.
METHODS:
We searched MEDLINE, EMBASE, OVID, the Cochrane Central Register of Controlled Trials. Relative risks (RRs) of long-term complications with or without treatment were studied. Also subgroup analyses including the status of drug-resistance, HBeAg and pre-existing compensated cirrhosis were done using relative risks of long-term complications either with or without treatment or among nucleos(t)ide analogues treatment groups.
RESULTS:
Six eligible studies (3644 patients in all) were included. Data showed the incidence of long-term complications in treatment groups was induced by 74%(RR:0.26, 95% CI: 0.15-0.47) compared with no treatment. Whether drug-resistant happened or not during the long-term therapy, the incidence of long-term complications was still significantly induced respectively by 45%(RR: 0.55,95%CI:0.40-0.76) and 78% (RR:0.22, 95%CI: 0.13-0.36). For both different status of HBeAg and pre-existing compensated cirrhosis, there was significant lower incidence of long-term complications in treatment groups compared with no treatment, too. Moreover, among the NA treatment groups, patients with drug-resistance had 2.64 times (RR:2.64, 95%CI: 1.58-4.41) higher chance of developing to long-term complications, and patients with pre-existing compensated cirrhosis also had 3.07 times (RR:3.07, 95%CI: 1.04-9.11) higher chance of developing to long-term complications.
CONCLUSIONS:
Long-term nucleos(t)ide analogue therapy for adults with CHB prevents or delays the development of long-term complications including decompensated cirrhosis, CHB-related death or CHB-related HCC in patients with CHB. The patients who need take antiviral drugs should receive the antiviral therapy as soon as possible.
PMID:21324130[PubMed – indexed for MEDLINE] PMCID:PMC3046930
Drug Discov Today. 2012 Apr;17(7-8):359-66.
Pharmacological and therapeutic effects of A3 adenosine receptor agonists.
Fishman P, Bar-Yehuda S, Liang BT, Jacobson KA.
Source
Can-Fite BioPharma Ltd, Kiryat-Matalon, 10 Bareket St, PO Box 7537, Petah-Tikva 49170, Israel.
Abstract
The A(3) adenosine receptor (A(3)AR) coupled to G(i) (inhibitory regulative guanine nucleotide-binding protein) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A(3)AR as a potential therapeutic target. Highly selective A(3)AR agonists have been synthesized and molecular recognition in the binding site has been characterized. In this article, we summarize preclinical and clinical human studies that demonstrate that A(3)AR agonists induce specific anti-inflammatory and anticancer effects through a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways.
At present, A(3)AR agonists are being developed for the treatment of inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis.
Published by Elsevier Ltd.PMID:22033198[PubMed – indexed for MEDLINE] PMCID: PMC3289754
Neoplasia. 2009 Nov;11(11):1132-45.
Adenosine A(3) receptor suppresses prostate cancer metastasis by inhibiting NADPH oxidase activity.
Jajoo S, Mukherjea D, Watabe K, Ramkumar V.
Source
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Abstract
Prostate cancer is the most commonly diagnosed and second most lethal malignancy in men, due mainly to a lack of effective treatment for the metastatic disease.
A number of recent studies have shown that activation of the purine nucleoside receptor, adenosine A(3) receptor (A(3)AR), attenuates proliferation of melanoma, colon, and prostate cancer cells.
In the present study, we determined whether activation of the A(3)AR reduces the ability of prostate cancer cells to migrate in vitro and metastasize in vivo. Using severe combined immunodeficient mice, we show that proliferation and metastasis of AT6.1 rat prostate cancer cells were decreased by the administration of A(3)AR agonist N(6)-(3-iodobenzyl) adenosine-5′-N-methyluronamide. In vitro studies show that activation of A(3)AR decreased high basal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity present in these cells, along with the expression of Rac1 and p47(phox) subunits of this enzyme. Inhibition of NADPH oxidase activity by the dominant-negative RacN17 or short interfering (si)RNA against p47(phox) reduced both the generation of reactive oxygen species and the invasion of these cells on Matrigel. In addition, we show that membrane association of p47(phox) and activation of NADPH oxidase is dependent on the activity of the extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase pathway. We also provide evidence that A(3)AR inhibits ERK1/2 activity in prostate cancer cells through inhibition of adenylyl cyclase and protein kinase A. We conclude that activation of the A(3)AR in prostate cancer cells reduces protein kinase A-mediated stimulation of ERK1/2, leading to reduced NADPH oxidase activity and cancer cell invasiveness.
PMID:19881949[PubMed – indexed for MEDLINE] PMCID:PMC2767215
Curr Pharm Des. 2006;12(34):4427-43.
The redox regulation of thiol dependent signaling pathways in cancer.
Giles GI.
School of Chemistry, Building F11, University of Sydney, NSW, Australia. giles_g@chem.usyd.edu.au
Abstract
Reactive oxygen species (ROS) play a central role as second messengers in many signal transduction pathways, where they can post-translationally modify proteins via the oxidation of redox sensitive cysteine residues. The range of cellular processes under redox regulation is extensive and includes both the proliferative and apoptotic pathways. Control of the cellular redox environment is therefore essential for normal physiological function and perturbations to this redox balance are characteristic of many pathological states. Oxidative stress is particularly prevalent in cancer, where many malignant cell types possess an abnormal redox metabolism involving down-regulation of antioxidant enzymes and impaired mitochondrial function. This provides a major opportunity to design therapeutic strategies to selectively target cancer cells based on their redox profile. This review will provide a background to this emerging field by summarizing the known redox biochemistry of ROS signaling. The mechanisms of ROS generation by the action of oxidoreductases and nitric oxide synthases will be discussed in conjunction with the cell’s major antioxidant defenses, with special emphasis placed on the subcellular location of these redox reactions. The effect of ROS on proliferation and apoptosis will be examined by looking at interactions with transcription factors and the Akt, TNF and MAPK signaling pathways. The review will also outline the major differences in redox metabolism between cancer cells and their non-malignant counterparts. Although the full extent of the ROS regulation of signaling pathways is only beginning to be mapped, early indications are that this paradigm will provide new therapeutic targets for cancer therapy.
PMID: 17168752 [PubMed – indexed for MEDLINE]
Cancer Lett. 2008 Jul 18;266(1):21-9. Epub 2008 Apr 18.
Redox signaling and cancer: the role of “labile” iron.
Galaris D, Skiada V, Barbouti A.
Laboratory of Biological Chemistry, University of Ioannina Medical School, Panepistimioupolis, 45110 Ioannina, Greece. dgalaris@cc.uoi.gr
Abstract
Reactive oxygen species (ROS) were viewed for a long time as unavoidable by-products of normal cell catabolism. This view has recently changed and it is now apparent that ROS generation is a tightly regulated process that plays a central role in cell signaling. Thus, it is known that regulated changes in intracellular ROS levels can induce biochemical signaling processes that control basic cellular functions, such as proliferation and apoptosis which are prevalent in the development of cancer. In this short review, we will try to provide a background to this emerging field by summarizing the biochemistry of ROS-mediated cell signaling and its relation to carcinogenesis. Special emphasis will be focused on the emerging role of the so called “labile” iron (the redox-active form of iron) in ROS-mediated signaling in relation to cancer development. It is tempting to speculate that elucidation of the exact molecular mechanisms that govern ROS-mediated regulation of cell signaling will provide the basis for development of new therapeutic strategies for cancer prevention and treatment.
PMID: 18374479 [PubMed – indexed for MEDLINE]
J Hepatol. 2010 Aug;53(2):348-56.
Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review.
Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A.
Source
2nd Department of Internal Medicine, Athens University Medical School, Athens, Greece. gepapath@med.uoa.gr
Abstract
BACKGROUND & AIMS:
Chronic hepatitis B patients are at increased risk for hepatocellular carcinoma (HCC). The effect of medium-term nucleos(t)ide analogue therapy on HCC incidence is unclear; therefore, we systematically reviewed all the data on HCC incidence from studies in chronic hepatitis B patients treated with nucleos(t)ide analogues.
METHODS:
We performed a literature search to identify studies with chronic hepatitis B patients treated with nucleos(t)ide analogues for> or = 24 months.
RESULTS:
Twenty-one studies including 3881 treated and 534 untreated patients met our inclusion criteria. HCC was diagnosed in 2.8% and 6.4% of treated and untreated patients, respectively, during a 46 (32-108) month period (p=0.003), in 10.8% and 0.5% of nucleos(t)ide naive patients with and without cirrhosis (p<0.001) and in 17.6% and 0% of lamivudine resistance patients with and without cirrhosis (p<0.001). HCC developed less frequently in nucleos(t)ide naive patients compared to those without virological remission (2.3% vs 7.5%, p<0.001), but there was no difference between lamivudine resistance patients with or without virological response to rescue therapy (5.9% vs 8.8%, p=0.466).
CONCLUSIONS:
Chronic hepatitis B patients receiving medium-term nucleos(t)ide analogue therapy had a significantly lower incidence of HCC compared to untreated patients but treatment does not completely eliminate the risk of HCC. Among the treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC.
Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.PMID:20483498[PubMed – indexed for MEDLINE]
Handb Exp Pharmacol. 2009;(193):399-441.
Adenosine receptors and cancer.
Fishman P, Bar-Yehuda S, Synowitz M, Powell JD, Klotz KN, Gessi S, Borea PA.
Source
Can-Fite BioPharma, Kiryat Matalon, Petach Tikva, 49170, Israel. pnina@canfite.co.il
Abstract
The A(1), A(2A), A(2B) and A(3) G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A(1)AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A(1)AR is mediated via tumor-associated microglial cells. Activation of the A(2A)AR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition of A(2A)AR activation by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A(2B)AR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A(2B)AR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A(3)AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-kappaB, known to act as an A(3)AR transcription factor. Interestingly, high A(3)AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A(3)AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-kappaB signaling pathways. Taken together, A(3)ARs that are abundantly expressed in tumor cells may be targeted by specific A(3)AR agonists, leading to tumor growth inhibition. The unique characteristics of these A(3)AR agonists make them attractive as drug candidates.
PMID:19639290[PubMed – indexed for MEDLINE] PMCID:PMC3598010
Clin Nutr. 2013 Jun 20. pii: S0261-5614(13)00180-5.
Immunonutrition improves functional capacities in head and neck and esophageal cancer patients undergoing radiochemotherapy: A randomized clinical trial.
Vasson MP, Talvas J, Perche O, Dillies AF, Bachmann P, Pezet D, Achim AC, Pommier P, Racadot S, Weber A, Ramdani M, Kwiatkowski F, Bouteloup C.
Source
CHU Clermont-Ferrand, Centre Jean Perrin, Unité de Nutrition, CLARA, F-63000 Clermont-Ferrand, France; Clermont Université, Université d’Auvergne, UMR 1019, Unité de Nutrition Humaine, CRNH-Auvergne, BP 10448, F-63000 Clermont-Ferrand, France. Electronic address: M-paule.vasson@udamail.fr.
Abstract
BACKGROUND & AIMS:
Malnutrition is frequent in head and neck (HN) and esophageal cancer patients and aggravated by radiochemotherapy (RCT), increasing morbi-mortality and treatment toxicity. Our goal was to investigate the effect of immunonutrition consisting of an arginine, omega-3 fatty acid, nucleotides-enriched diet on nutritional status, and functional capacity in HN or esophageal cancer patients undergoing RCT.
METHODS:
37 patients were randomized in a double-blind clinical trial. 5 days before and until the end of RCT (5-7 weeks), they received either an Immunomodulating Enteral Nutrition (IEN) or an isonitrogenous, isoenergetic Standard Enteral Nutrition (SEN). Anthropometrical parameters, nutritional risk index (NRI), serum albumin, plasma antioxidant capacity, and functional capacity were recorded between the beginning and the end of RCT.
RESULTS:
A significant gain in total body weight (+2.1 ± 3.1 kg) was observed in IEN patients. Albuminemia and NRI were improved concomitantly in IEN malnourished patients. Plasma antioxidant capacity was improved (+100 ± 13 μM EqTrolox) in IEN patients. Functional capacity measured by WHO Performance Status and Karnofsky index was maintained in IEN patients but significantly reduced in SEN patients.
CONCLUSIONS:
These preliminary data show that immunonutrition could improve the nutritional status together with functional capacity in HN and esophageal cancer patients undergoing RCT.
CLINICAL TRIAL REGISTRATION:
This clinical trial promoted by the University Hospital Center of Clermont-Ferrand has been registered at ClinicalTrial.gov website under the following reference: NCT00333099.
Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.