Journal of Literature Pharmacy Sciences

Tümör Gelişiminde ve Tedavisinde Dopamin ve Dopamin Reseptörlerinin Rolü
Role of Dopamine and Dopamine Receptors in Tumor Progression and Therapy
Orçun AVŞARa
aHitit Üniversitesi Fen-Edebiyat Fakültesi, Moleküler Biyoloji ve Genetik Bölümü, Çorum, TÜRKİYE
J Lit Pharm Sci. 2020;9(3):250-8
doi: 10.5336/pharmsci.2020-73635
Article Language: TR
Full Text
ÖZET
 Önemli bir katekolamin nörotransmitter olan dopamin, santral sinir sisteminde ve sindirim sistemi, dalak ve pankreas gibi periferik dokularda sentez edilmektedir. Hem santral sinir sisteminde hem de periferal sistemde dopamin, çeşitli biyolojik fonksiyonları dopamin reseptörleri aracılığıyla düzenlemektedir. Santral sinir sistemindeki dopamin reseptörleri, D1-benzeri ve D2-benzeri olmak üzere 2 alt gruba ayrılmaktadır. Diğer taraftan, periferdeki dopamin reseptörleri ise DA1 ve DA2 olmak üzere 2 alt gruba ayrılmaktadır. Dopamin reseptörlerinin ekpresyon düzeyleri, farklı tümör tiplerinde ve tümör gelişiminin farklı aşamalarında farklılık göstermektedir. Nöron kültürü çalışmalarında dopamin tarafından hücre siklusunun durmasının, DNA fragmentasyonunun ve apoptozun indüklendiği gösterilmiştir. Birçok çalışmada dopaminin anjiyogenezi baskılayarak, tümör büyümesini inhibe ettiği ve bu süreci yöneten en önemli bileşenin ise DRD2 olduğu belirlenmiştir. Matriks metalloproteinazlar (MMPs), tümör invazyonu ve metastazında önemli rol oynamaktadır. Dopamin, DRD2 aracılığıyla MMP-13 ekspresyon seviyelerinin düşmesine neden olmaktadır. Dopamin ve reseptörleri birçok immün sistem hücresinde sentez edilmektedir. Dopamin, nöral sistem ile immün sistem arasındaki iletişimi sağlayan en önemli bileşenlerdendir. Ek olarak dopamin, yardımcı T hücrelerinin farklılaşmasını, polarizasyonunu, sitokin sekresyonunu ve efektör fonksiyonunu etkilemektedir. Dopamin reseptörlerinin bloke edilerek ya da aktive edilerek hedeflenmesi, kanser tedavisinde temel bir stratejidir. Dopamin reseptörlerinin ekspresyon özelliklerinin, değişen kanserli durumlarda detaylı olarak bilinmesi kanser tedavisi açısından oldukça önemlidir. Benzer şekilde, dopamin ve immün sistem arasındaki etkileşimlerin daha iyi anlaşılması, kanser tedavisi için önem arz etmektedir. Bu derlemede, dopamin ve dopamin reseptörlerinin kanser hücre ölümü, anjiyogenez, invazyon ve metastaz ile ilişkisi açıklanmaya çalışılmıştır. Ek olarak, dopamin ve dopamin reseptörleri ile immün sistem arasındaki ilişki açıklanmıştır.

Anahtar Kelimeler: Dopamin; apoptoz; dopamin reseptörü; tümör hücresi; immün sistem; invazyon; metastaz
ABSTRACT
 Dopamine, a significant catecholamine neurotransmitter, is synthesized in the central nervous system and peripheral tissues such as the digestive system, spleen and pancreas. Dopamine both in the central nervous system and in the peripheral system modulate several biological functions via dopamine receptors. Dopamine receptors in the central nervous system are divided into two subtypes: D1-like and D2-like. On the other hand, peripheral dopamine receptors are divided into two subtypes: DA1 ve DA2. The expression levels of dopamine receptors vary across different types of tumor and at different stages of tumor progression. In studies conducted with neuron culture, cell cycle arrest, DNA fragmentation and apoptosis have been shown to be induced by dopamine. In many studies, it has been determined that dopamine inhibits tumor growth by suppressing angiogenesis and DRD2 is the most significant component governing this process. Matrix metalloproteinases (MMPs) play an important role in tumor invasion and metastasis. Dopamine downregulates MMP-13 levels via DRD2. Dopamine and the receptors are generated in several immune cells. Dopamine is one of the most important components of the interaction between neural system and immune system. Furthermore, dopamine modulates the differentiation, polarization, cytokine secretion and effector function of T helper cells. Targeting dopamine receptors by blocking or activating is a fundamental strategy in cancer treatment. It is significant to know the expression profiles of dopamine receptors in changing cancer conditions for cancer treatment in detail. Similarly, a better understanding of the interactions between dopamine and the ımmune system has the importance for cancer treatment. In this review, the relationship between dopamine and dopamine receptors and cancer cell death, angiogenesis, invasion and metastasis has been tried to clarify. Furthermore, the association between dopamine, dopamine receptors and the immune system has been elucidated.

Keywords: Dopamine; apoptosis; dopamine receptor; tumor cell; immune system; invasion; metastasis
REFERENCES:
  1. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63(1):182-217.[Crossref] [PubMed] 
  2. Anden NE, Carlsson A, Dahlstroem A, Fuxe K, Hillarp NA, Larsson K. Demonstration and mapping out of nigro-neostriatal dopamine neurons. Life Sci (1962). 1964;3:523-30.[Crossref] [PubMed] 
  3. Iversen SD, Iversen LL. Dopamine: 50 years in perspective. Trends Neurosci. 2007;30(5):188-93.[Crossref] [PubMed] 
  4. Ehringer H, Hornykiewicz O. [Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system]. Klin Wochenschr. 1960;15;38:1236-9.[Crossref] [PubMed] 
  5. Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. Br J Pharmacol. 2015;172(1):1-23.[Crossref] [PubMed] [PMC] 
  6. Vallone D, Picetti R, Borrelli E. Structure and function of dopamine receptors. Neurosci Biobehav Rev. 2000;24(1):125-32.[Crossref] [PubMed] 
  7. Jose PA, Raymond JR, Bates MD, Aperia A, Felder RA, Carey RM, et al. The renal dopamine receptors. J Am Soc Nephrol. 1992;2(8):1265-78.[PubMed] 
  8. Goldberg LI, Rajfer SI. Dopamine receptors: applications in clinical cardiology. Circulation. 1985;72(2):245-8.[Crossref] [PubMed] 
  9. Spano PF, Govoni S, Trabucchi M. Studies on the pharmacological properties of dopamine receptors in various areas of the central nervous system. Adv Biochem Psychopharmacol. 1978;19:155-65.[PubMed] 
  10. Wang X, Wang ZB, Luo C, Mao XY, Li X, Yin JY, et al. The prospective value of dopamine receptors on bio-behavior of tumor. J Cancer. 2019;3;10(7):1622-32.[Crossref] [PubMed] [PMC] 
  11. Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry. 2012;69(8):776-86.[Crossref] [PubMed] [PMC] 
  12. Ji J, Sundquist K, Ning Y, Kendler KS, Sundquist J, Chen X, et al. Incidence of cancer in patients with schizophrenia and their first-degree relatives: a population-based study in Sweden. Schizophr Bull. 2013;39(3):527-36.[Crossref] [PubMed] [PMC] 
  13. Wu Chou AI, Wang YC, Lin CL, Kao CH. Female schizophrenia patients and risk of breast cancer: a population-based cohort study. Schizophr Res. 2017;188:165-71.[Crossref] [PubMed] 
  14. Arrillaga-Romany I, Chi AS, Allen JE, Oster W, Wen PY, Batchelor TT, et al. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget. 2017;12;8(45):79298-304.[Crossref] [PubMed] [PMC] 
  15. Driver JA, Logroscino G, Buring JE, Gaziano JM, Kurth T. A prospective cohort study of cancer incidence following the diagnosis of Parkinson's disease. Cancer Epidemiol Biomarkers Prev. 2007;16(6):1260-5.[Crossref] [PubMed] 
  16. Kim J, Oh JH, Harlem H, Culler MD, Ku CR, Lee EJ, et al. Therapeutic effect of a novel chimeric molecule targeting both somatostatin and dopamine receptors on growth hormone-secreting pituitary adenomas. Endocrinol Metab (Seoul). 2020;35(1):177-87.[Crossref] [PubMed] [PMC] 
  17. Porat S, Premkumar A, Simantov R. Dopamine induces phenotypic differentiation or apoptosis in a dose-dependent fashion: involvement of the dopamine transporter and p53. Dev Neurosci. 2001;23(6):432-40.[Crossref] [PubMed] 
  18. He Q, Yuan LB. Dopamine inhibits proliferation, induces differentiation and apoptosis of K562 leukaemia cells. Chin Med J (Engl). 2007;5;120(11):970-4.[Crossref] [PubMed] 
  19. Chen J, Wersinger C, Sidhu A. Chronic stimulation of D1 dopamine receptors in human SK-N-MC neuroblastoma cells induces nitric-oxide synthase activation and cytotoxicity. J Biol Chem. 2003;25;278(30):28089-100.[Crossref] [PubMed] 
  20. Wang S, Mou Z, Ma Y, Li J, Li J, Ji X, et al. Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: involvement of eradicating cancer stem-like cells. Biochem Pharmacol. 2015;15;95(2):98-109.[Crossref] [PubMed] 
  21. Gao J, Gao F. Dopamine D1 receptors induce apoptosis of osteosarcoma cells via changes of MAPK pathway. Clin Exp Pharmacol Physiol. 2017;44(11):1166-8.[Crossref] [PubMed] 
  22. Akiyama S, Shiraishi N, Kuratomi Y, Nakagawa M, Kuwano M. Circumvention of multiple-drug resistance in human cancer cells by thioridazine, trifluoperazine, and chlorpromazine. J Natl Cancer Inst. 1986;76(5):839-44.[PubMed] 
  23. Shin JH, Park SJ, Kim ES, Jo YK, Hong J, Cho DH, et al. Sertindole, a potent antagonist at dopamine D2 receptors, induces autophagy by increasing reactive oxygen species in SH-SY5Y neuroblastoma cells. Biol Pharm Bull. 2012;35(7):1069-75.[Crossref] [PubMed] 
  24. Chen J, Zhang L, Zhou H, Wang W, Luo Y, Yang H, et al. Inhibition of autophagy promotes cisplatin-induced apoptotic cell death through Atg5 and Beclin 1 in A549 human lung cancer cells. Mol Med Rep. 2018;17(5):6859-65.[Crossref] [PubMed] 
  25. Wang Z, Liu Z, Wu S. Long non-coding RNA CTA sensitizes osteosarcoma cells to doxorubicin through inhibition of autophagy. Oncotarget. 2017;9;8(19):31465-77.[Crossref] [PubMed] [PMC] 
  26. Teunis MA, Kavelaars A, Voest E, Bakker JM, Ellenbroek BA, Cools AR, et al. Reduced tumor growth, experimental metastasis formation, and angiogenesis in rats with a hyperreactive dopaminergic system. FASEB J. 2002;16(11):1465-7.[Crossref] [PubMed] 
  27. Jiang SH, Hu LP, Wang X, Li J, Zhang ZG. Neurotransmitters: emerging targets in cancer. Oncogene. 2020;39(3):503-15.[Crossref] [PubMed] 
  28. Sarkar C, Chakroborty D, Mitra RB, Banerjee S, Dasgupta PS, Basu S, et al. Dopamine in vivo inhibits VEGF-induced phosphorylation of VEGFR-2, MAPK, and focal adhesion kinase in endothelial cells. Am J Physiol Heart Circ Physiol. 2004;287(4):H1554-60.[Crossref] [PubMed] 
  29. Chakroborty D, Sarkar C, Mitra RB, Banerjee S, Dasgupta PS, Basu S, et al. Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis. Clin Cancer Res. 2004;1;10(13):4349-56.[Crossref] [PubMed] 
  30. Sarkar C, Chakroborty D, Chowdhury UR, Dasgupta PS, Basu S. Dopamine increases the efficacy of anticancer drugs in breast and colon cancer preclinical models. Clin Cancer Res. 2008;15;14(8):2502-10.[Crossref] [PubMed] 
  31. Osinga TE, Links TP, Dullaart RPF, Pacak K, van der Horst-Schrivers ANA, Kerstens MN, et al. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma. FASEB J. 2017;31(6):2226-40.[Crossref] [PubMed] [PMC] 
  32. Sarkar C, Chakroborty D, Dasgupta PS, Basu S. Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia. Int J Cancer. 2015;1;137(3):744-9.[Crossref] [PubMed] [PMC] 
  33. An JJ, Cho SR, Jeong DW, Park KW, Ahn YS, Baik JH, et al. Anti-proliferative effects and cell death mediated by two isoforms of dopamine D2 receptors in pituitary tumor cells. Mol Cell Endocrinol. 2003;29;206(1-2):49-62.[Crossref] [PubMed] 
  34. Chakroborty D, Sarkar C, Basu B, Dasgupta PS, Basu S. Catecholamines regulate tumor angiogenesis. Cancer Res. 2009;1;69(9):3727-30.[Crossref] [PubMed] 
  35. Hoeppner LH, Wang Y, Sharma A, Javeed N, Van Keulen VP, Wang E, et al. Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells. Mol Oncol. 2015;9(1):270-81.[Crossref] [PubMed] [PMC] 
  36. Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med. 2001;7(5):569-74.[Crossref] [PubMed] 
  37. Cherubini E, Di Napoli A, Noto A, Osman GA, Esposito MC, Mariotta S, et al. Genetic and functional analysis of polymorphisms in the human dopamine receptor and transporter genes in small cell lung cancer. J Cell Physiol. 2016;231(2):345-56.[Crossref] [PubMed] 
  38. Jandaghi P, Najafabadi HS, Bauer AS, Papadakis AI, Fassan M, Hall A, et al. Expression of DRD2 is increased in human pancreatic ductal adenocarcinoma and inhibitors slow tumor growth in mice. Gastroenterology. 2016;151(6):1218-31.[Crossref] [PubMed] 
  39. Yong M, Yu T, Tian S, Liu S, Xu J, Hu J, et al. DR2 blocker thioridazine: a promising drug for ovarian cancer therapy. Oncol Lett. 2017;14(6):8171-7.[Crossref] [PubMed] [PMC] 
  40. Shen J, Ma B, Zhang X, Sun X, Han J, Wang Y, et al. Thioridazine has potent antitumor effects on lung cancer stem-like cells. Oncol Lett. 2017;13(3):1563-8.[Crossref] [PubMed] [PMC] 
  41. Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med. 2001;7(5):569-74.[Crossref] [PubMed] 
  42. Asada M, Ebihara S, Numachi Y, Okazaki T, Yamanda S, Ikeda K, et al. Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter. Int J Cancer. 2008;1;123(3):511-8.[Crossref] [PubMed] 
  43. Huang H, Wu K, Ma J, Du Y, Cao C, Nie Y, et al. Dopamine D2 receptor suppresses gastric cancer cell invasion and migration via inhibition of EGFR/AKT/MMP-13 pathway. Int Immunopharmacol. 2016;39:113-20.[Crossref] [PubMed] 
  44. Lu M, Li J, Luo Z, Zhang S, Xue S, Wang K, et al. Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis. Onco Targets Ther. 2015;22;8:1543-52.[Crossref] [PubMed] [PMC] 
  45. Li H, Jia Y, Peng H, Li J. Recent developments in dopamine-based materials for cancer diagnosis and therapy. Adv Colloid Interface Sci. 2018;252:1-20.[Crossref] [PubMed] 
  46. Pulkoski-Gross A, Li J, Zheng C, Li Y, Ouyang N, Rigas B, et al. Repurposing the antipsychotic trifluoperazine as an antimetastasis agent. Mol Pharmacol. 2015;87(3):501-12.[Crossref] [PubMed] [PMC] 
  47. Kline CLB, Ralff MD, Lulla AR, Wagner JM, Abbosh PH, Dicker DT, et al. Role of dopamine receptors in the anticancer activity of ONC201. Neoplasia. 2018;20(1):80-91.[Crossref] [PubMed] [PMC] 
  48. Wu XY, Zhang CX, Deng LC, Xiao J, Yuan X, Zhang B, et al. Overexpressed D2 dopamine receptor inhibits non-small cell lung cancer progression through inhibiting NF-κB signaling pathway. Cell Physiol Biochem. 2018;48(6):2258-72.[Crossref] [PubMed] 
  49. Weissenrieder JS, Neighbors JD, Mailman RB, Hohl RJ. Cancer and the dopamine D2 receptor: a pharmacological perspective. J Pharmacol Exp Ther. 2019;370(1):111-26.[Crossref] [PubMed] [PMC] 
  50. Avsar O, Kuskucu A, Sancak S, Genc E. Are dopaminergic genotypes risk factors for eating behavior and obesity in adults? Neurosci Lett. 2017;27;654:28-32.[Crossref] [PubMed] 
  51. Avsar O, Kuskucu A, Sancak S, Genc E. Do vesicular monoamine transporter 2 genotypes relate to obesity and eating behavior? Neuropsychiatry. 2017;7(6):1020-5.[Crossref] 
  52. Zhang X, Liu Q, Liao Q, Zhao Y. Potential roles of peripheral dopamine in tumor immunity. J Cancer. 2017;25;8(15):2966-73.[Crossref] [PubMed] [PMC] 
  53. Sarkar C, Chakroborty D, Basu S. Neurotransmitters as regulators of tumor angiogenesis and immunity: the role of catecholamines. J Neuroimmune Pharmacol. 2013;8(1):7-14.[Crossref] [PubMed] [PMC] 
  54. Peters MA, Walenkamp AM, Kema IP, Meijer C, de Vries EG, Oosting SF, et al. Dopamine and serotonin regulate tumor behavior by affecting angiogenesis. Drug Resist Updat. 2014;17(4-6):96-104.[Crossref] [PubMed] 
  55. Basu S, Dasgupta PS. Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol. 2000;24;102(2):113-24.[Crossref] [PubMed] 
  56. Pacheco R, Contreras F, Zouali M. The dopaminergic system in autoimmune diseases. Front Immunol. 2014;21;5:117.[Crossref] [PubMed] [PMC] 
  57. Redelman D, Welniak LA, Taub D, Murphy WJ. Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network. Cell Immunol. 2008;252(1-2):111-21.[Crossref] [PubMed] [PMC] 
  58. Mikulak J, Bozzo L, Roberto A, Pontarini E, Tentorio P, Hudspeth K, et al. Dopamine inhibits the effector functions of activated NK cells via the upregulation of the D5 receptor. J Immunol. 2014;15;193(6):2792-800.[Crossref] [PubMed] 
  59. Watanabe Y, Nakayama T, Nagakubo D, Hieshima K, Jin Z, Katou F, et al. Dopamine selectively induces migration and homing of naive CD8+ T cells via dopamine receptor D3. J Immunol. 2006;15;176(2):848-56.[Crossref] [PubMed] 
  60. Nakano K, Higashi T, Takagi R, Hashimoto K, Tanaka Y, Matsushita S, et al. Dopamine released by dendritic cells polarizes Th2 differentiation. Int Immunol. 2009;21(6):645-54.[Crossref] [PubMed] 
  61. Wu J, Zhang R, Tang N, Gong Z, Zhou J, Chen Y, et al. Dopamine inhibits the function of Gr-1+CD115+ myeloid-derived suppressor cells through D1-like receptors and enhances anti-tumor immunity. J Leukoc Biol. 2015;97(1):191-200.[Crossref] [PubMed] [PMC] 
  62. Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res. 2015;128:95-139.[Crossref] [PubMed] [PMC] 
  63. Mikulak J, Bozzo L, Roberto A, Pontarini E, Tentorio P, Hudspeth K, et al. Dopamine inhibits the effector functions of activated NK cells via the upregulation of the D5 receptor. J Immunol. 2014;15;193(6):2792-800.[Crossref] [PubMed] 
  64. Ogura K, Sato-Matsushita M, Yamamoto S, Hori T, Sasahara M, Iwakura Y, et al. NK cells control tumor-promoting function of neutrophils in mice. Cancer Immunol Res. 2018;6(3):348-57.[Crossref] [PubMed] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com