Journal of Literature Pharmacy Sciences

Mikotoksinlerin İn Vitro ve İn Vivo Antikanser Aktivitelerinin Değerlendirilmesi
Evaluation of In Vitro and In Vivo Anticancer Activities of Mycotoxins
Hande YÜCEa, Songül ÜNÜVARa
aİnönü Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Malatya, Türkiye
J Lit Pharm Sci. 2022;11(2):143-51
doi: 10.5336/pharmsci.2021-86805
Article Language: TR
Full Text
ÖZET
 Mikotoksinler, hasat öncesi, hasat sırasında ve/veya hasat sonrası tarımsal ürünleri kontamine eden ve çoğunlukla hayvan ve insanlarda toksisiteye neden olan, mantarlar tarafından salınan ikincil metabolitlerdir. Bu derlemenin amacı, mantar toksinlerinin antikanser aktivitelerinin mekanizmalarını ve yeni antikanser ilaç geliştirilmesindeki önemini açıklamaktır. Gıda, tahıl ve yemlerde yaygın olarak kontaminasyona neden olan mikotoksinler, çeşitli mantar türleri tarafından oluşturulan ikincil metabolitlerdir. Başlıca mikotoksinler trikotesenler, fumonisinler ve zearalenon, patulin; bunların dışında fusarik asit, moniliformin, fusaproliferin, fusariosis, enniatinler ve beauverisin, MT81 olarak bilinmektedir. Mikotoksinlere uzun dönem yüksek dozda maruziyet, ciddi sağlık sorunlarına yol açmaktadır. Ancak mikotoksinlerle ilgili çalışmalarda, uygun dozlarda birçoğunun in vitro antikanser aktivite gösterdiği bulunmuştur. İnsanlarda kanserin gelişimi, çeşitli endojen ve ekzojen uyaranların aracılık ettiği hücresel ve moleküler değişiklikleri ve oksidatif DNA hasarını içeren karmaşık süreçleri kapsar. Kanserin ilerlemesinde ana mekanizmalardan biri olan oksidatif stres ve reaktif oksijen türleri, antikanser ilaç geliştirmede önemli hedefler olarak düşünülmektedir. Birçok mikotoksinin bu mekanizma ile antikanser aktivite gösterdiği bilinmektedir. Patulin, T-2 toksin, beauverisin, zearalenon, MT81, rubratoksin gibi mikotoksinlerin farklı hücre hatlarında antikanser aktiviteleri gösterilmiştir. Hem in vitro hem de in vivo çalışmalar, mikotoksinlerin toksikokinetiğinin, biyoyararlanımının ve etki mekanizmalarının ilgili türlere bağlı olarak değiştiğini göstermiştir, ancak spesifik yanıtları daha iyi anlamak için ek çalışmalara ihtiyaç vardır. Bu derlemede, önemli mikotoksinlere ve bunların yapısal analoglarının in vitro ve in vivo antikanser etkilerinin değerlendirildiği literatür çalışmalarına yer verilmiştir.

Anahtar Kelimeler: Mikotoksin; antikanser aktivite; mantarlar; hücre kültürü
ABSTRACT
 Mycotoxins are secondary metabolites released by fungi that contaminate pre-harvest, during-harvest, and/or post-harvest agricultural products and cause toxicity mostly to animals and humans. The purpose of this review is to explain the mechanisms of anticancer activities of fungal toxins and their importance in the development of new anticancer drugs. Mycotoxins, which commonly cause contamination of food, grain, and feed, are secondary metabolites produced by various fungal species. The main mycotoxins are trichothecenes, fumonisins, zearalenone, patulin, fusaric acid, moniliformin, fusaproliferin, fusariosis, enniatins, beauvericin, and MT81. Long-term high-dose exposure to mycotoxins causes serious health problems. However, studies on mycotoxins have found that most of them show in vitro anticancer activity at appropriate doses. The development of cancer in humans encompasses complex processes that include oxidative DNA damage and cellular and molecular changes mediated by a variety of endogenous and exogenous stimuli. Oxidative stress and reactive oxygen species, one of the main mechanisms in cancer progression, are considered important targets in anticancer drug development. It is known that many mycotoxins show anticancer activity by this mechanism. Anticancer activities of mycotoxins such as patulin, T-2 toxin, beauvericin, zearalenone, MT81, and rubratoxin have been demonstrated in different cell lines. Both in vitro and in vivo studies have shown that the toxicokinetics, bioavailability, and mechanisms of action of mycotoxins vary depending on the species involved, but additional studies are needed to better understand the specific responses. In this review, literature studies evaluating the in vitro and in vivo anticancer effects of important mycotoxins and their structural analogs are included.

Keywords: Mycotoxin; anticancer activity; mushrooms; cell culture
REFERENCES:
  1. Forgacs J, Carll WT. Mycotoxicoses. Adv Vet Sci. 1962;7:273-382.
  2. Peto J. Cancer epidemiology in the last century and the next decade. Nature. 2001;411(6835):390-5. [Crossref]  [PubMed] 
  3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74-108. [Crossref]  [PubMed] 
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. [Crossref]  [PubMed] 
  5. Pusztahelyi T, Holb IJ, Pócsi I. Secondary metabolites in fungus-plant interactions. Front Plant Sci. 2015;6:573. [Crossref]  [PubMed]  [PMC] 
  6. Heidtmann-Bemvenuti R, Mendes GL, Scaglioni PT, Badiale-Furlong E, Souza-Soares LA. Biochemistry and metabolism of mycotoxins: A review. Afr J Food Sci. 2011;5(16):861-9.[Crossref] 
  7. Alvi KA, Rabenstein J, Woodard J, Baker DD, Bergthold JD, Lynch J, et al. 14'-hydroxymytoxin B and 16-hydroxyroridin E, two new cytotoxic trichothecenes from Myrothecium roridum. J Nat Prod. 2002;65(5):742-4. [Crossref]  [PubMed] 
  8. Antony M, Shukla Y, Janardhanan KK. Protective effect of tenuazonic acid against dimethyl benz(a)antracene-induced skin carcinogenesis in mice. Teratog Carcinog Mutagen. 2002;22(4):309-14. [Crossref]  [PubMed] 
  9. Laurent A, Nicco C, Chéreau C, Goulvestre C, Alexandre J, Alves Aet al. Controlling tumor growth by modulating endogenous production of reactive oxygen species. Cancer Res. 2005;65(3):948-56. [Crossref]  [PubMed] 
  10. Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P. Redox regulation of cell survival. Antioxid Redox Signal. 2008;10(8):1343-74. [Crossref]  [PubMed]  [PMC] 
  11. Giles GI. The redox regulation of thiol dependent signaling pathways in cancer. Curr Pharm Des. 2006;12(34):4427-43. [Crossref]  [PubMed] 
  12. Rodrigues MS, Reddy MM, Sattler M. Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications. Antioxid Redox Signal. 2008;10(10):1813-48. [Crossref]  [PubMed] 
  13. Boussabbeh M, Ben Salem I, Prola A, Guilbert A, Bacha H, Abid-Essefi S, et al. Patulin induces apoptosis through ROS-mediated endoplasmic reticulum stress pathway. Toxicol Sci. 2015;144(2):328-37. [Crossref]  [PubMed] 
  14. Ayed-Boussema I, Abassi H, Bouaziz C, Hlima WB, Ayed Y, Bacha H. Antioxidative and antigenotoxic effect of vitamin E against patulin cytotoxicity and genotoxicity in HepG2 cells. Environ Toxicol. 2013;28(6):299-306. [Crossref]  [PubMed] 
  15. Liu BH, Yu FY, Wu TS, Li SY, Su MC, Wang MC, Shih SM. Evaluation of genotoxic risk and oxidative DNA damage in mammalian cells exposed to mycotoxins, patulin and citrinin. Toxicol Appl Pharmacol. 2003;191(3):255-63. [Crossref]  [PubMed] 
  16. Kwon O, Soung NK, Thimmegowda NR, Jeong SJ, Jang JH, Moon DO, et al. Patulin induces colorectal cancer cells apoptosis through EGR-1 dependent ATF3 up-regulation. Cell Signal. 2012;24(4):943-50. [Crossref]  [PubMed]  [PMC] 
  17. Assunção R, Alvito P, Kleiveland CR, Lea TE. Characterization of in vitro effects of patulin on intestinal epithelial and immune cells. Toxicol Lett. 2016;250-251:47-56. [Crossref]  [PubMed] 
  18. Lu X, Zhang E, Yin S, Fan L, Hu H. Methylseleninic acid prevents patulin-ınduced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress and ınactivation of p53 and MAPKs. J Agric Food Chem. 2017;65(26):5299-305. [Crossref]  [PubMed] 
  19. Alam MN, Yu JQ, Beale P, Huq F. Dose and sequence dependent synergism from the combination of oxaliplatin with emetine and patulin against colorectal cancer. Anticancer Agents Med Chem. 2020;20(2):264-73. [Crossref]  [PubMed] 
  20. Alam MN, Yu JQ, Beale P, Huq F. Cisplatin in combination with emetine and patulin showed dose and sequence dependent synergism against ovarian cancer. Synergy. 2020;10:100060.[Crossref] 
  21. Abastabar M, Akbari A, Akhtari J, Hedayati MT, Shokohi T, Mehrad-Majd H, et al. In vitro antitumor activity of patulin on cervical and colorectal cancer cell lines. Curr Med Mycol. 2017;3(1):25-9. [Crossref]  [PubMed]  [PMC] 
  22. Liu BH, Wu TS, Yu FY, Wang CH. Mycotoxin patulin activates the p38 kinase and JNK signaling pathways in human embryonic kidney cells. Toxicol Sci. 2006;89(2):423-30. [Crossref]  [PubMed] 
  23. Guo X, Dong Y, Yin S, Zhao C, Huo Y, Fan L, et al. Patulin induces pro-survival functions via autophagy inhibition and p62 accumulation. Cell Death Dis. 2013;4(10):e822. [Crossref]  [PubMed]  [PMC] 
  24. Ferrer E, Juan-García A, Font G, Ruiz MJ. Reactive oxygen species induced by beauvericin, patulin and zearalenone in CHO-K1 cells. Toxicol In Vitro. 2009;23(8):1504-9. [Crossref]  [PubMed] 
  25. Alves I, Oliveira NG, Laires A, Rodrigues AS, Rueff J. Induction of micronuclei and chromosomal aberrations by the mycotoxin patulin in mammalian cells: role of ascorbic acid as a modulator of patulin clastogenicity. Mutagenesis. 2000;15(3):229-34. [Crossref]  [PubMed] 
  26. Burghardt RC, Barhoumi R, Lewis EH, Bailey RH, Pyle KA, Clement BA, et al. Patulin-induced cellular toxicity: a vital fluorescence study. Toxicol Appl Pharmacol. 1992;112(2):235-44. [Crossref]  [PubMed] 
  27. Turkmen NB, Yuce H, Ozek DA, Aslan S, Yasar S, Unuvar S. Dose dependent cytotoxic activity of patulin on neuroblastoma, colon and breast cancer cell line. Ann Med Res. 2021;28(9):1767-70.[Crossref] 
  28. Shin CG, An DG, Song HH, Lee C. Beauvericin and enniatins H, I and MK1688 are new potent inhibitors of human immunodeficiency virus type-1 integrase. J Antibiot (Tokyo). 2009;62(12):687-90. [Crossref]  [PubMed] 
  29. Moretti A, Belisario A, Tafuri A, Ritieni A, Corazza L, Logrieco A. Production of beauvericin by different races of Fusarium oxysporum f. sp. melonis, the Fusarium wilt agent of muskmelon. Eur J Plant Pathol. 2002;108(7):661-6. [Crossref] 
  30. Jow GM, Chou CJ, Chen BF, Tsai JH. Beauvericin induces cytotoxic effects in human acute lymphoblastic leukemia cells through cytochrome c release, caspase 3 activation: the causative role of calcium. Cancer Lett. 2004;216(2):165-73. [Crossref]  [PubMed] 
  31. Tonshin AA, Teplova VV, Andersson MA, Salkinoja-Salonen MS. The Fusarium mycotoxins enniatins and beauvericin cause mitochondrial dysfunction by affecting the mitochondrial volume regulation, oxidative phosphorylation and ion homeostasis. Toxicology. 2010;276(1):49-57. [Crossref]  [PubMed] 
  32. Lin HI, Lee YJ, Chen BF, Tsai MC, Lu JL, Chou CJ, et al. Involvement of Bcl-2 family, cytochrome c and caspase 3 in induction of apoptosis by beauvericin in human non-small cell lung cancer cells. Cancer Lett. 2005;230(2):248-59. [Crossref]  [PubMed] 
  33. Tao YW, Lin YC, She ZG, Lin MT, Chen PX, Zhang JY. Anticancer activity and mechanism investigation of beauvericin isolated from secondary metabolites of the mangrove endophytic fungi. Anticancer Agents Med Chem. 2015;15(2):258-66. [Crossref]  [PubMed] 
  34. Wu Q, Patocka J, Nepovimova E, Kuca K. A review on the synthesis and bioactivity aspects of beauvericin, a Fusarium mycotoxin. Front Pharmacol. 2018;9:1338. [Crossref]  [PubMed]  [PMC] 
  35. Mallebrera B, Juan-Garcia A, Font G, Ruiz MJ. Mechanisms of beauvericin toxicity and antioxidant cellular defense. Toxicol Lett. 2016;246:28-34. [Crossref]  [PubMed] 
  36. Prosperini A, Juan-García A, Font G, Ruiz MJ. Beauvericin-induced cytotoxicity via ROS production and mitochondrial damage in Caco-2 cells. Toxicol Lett. 2013;222(2):204-11. [Crossref]  [PubMed] 
  37. Dornetshuber R, Heffeter P, Lemmens-Gruber R, Elbling L, Marko D, Micksche M, et al. Oxidative stress and DNA interactions are not involved in Enniatin- and Beauvericin-mediated apoptosis induction. Mol Nutr Food Res. 2009;53(9):1112-22. [Crossref]  [PubMed] 
  38. Li Y, Zhang B, He X, Cheng WH, Xu W, Luo Y, et al. Analysis of individual and combined effects of ochratoxin A and zearalenone on HepG2 and KK-1 cells with mathematical models. Toxins (Basel). 2014;6(4):1177-92. [Crossref]  [PubMed]  [PMC] 
  39. Yip KY, Wan MLY, Wong AST, Korach KS, El-Nezami H. Combined low-dose zearalenone and aflatoxin B1 on cell growth and cell-cycle progression in breast cancer MCF-7 cells. Toxicol Lett. 2017;281:139-51. [Crossref]  [PubMed]  [PMC] 
  40. Ayers S, Graf TN, Adcock AF, Kroll DJ, Matthew S, Carcache de Blanco EJ, et al. Resorcylic acid lactones with cytotoxic and NF-κB inhibitory activities and their structure-activity relationships. J Nat Prod. 2011;74(5):1126-31. [Crossref]  [PubMed]  [PMC] 
  41. Hueza IM, Raspantini PC, Raspantini LE, Latorre AO, Górniak SL. Zearalenone, an estrogenic mycotoxin, is an immunotoxic compound. Toxins (Basel). 2014;6(3):1080-95. [Crossref]  [PubMed]  [PMC] 
  42. Tadpetch K, Kaewmee B, Chantakaew K, Kantee K, Rukachaisirikul V, Phongpaichit S. Synthesis and cytotoxic activities of semisynthetic zearalenone analogues. Bioorg Med Chem Lett. 2016;26(15):3612-6. [Crossref]  [PubMed] 
  43. Pinton P, Oswald IP. Effect of deoxynivalenol and other Type B trichothecenes on the intestine: a review. Toxins (Basel). 2014;6(5):1615-43. [Crossref]  [PubMed]  [PMC] 
  44. McCormick SP, Stanley AM, Stover NA, Alexander NJ. Trichothecenes: from simple to complex mycotoxins. Toxins (Basel). 2011;3(7):802-14. [Crossref]  [PubMed]  [PMC] 
  45. Allahyari H, Heidari S, Ghamgosha M, Saffarian P, Amani J. Immunotoxin: a new tool for cancer therapy. Tumour Biol. 2017;39(2):1010428317692226. [Crossref]  [PubMed] 
  46. Woldemichael GM, Turbyville TJ, Vasselli JR, Linehan WM, McMahon JB. Lack of a functional VHL gene product sensitizes renal cell carcinoma cells to the apoptotic effects of the protein synthesis inhibitor verrucarin A. Neoplasia. 2012;14(8):771-7. [Crossref]  [PubMed]  [PMC] 
  47. Su J, Zhao P, Kong L, Li X, Yan J, Zeng Y, et al. Trichothecin induces cell death in NF-κB constitutively activated human cancer cells via inhibition of IKKβ phosphorylation. PLoS One. 2013;8(8):e71333. [Crossref]  [PubMed]  [PMC] 
  48. Liu Y, Gao X, Deeb D, Zhang Y, Shaw J, Valeriote FA, et al. Mycotoxin verrucarin A inhibits proliferation and induces apoptosis in prostate cancer cells by inhibiting prosurvival Akt/NF-kB/mTOR signaling. J Exp Ther Oncol. 2016;11(4):251-60. [PubMed] 
  49. Jayasooriya RGPT, Moon DO, Park SR, Choi YH, Asami Y, Kim MO, et al. Combined treatment with verrucarin A and tumor necrosis factor-α sensitizes apoptosis by overexpression of nuclear factor-kappaB-mediated Fas. Environ Toxicol Pharmacol. 2013;36(2):303-10. [Crossref]  [PubMed] 
  50. Choudhury SM, Gupta M, Majumder UK. Antineoplastic activities of MT81 and its structural analogue in Ehrlich ascites carcinoma-bearing Swiss Albino mice. Oxid Med Cell Longev. 2010;3(1):61-70. [Crossref]  [PubMed]  [PMC] 
  51. Gupta M, Majumdar UK, Ray MR, Mukhopadhayay DK. Inhibition of experimental murine tumors by MT81, a new mycotoxin from Penicillium nigricans. Neoplasma. 1997;44(5):329-33. [PubMed] 
  52. Pan XQ, Harday J. Electromicroscopic observations on gliotoxin-induced apoptosis of cancer cells in culture and human cancer xenografts in transplanted SCID mice. In Vivo. 2007;21(2):259-65. [PubMed] 
  53. Kobayashi M, Müllbacher A, Waring P, Hapel AJ. Gliotoxin treatment selectively spares M-CSF- plus IL-3-responsive multipotent haemopoietic progenitor cells in bone marrow. Eur J Haematol. 1991;46(4):205-11. [Crossref]  [PubMed] 
  54. Chen J, Lou Q, He L, Wen C, Lin M, Zhu Z, et al. Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells. Int J Oncol. 2018;52(3):1023-32. [Crossref]  [PubMed] 
  55. Manh Hung LV, Song YW, Cho SK. Effects of the combination of gliotoxin and adriamycin on the adriamycin-resistant non-small-cell lung cancer A549 cell line. Mar Drugs. 2018;16(4):105. [Crossref]  [PubMed]  [PMC] 
  56. Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13(5):555-62. [Crossref]  [PubMed] 
  57. Gilmore AP. Anoikis. Cell Death Differ. 2005;12 Suppl 2:1473-7. [Crossref]  [PubMed] 
  58. Nguyen VT, Lee JS, Qian ZJ, Li YX, Kim KN, Heo SJ, et al. Gliotoxin isolated from marine fungus Aspergillus sp. induces apoptosis of human cervical cancer and chondrosarcoma cells. Mar Drugs. 2013;12(1):69-87. [Crossref]  [PubMed]  [PMC] 
  59. Axelsson V, Holback S, Sjögren M, Gustafsson H, Forsby A. Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells. Biochem Biophys Res Commun. 2006 ;345(3):1068-74. [Crossref]  [PubMed] 
  60. Anselmi K, Stolz DB, Nalesnik M, Watkins SC, Kamath R, Gandhi CR. Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: exacerbation by caspase and serine protease inhibition. J Hepatol. 2007;47(1):103-13. [Crossref]  [PubMed]  [PMC] 
  61. Kweon YO, Paik YH, Schnabl B, Qian T, Lemasters JJ, Brenner DA. Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J Hepatol. 2003;39(1):38-46. [Crossref]  [PubMed] 
  62. George Thompson AM, Ursu O, Babkin P, Iancu CV, Whang A, Oprea TI, et al. Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation. Sci Rep. 2016;6:24240. [Crossref]  [PubMed]  [PMC] 
  63. Peterson JR, Mitchison TJ. Small molecules, big impact: a history of chemical inhibitors and the cytoskeleton. Chem Biol. 2002;9(12):1275-85. [Crossref]  [PubMed] 
  64. Scherlach K, Boettger D, Remme N, Hertweck C. The chemistry and biology of cytochalasans. Nat Prod Rep. 2010;27(6):869-86. [Crossref]  [PubMed] 
  65. Trendowski M. Using cytochalasins to improve current chemotherapeutic approaches. Anticancer Agents Med Chem. 2015;15(3):327-35. [Crossref]  [PubMed]  [PMC] 
  66. Wilson BJ, Harbison RD. Rubratoxins. J Am Vet Med Assoc. 1973;163(11):1274-6. [PubMed] 
  67. Wang T, Zhang Y, Wang Y, Pei YH. Anti-tumor effects of Rubratoxin B on cell toxicity, inhibition of cell proliferation, cytotoxic activity and matrix metalloproteinase-2,9. Toxicol In Vitro. 2007;21(4):646-50. [Crossref]  [PubMed] 
  68. Hauser D, Weber HP, Sigg HP. [Isolation and configuration of Chaetocin]. Helv Chim Acta. 1970;53(5):1061-73. [Crossref]  [PubMed] 
  69. Yamada A, Kataoka T, Nagai K. The fungal metabolite gliotoxin: immunosuppressive activity on CTL-mediated cytotoxicity. Immunol Lett. 2000;71(1):27-32. [Crossref]  [PubMed] 
  70. Ozyerli-Goknar E, Sur-Erdem I, Seker F, Cingöz A, Kayabolen A, Kahya-Yesil Z, et al. The fungal metabolite chaetocin is a sensitizer for pro-apoptotic therapies in glioblastoma. Cell Death Dis. 2019;10(12):894. [Crossref]  [PubMed]  [PMC] 
  71. Truitt L, Hutchinson C, DeCoteau JF, Geyer CR. Chaetocin antileukemia activity against chronic myelogenous leukemia cells is potentiated by bone marrow stromal factors and overcomes innate imatinib resistance. Oncogenesis. 2014;3(10):e122. [Crossref]  [PubMed]  [PMC] 
  72. Liu X, Guo S, Liu X, Su L. Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells. Apoptosis. 2015;20(11):1499-507. [Crossref]  [PubMed] 
  73. Prosperini A, Meca G, Font G, Ruiz MJ. Study of the cytotoxic activity of beauvericin and fusaproliferin and bioavailability in vitro on Caco-2 cells. Food Chem Toxicol. 2012;50(7):2356-61. [Crossref]  [PubMed] 
  74. Hoque N, Hasan CM, Rana MS, Varsha A, Sohrab MH, Rahman KM. Fusaproliferin, a fungal mycotoxin, shows cytotoxicity against pancreatic cancer cell lines. Molecules. 2018;23(12):3288. [Crossref]  [PubMed]  [PMC] 
  75. Voss KA, Porter JK, Bacon CW, Meredith FI, Norred WP. Fusaric acid and modification of the subchronic toxicity to rats of fumonisins in F. moniliforme culture material. Food Chem Toxicol. 1999;37(8):853-61. [Crossref]  [PubMed] 
  76. Devnarain N, Tiloke C, Nagiah S, Chuturgoon AA. Fusaric acid induces oxidative stress and apoptosis in human cancerous oesophageal SNO cells. Toxicon. 2017;126:4-11. [Crossref]  [PubMed] 
  77. Fernandez-Pol JA, Klos DJ, Hamilton PD. Cytotoxic activity of fusaric acid on human adenocarcinoma cells in tissue culture. Anticancer Res. 1993;13(1):57-64. [PubMed] 
  78. Mamur S, Ünal F, Yılmaz S, Erikel E, Yüzbaşıoğlu D. Evaluation of the cytotoxic and genotoxic effects of mycotoxin fusaric acid. Drug Chem Toxicol. 2020;43(2):149-57. [Crossref]  [PubMed] 
  79. Ghazi T, Nagiah S, Chuturgoon AA. Fusaric acid decreases p53 expression by altering promoter methylation and m6A RNA methylation in human hepatocellular carcinoma (HepG2) cells. Epigenetics. 2021;16(1):79-91. [Crossref]  [PubMed]  [PMC] 

.: Up To Date

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