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Wistar Ratlarında Dietilnitrozamin Uygulanarak Oluşturulan Hepatoselüler Karsinom Modelinde Silimarinin Antikanserojenik Etkileri

Yıl 2020, Cilt: 2 Sayı: 1, 7 - 16, 13.07.2020

Emin Karakurt , Serpil Dağ

Öz

Bu çalışmada Wistar ratlarında Dietilnitrozamin (DEN) uygulaması yapılarak oluşturulan hepatoselüler karsinom (HCC) modelinde, Silimarin’in antikanserojenik etkileri immunohistokimyasal yöntemlerle araştırılması amaçlandı. 50 adet 2 aylık Wistar Albino cinsi erkek rat rastgele olacak şekilde 5 gruba ayrıldı. Kontrol grubundaki ratlara 20 hafta boyunca pelet yem ve içme suyu verildi. Sham grubundaki hayvanlara % 0.9 NaCl içerisinde çözdürülmüş propilen glikol intraperitoneal yolla haftada 3 kez olmak üzere 20 hafta boyunca verildi. DEN grubundaki hayvanlara 50 mg/kg dozunda haftada 1 kez olmak üzere 20 hafta boyunca DEN uygulaması yapıldı. DEN+Silimarin grubundaki ratlara DEN uygulamasından 1 hafta önce başlayacak şekilde 100 mg/kg dozunda haftada 3 kez olmak üzere 21 hafta boyunca intraperitoneal yolla Silimarin uygulandı. Silimarin grubundaki ratlara 100 mg/kg dozunda 20 hafta boyunca intraperitoneal yolla haftada 3 kez olmak üzere Silimarin uygulandı. 21 hafta sonunda DEN ve DEN+Silimarin gruplarında makroskobik olarak multifokal nodüler yapılar tespit edildi. Mikroskobik incelemeler sonucunda DEN ve DEN+Silimarin gruplarında HCC’nin trabeküler ve asiner paternini içeren miks tipi tespit edildi. iNOS, Nitrotirozin, PCNA, GSTPi, MMP-9, HPIP ve TUNEL boyamaları sonucunda DEN ve DEN+Silimarin grupları arasında istatistiki karşılaştırmada anlamlı sonuç bulunamadı (P > 0.05).

Anahtar Kelimeler

Dietilnitrozamin hepatoselüler karsinom karaciğer kanseri ratlar silimarin

Destekleyen Kurum

KAÜ Bilimsel Araştırma Projeleri Koordinatörlüğü

Proje Numarası

2016-TS-08

Kaynakça

  • Referans1 Abdel Salam OM, Sleem AA, Omara EA, Hassan NS (2007) Effect of ribavirin alone or combined with silymarin on carbon tetrachloride induced hepatic damage in rats. Drug Target Insights 2:19-27. https://doi.org/10.1177/117739280700200014
  • Referans2 Abdo W, Hirata A, Shukry M, Kamal T, Abdel-Sattar E, Mahrous E, Yanai T (2015) Calligonum comosum extract inhibits diethylnitrosamine-induced hepatocarcinogenesis in rats. Oncol Lett 10:716–722. https://doi.org/10.3892/ol.2015.3313
  • Referans3 Abike F, Zengeroğlu S (2010) Epitelyal over karsinomlarında PCNA ekspresyonu. Türk Hijyen ve Deneysel Biyoloji Dergisi 2010; 67:173-178.
  • Referans4 Aköz M, Vatansev H, Gürbilek M, Akkuş İ, Vatansev C, Kaptanoğlu B (2000) Glutatyon S-transferaz (GST) izoenzimlerinin çeşitli kanser vakalarında araştırılması. Genel Tıp Derg 10: 1-6.
  • Referans5 Ashraf M, Abid F, Riffat S, Bashir S, Iqbal J, Sarfraz M, Afzal A, Zaheer M (2015) Rationalized and complementary findings of silymarin (milk thistle) in Pakistani healthy volunteers. Acta Pol Pharm 72:607-614.
  • Referans6 Ben Rahal N, Barba FJ, Barth D, Chevalot I (2015) Supercritical CO₂ extraction of oil, fatty acids and flavonolignans from milk thistle seeds: Evaluation of their antioxidant and cytotoxic activities in Caco-2 cells. Food Chem Toxicol 83:275-282. https://doi.org/10.1016/j.fct.2015.07.006
  • Referans7 Beydogan AB, Bolkent S (2016) The effects of silibin administration for different time periods on mouse liver with Ehrlich ascites carcinoma. Pharmacol Rep 68:543-549. https://doi.org/10.1016/j.pharep.2015.12.003
  • Referans8 Bharati S, Rishi P, Koul A (2014) Azadirachta indica modulates electrical properties and type of cell death in NDEA-induced hepatic tumors. Cell Biochem Biophys 70:383-390. https://doi.org/10.1007/s12013-014-9923-6
  • Referans9 Bingül İ, Başaran-Küçükgergin C, Tekkeşin MS, Olgaç V, Doğru-Abbasoğlu S, Uysal M (2013) Effect of blueberry pretreatment on diethylnitrosamine-induced oxidative stress and liver injury in rats. Environ Toxicol Pharmacol 36:529-538. . https://doi.org/10.1016/j.etap.2013.05.014
  • Referans10 Bosch-Barrera J, Menendez JA (2015) Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy. Cancer Treat Rev 41:540-546. https://doi.org/ 10.1016/j.ctrv.2015.04.008
  • Referans11 Bugide S, Gonugunta VK, Penugurti V, Malisetty VL, Vadlamudi RK, Manavathi B (2017) HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation. Cell Oncol 40:133-144. https://doi.org/ 10.1007/s13402-016-0308-2
  • Referans12 Chen B, Zhao J, Zhang S, Zhang Y, Huang Z (2016) HPIP promotes gastric cancer cell proliferation through activation of cap-dependent translation. Oncol Rep 36:3664-3672. https://doi.org/10.3892/or.2016.5157
  • Referans13 Coşkun G, Özgür H (2011) Apoptoz ve Nekrozun Moleküler Mekanizması. Çukurova Üniversitesi Tıp Fakültesi Arşiv Kaynak Tarama Dergisi 20:145-158.
  • Referans14 Deep G, Raina K, Singh RP, Oberlies NH, Kroll DJ, Agarwal R (2008) Isosilibinin inhibits advanced human prostate cancer growth in athymic nude mice: comparison with silymarin and silibinin. Int J Can 123:2750-2758. https://doi.org/10.1002/ijc.23879
  • Referans15 Dinçel GÇ, Kul O (2016) Patolojik Apoptozis ve Tanı Yöntemleri. Gümüşhane University Journal of Health Sciences 5:86-108.
  • Referans16 Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495-516. https://doi.org/10.1080/01926230701320337
  • Referans17 Eo HJ, Park GH, Song HM, Lee JW, Kim MK, Lee MH, Lee JR, Koo JS, Jeong JB (2015) Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells. Int Immunopharmacol 24:1-6. https://doi.org/ 10.1016/j.intimp.2014.11.009
  • Referans18 Eröz R, Karataş A, Alkoç OA, Baltaci D, Oktay M, Çolakoğlu S (2012) Apoptozis Hakkında Bilinenler (Literatür Taraması). Düzce Tıp Dergisi 14:87-101.
  • Referans19 Fan L, Ma Y, Liu Y, Zheng D, Huang G (2014) Silymarin induces cell cycle arrest and apoptosis in ovarian cancer cells. Eur J Pharmacol 743:79-88. https://doi.org/10.1016/j.ejphar.2014.09.019
  • Referans20 Fujise Y, Okano J, Nagahara T, Abe R, Imamoto R, Murawaki Y (2012) Preventive effect of caffeine and curcumin on hepato-carcinogenesis in diethylnitrosamine-induced rats. Int J Oncol 40:1779-1788. https://doi.org/10.3892/ijo.2012.1343
  • Referans21 Gopalakrishnan R, Sundaram J, Sattu K, Pandi A, Thiruvengadam D (2013) Dietary supplementation of silymarin is associated with decreased cell proliferation, increased apoptosis, and activation of detoxification system in hepatocellular carcinoma. Mol Cell Biochem 377:163-176. https://doi.org/10.1007/s11010-013-1582-1
  • Referans22 Gupta P, Bansal MP, Koul A (2013) Evaluating the effect of lycopene from Lycopersicum esculentum on apoptosis during NDEA induced hepatocarcinogenesis. Biochem Biophys Res Commun 434:479-485. https://doi.org/10.1016/j.bbrc.2013.03.099
  • Referans23 Imamoto R, Okano JI, Sawada S, Fujise Y, Abe R, Murawaki Y (2014) Null anticarcinogenic effect of silymarin on diethylnitrosamine-induced hepatocarcinogenesis in rats. Exp Ther Med 7:31-38. https://doi.org/10.3892/etm.2013.1391
  • Referans24 Jin Z, El-Deiry WS (2005) Overview of cell death signaling pathways. Cancer Biol Ther 4:139-163. https://doi.org/10.4161/cbt.4.2.1508
  • Referans25 Kaya C, Çalişkan Y, Yönden Z (2012) Apoptozis. Mustafa Kemal Üniversitesi Tıp Dergisi 3: 26-37.
  • Referans26 Man S, Li J, Fan W, Chai H, Liu Z, Gao W (2015) Inhibition of pulmonary adenoma in diethylnitrosamine-induced rats by Rhizoma paridis saponins. J Steroid Biochem Mol Biol 154:62-67. https://doi.org/10.1016/j.jsbmb.2015.07.004
  • Referans27 Mansour MA, Aljoufi MA, Al-Hosaini K, Al-Rikabi AC, Nagi MN (2014) Possible role of selective, irreversible, proteasome inhibitor (carfilzomib) in the treatment of rat hepatocellular carcinoma. Chem Biol Interact 215:17-24. https://doi.org/10.1016/j.cbi.2014.03.001
  • Referans28 Matsuda M, Nakamoto Y, Suzuki S, Kurata T, Kaneko S (2005) Interferon-γ-mediated hepatocarcinogenesis in mice treated with diethylnitrosamine. Lab Invest 85:655-663. https://doi.org/10.1038/labinvest.3700257
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  • Referans31 Patial V, S M, Sharma S, Pratap K, Singh D, Padwad YS (2015) Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats. Environ Toxicol Pharmacol 40:445-452. https://doi.org/10.1016/j.etap.2015.07.012
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Anticancerogenic Effects of Silymarin on Diethylnitrosamine-Induced Hepatocellular Carcinoma in Wistar Rats

Yıl 2020, Cilt: 2 Sayı: 1, 7 - 16, 13.07.2020

Emin Karakurt , Serpil Dağ

Öz

The aim of this study was to evaluate the anticancerogenic effect of Silimarin by immunohistochemical methods on Diethylnitrosamine (DEN) induced Hepatocellular carcinoma (HCC) model in Wistar rats. Fifty male Wistar-Albino rats aging 2 months were randomly divided into 5 equal groups. The Control group rats were given pellet feed and drinking water for 20 weeks. The Sham group rats were injected intraperitoneally Propylene glycol dissolved in %0.9 NaCl three times a week. The Silymarin group rats were injected intraperitoneally 100 mg/kg Silymarin three times a week for 20 weeks. The DEN group rats were injected intraperitoneally 50 mg/kg DEN once a week for 20 weeks. The DEN+Silymarin group rats were injected 50 mg/kg DEN once a week for 20 weeks. Silymarin at a dose of 100 mg/kg was injected intraperitoneally for 21 weeks, three times a week, starting 1 week before DEN administration. At the end of 21 weeks, macroscopically multifocal nodular structures were detected in the DEN and DEN+Silymarin group. A mix pattern of trabecular and acinar structures of HCC was observed in DEN and DEN+Silymarin groups. Besides; No statistically significant results were found between DEN and DEN + Silymarin groups in terms of iNOS, Nitrotyrosine, PCNA, GSTPi, MMP-9, HPIP and TUNEL staining (P > 0.05).

Anahtar Kelimeler

Diethylnitrosamine hepatocellular carcinoma liver cancer rats silymarin

Proje Numarası

2016-TS-08

Kaynakça

  • Referans1 Abdel Salam OM, Sleem AA, Omara EA, Hassan NS (2007) Effect of ribavirin alone or combined with silymarin on carbon tetrachloride induced hepatic damage in rats. Drug Target Insights 2:19-27. https://doi.org/10.1177/117739280700200014
  • Referans2 Abdo W, Hirata A, Shukry M, Kamal T, Abdel-Sattar E, Mahrous E, Yanai T (2015) Calligonum comosum extract inhibits diethylnitrosamine-induced hepatocarcinogenesis in rats. Oncol Lett 10:716–722. https://doi.org/10.3892/ol.2015.3313
  • Referans3 Abike F, Zengeroğlu S (2010) Epitelyal over karsinomlarında PCNA ekspresyonu. Türk Hijyen ve Deneysel Biyoloji Dergisi 2010; 67:173-178.
  • Referans4 Aköz M, Vatansev H, Gürbilek M, Akkuş İ, Vatansev C, Kaptanoğlu B (2000) Glutatyon S-transferaz (GST) izoenzimlerinin çeşitli kanser vakalarında araştırılması. Genel Tıp Derg 10: 1-6.
  • Referans5 Ashraf M, Abid F, Riffat S, Bashir S, Iqbal J, Sarfraz M, Afzal A, Zaheer M (2015) Rationalized and complementary findings of silymarin (milk thistle) in Pakistani healthy volunteers. Acta Pol Pharm 72:607-614.
  • Referans6 Ben Rahal N, Barba FJ, Barth D, Chevalot I (2015) Supercritical CO₂ extraction of oil, fatty acids and flavonolignans from milk thistle seeds: Evaluation of their antioxidant and cytotoxic activities in Caco-2 cells. Food Chem Toxicol 83:275-282. https://doi.org/10.1016/j.fct.2015.07.006
  • Referans7 Beydogan AB, Bolkent S (2016) The effects of silibin administration for different time periods on mouse liver with Ehrlich ascites carcinoma. Pharmacol Rep 68:543-549. https://doi.org/10.1016/j.pharep.2015.12.003
  • Referans8 Bharati S, Rishi P, Koul A (2014) Azadirachta indica modulates electrical properties and type of cell death in NDEA-induced hepatic tumors. Cell Biochem Biophys 70:383-390. https://doi.org/10.1007/s12013-014-9923-6
  • Referans9 Bingül İ, Başaran-Küçükgergin C, Tekkeşin MS, Olgaç V, Doğru-Abbasoğlu S, Uysal M (2013) Effect of blueberry pretreatment on diethylnitrosamine-induced oxidative stress and liver injury in rats. Environ Toxicol Pharmacol 36:529-538. . https://doi.org/10.1016/j.etap.2013.05.014
  • Referans10 Bosch-Barrera J, Menendez JA (2015) Silibinin and STAT3: A natural way of targeting transcription factors for cancer therapy. Cancer Treat Rev 41:540-546. https://doi.org/ 10.1016/j.ctrv.2015.04.008
  • Referans11 Bugide S, Gonugunta VK, Penugurti V, Malisetty VL, Vadlamudi RK, Manavathi B (2017) HPIP promotes epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer cells through PI3K/AKT pathway activation. Cell Oncol 40:133-144. https://doi.org/ 10.1007/s13402-016-0308-2
  • Referans12 Chen B, Zhao J, Zhang S, Zhang Y, Huang Z (2016) HPIP promotes gastric cancer cell proliferation through activation of cap-dependent translation. Oncol Rep 36:3664-3672. https://doi.org/10.3892/or.2016.5157
  • Referans13 Coşkun G, Özgür H (2011) Apoptoz ve Nekrozun Moleküler Mekanizması. Çukurova Üniversitesi Tıp Fakültesi Arşiv Kaynak Tarama Dergisi 20:145-158.
  • Referans14 Deep G, Raina K, Singh RP, Oberlies NH, Kroll DJ, Agarwal R (2008) Isosilibinin inhibits advanced human prostate cancer growth in athymic nude mice: comparison with silymarin and silibinin. Int J Can 123:2750-2758. https://doi.org/10.1002/ijc.23879
  • Referans15 Dinçel GÇ, Kul O (2016) Patolojik Apoptozis ve Tanı Yöntemleri. Gümüşhane University Journal of Health Sciences 5:86-108.
  • Referans16 Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495-516. https://doi.org/10.1080/01926230701320337
  • Referans17 Eo HJ, Park GH, Song HM, Lee JW, Kim MK, Lee MH, Lee JR, Koo JS, Jeong JB (2015) Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells. Int Immunopharmacol 24:1-6. https://doi.org/ 10.1016/j.intimp.2014.11.009
  • Referans18 Eröz R, Karataş A, Alkoç OA, Baltaci D, Oktay M, Çolakoğlu S (2012) Apoptozis Hakkında Bilinenler (Literatür Taraması). Düzce Tıp Dergisi 14:87-101.
  • Referans19 Fan L, Ma Y, Liu Y, Zheng D, Huang G (2014) Silymarin induces cell cycle arrest and apoptosis in ovarian cancer cells. Eur J Pharmacol 743:79-88. https://doi.org/10.1016/j.ejphar.2014.09.019
  • Referans20 Fujise Y, Okano J, Nagahara T, Abe R, Imamoto R, Murawaki Y (2012) Preventive effect of caffeine and curcumin on hepato-carcinogenesis in diethylnitrosamine-induced rats. Int J Oncol 40:1779-1788. https://doi.org/10.3892/ijo.2012.1343
  • Referans21 Gopalakrishnan R, Sundaram J, Sattu K, Pandi A, Thiruvengadam D (2013) Dietary supplementation of silymarin is associated with decreased cell proliferation, increased apoptosis, and activation of detoxification system in hepatocellular carcinoma. Mol Cell Biochem 377:163-176. https://doi.org/10.1007/s11010-013-1582-1
  • Referans22 Gupta P, Bansal MP, Koul A (2013) Evaluating the effect of lycopene from Lycopersicum esculentum on apoptosis during NDEA induced hepatocarcinogenesis. Biochem Biophys Res Commun 434:479-485. https://doi.org/10.1016/j.bbrc.2013.03.099
  • Referans23 Imamoto R, Okano JI, Sawada S, Fujise Y, Abe R, Murawaki Y (2014) Null anticarcinogenic effect of silymarin on diethylnitrosamine-induced hepatocarcinogenesis in rats. Exp Ther Med 7:31-38. https://doi.org/10.3892/etm.2013.1391
  • Referans24 Jin Z, El-Deiry WS (2005) Overview of cell death signaling pathways. Cancer Biol Ther 4:139-163. https://doi.org/10.4161/cbt.4.2.1508
  • Referans25 Kaya C, Çalişkan Y, Yönden Z (2012) Apoptozis. Mustafa Kemal Üniversitesi Tıp Dergisi 3: 26-37.
  • Referans26 Man S, Li J, Fan W, Chai H, Liu Z, Gao W (2015) Inhibition of pulmonary adenoma in diethylnitrosamine-induced rats by Rhizoma paridis saponins. J Steroid Biochem Mol Biol 154:62-67. https://doi.org/10.1016/j.jsbmb.2015.07.004
  • Referans27 Mansour MA, Aljoufi MA, Al-Hosaini K, Al-Rikabi AC, Nagi MN (2014) Possible role of selective, irreversible, proteasome inhibitor (carfilzomib) in the treatment of rat hepatocellular carcinoma. Chem Biol Interact 215:17-24. https://doi.org/10.1016/j.cbi.2014.03.001
  • Referans28 Matsuda M, Nakamoto Y, Suzuki S, Kurata T, Kaneko S (2005) Interferon-γ-mediated hepatocarcinogenesis in mice treated with diethylnitrosamine. Lab Invest 85:655-663. https://doi.org/10.1038/labinvest.3700257
  • Referans29 Medhat A, Mansour S, El-Sonbaty S, Kandil E, Mahmoud M (2017) Evaluation of the antitumor activity of platinum nanoparticles in the treatment of hepatocellular carcinoma induced in rats. Tumour Biol 39:1-10. https://doi.org/10.1177/1010428317717259
  • Referans30 Merhan O, Özcan A, Atakişi E, Öğün M, Kükürt A (2016) The Effect of β-carotene on Acute Phase Response in Diethylnitrosamine Given Rabbits. Kafkas Univ Vet Fak Derg 22:533-537. https://doi.org/10.9775/kvfd.2016.14995
  • Referans31 Patial V, S M, Sharma S, Pratap K, Singh D, Padwad YS (2015) Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats. Environ Toxicol Pharmacol 40:445-452. https://doi.org/10.1016/j.etap.2015.07.012
  • Referans32 Raghunandhakumar S, Paramasivam A, Senthilraja S, Naveenkumar C, Asokkumar S, Binuclara J, Jagan S, Anandakumar P, Devaki T (2013) Thymoquinone inhibits cell proliferation through regulation of G1/S phase cell cycle transition in N-nitrosodiethylamine-induced experimental rat hepatocellular carcinoma. Toxicol Lett 223:60-72. https://doi.org/10.1016/j.toxlet.2013.08.018
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  • Referans34 Shirakami Y, Gottesman ME, Blaner WS (2012) Diethylnitrosamine-induced hepatocarcinogenesis is suppressed in lecithin:retinol acyltransferase-deficient mice primarily through retinoid actions immediately after carcinogen administration. Carcinogenesis 33:268-274. https://doi.org/10.1093/carcin/bgr275
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  • Referans36 Sivaramakrishnan V, Niranjali Devaraj S (2009) Morin regulates the expression of NF-kappaB-p65, COX-2 and matrix metalloproteinases in diethylnitrosamine induced rat hepatocellular carcinoma. Chem Biol Interact 180:353-359. https://doi.org/10.1016/j.cbi.2009.02.004
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Toplam 49 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Veteriner Cerrahi
Bölüm Araştırma Makalesi
Yazarlar

Emin Karakurt

Serpil Dağ 0000-0001-7667-689X

Proje Numarası 2016-TS-08
Yayımlanma Tarihi 13 Temmuz 2020
Yayımlandığı Sayı Yıl 2020Cilt: 2 Sayı: 1

Kaynak Göster

APA Karakurt, E., & Dağ, S. (2020). Anticancerogenic Effects of Silymarin on Diethylnitrosamine-Induced Hepatocellular Carcinoma in Wistar Rats. Turkish Veterinary Journal, 2(1), 7-16.
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