Nf-kb ve oksidatif stresin inhibisyonu ile peripheral nöropatinin iyileştirilmesi ve kanser kemoterapi sonuçlarının geliştirilmesi
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Date
2017
Authors
Coşkun, Melis Debreli
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Publisher
Uludağ Üniversitesi
Abstract
Pankreas kanseri geleneksel tedavisinde meydana gelen ilaç direnci ve periferik nöropati sebebiyle sağ kalım süresini ve yaşam kalitesini düşürmektedir. Pankreas kanseri tedavisinde daha etkin, direnç geliştirmeyen ve nöropati oluşturmayacak yeni kemoterapötik ve kemopreventiflerin bulunması önem arz etmektedir. Bu tez çalışmasında kemoterapötik ilaçların indüklediği NF-κB/ROS aktivitesi inhibe edilerek, nöropatik ağrı gelişimini azaltmak ve kanser kemoterapi sonuçlarını iyileştirmek amacıyla NDAT, XT199, OT-404 ve EGCG bileşiklerinin etkilerinin klinik öncesi yöntemlerle (in vitro ve in vivo) değerlendirilmesi amaçlanmıştır. Kemoterapötik ilaçların (sisplatin ve gemsitabin) ve LPS'in indüklediği NF-κB/ROS aktivitesi üzerine, αvβ3 integrin reseptör antagonistleri (NDAT ve XT199) ve antioksidanların (EGCG ve OT-404) anti-inflamatuar etkileri HeLa ve THP1 hücrelerinde lusiferaz yöntemi ile araştırıldı. NDAT, XT199, EGCG ve OT-404'ün tek başına ve sisplatin ile kombine halde pankreas kanseri üzerine antitümör etkileri, ortotopik pankreas kanseri fare tümör modelinde, in vivo görüntüleme sistemi (IVIS) ve histopatolojik değerlendirme ile araştırıldı. NDAT, XT199, EGCG ve OT-404'ün tek başına ve sisplatin ile kombine halde anti-inflamatuar etkileri, nöropatik ağrı patogenezinde yer alan NF-κB ile ilişkili sitokinlerin (IL-1, IL-6, IL-10, IL-17, TNF- ve IFN-) ortotopik pankreas tümörlü farelerin plazma örneklerinden Bio-Plex sitokin yöntemi ile analiz edilmesi sonucu belirlendi. NDAT, XT199, EGCG ve OT-404'ün kemoterapinin-indüklediği periferik nöropati (CIPN) üzerindeki nöroprotektif etkilerini belirlemek adına farelerin arka-ayaklarının davranışsal duruş değerlendirmesi yapıldı. Bu tez çalışmasında, NDAT ve XT199'un pankreas kanseri tedavisinde NF-κB sinyal yolağı inhibitörü olarak, antitümör ve anti-inflamatuar etkili potansiyel kemoterapötik ajanlar OT-404'ün ise kemoprotektif bir ajan olabileceği in vitro ve in vivo çalışmalarla gösterilmiştir. Ayrıca bu bileşiklerin geleneksel kemoterapi ile gelişen ilaç direncinin üstesinden geldiği ve CIPN'yi azalttığı da belirlenmiştir. Sonuç olarak bu tez, pankreas kanseri tedavisinde ilaç direncini yıkan, periferik nöropatiyi iyileştiren yeni tedavi seçeneği sunan orijinal bir çalışmadır.
Pancreatic cancer decreases the survival time and the quality of life because of the drug resistance and peripheral neuropathy which occur during the conventional treatment. It is important to find novel, more effective chemotherapeutic and chemopreventive agents which do not lead to drug resistance or neuropathy in the treatment of pancreatic cancer. The aim of this thesis is to evaluate the effect of the compounds NDAT, XT199, OT-404 and EGCG using preclinical methods (in vitro and in vivo) in order to reduce the development of neuropathic pain and to improve the cancer chemotherapy outcomes by inhibiting the NF-κB/ROS activity induced by chemotherapeutic drugs. The anti-inflammatory effects of the αvβ3 integrin receptor antagonists (NDAT and XT199) and antioxidants (EGCG and OT-404) on the NF-κB/ROS activity induced by the chemotherapeutic drugs (cisplatin and gemcitabine) and LPS was studied using the luciferase assay in HeLa and THP1 cells. The antitumor action of NDAT, XT199, EGCG and OT-404, alone and in combination with cisplatin, on the pancreatic cancer was studied in the orthotopic pancreatic cancer mouse tumor model, using in vivo imaging system (IVIS) and histopathology assessment. The anti-inflammatory effects of the NDAT, XT199, EGCG and OT-404, alone and in combination with cisplatin, were evaluated by the analysis of NF-κB-related cytokines (IL-1, IL-6, IL-10, IL-17, TNF- and IFN-) involved in the neuropathic pain pathogenesis, from plasma samples of mice bearing orthotopic pancreatic tumors using Bio-Plex cytokine assay. To determine the neuroprotective effects of NDAT, XT199, EGCG and OT-404 on the chemotherapy-induced peripheral neuropathy (CIPN), the behavioral hind limb posture of mice was evaluated. Using in vitro and in vivo studies, this thesis demonstrates that in the treatment of pancreatic cancer, NDAT and XT199 can be NF-κB signalling pathway inhibitors and the potential chemotherapeutic agents with antitumor and anti-inflammatory effects OT-404 can be a chemoprotective agent. It was also determined that these compounds overcome the drug resistance and reduce CIPN which develop during the conventional chemotherapy. In conclusion, this thesis is an original study offering a novel treatment option which overcomes the drug resistance and ameliorates peripheral neuropathy in the treatment of pancreatic cancer.
Pancreatic cancer decreases the survival time and the quality of life because of the drug resistance and peripheral neuropathy which occur during the conventional treatment. It is important to find novel, more effective chemotherapeutic and chemopreventive agents which do not lead to drug resistance or neuropathy in the treatment of pancreatic cancer. The aim of this thesis is to evaluate the effect of the compounds NDAT, XT199, OT-404 and EGCG using preclinical methods (in vitro and in vivo) in order to reduce the development of neuropathic pain and to improve the cancer chemotherapy outcomes by inhibiting the NF-κB/ROS activity induced by chemotherapeutic drugs. The anti-inflammatory effects of the αvβ3 integrin receptor antagonists (NDAT and XT199) and antioxidants (EGCG and OT-404) on the NF-κB/ROS activity induced by the chemotherapeutic drugs (cisplatin and gemcitabine) and LPS was studied using the luciferase assay in HeLa and THP1 cells. The antitumor action of NDAT, XT199, EGCG and OT-404, alone and in combination with cisplatin, on the pancreatic cancer was studied in the orthotopic pancreatic cancer mouse tumor model, using in vivo imaging system (IVIS) and histopathology assessment. The anti-inflammatory effects of the NDAT, XT199, EGCG and OT-404, alone and in combination with cisplatin, were evaluated by the analysis of NF-κB-related cytokines (IL-1, IL-6, IL-10, IL-17, TNF- and IFN-) involved in the neuropathic pain pathogenesis, from plasma samples of mice bearing orthotopic pancreatic tumors using Bio-Plex cytokine assay. To determine the neuroprotective effects of NDAT, XT199, EGCG and OT-404 on the chemotherapy-induced peripheral neuropathy (CIPN), the behavioral hind limb posture of mice was evaluated. Using in vitro and in vivo studies, this thesis demonstrates that in the treatment of pancreatic cancer, NDAT and XT199 can be NF-κB signalling pathway inhibitors and the potential chemotherapeutic agents with antitumor and anti-inflammatory effects OT-404 can be a chemoprotective agent. It was also determined that these compounds overcome the drug resistance and reduce CIPN which develop during the conventional chemotherapy. In conclusion, this thesis is an original study offering a novel treatment option which overcomes the drug resistance and ameliorates peripheral neuropathy in the treatment of pancreatic cancer.
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Keywords
Pankreas kanseri, NF-κB, Kemoterapi, αvβ3 integrin reseptör antagonisti, Antioksidan, Periferik nöropati, Pancreatic cancer, NF-κB, Chemotherapy, αvβ3 integrin receptor antagonists, Antioxidan, Peripheral neuropathy
Citation
Coşkun, M. D. (2017). Nf-kb ve oksidatif stresin inhibisyonu ile peripheral nöropatinin iyileştirilmesi ve kanser kemoterapi sonuçlarının geliştirilmesi. Yayınlanmamış doktora tezi. Uludağ Üniversitesi Fen Bilimleri Enstitüsü.