Sisteinil Lökotrien Reseptör Antagonisti Montelukast'ın Pankreatik Duktal Adenokarsinom Hücrelerinde Antikanserojenik Etkilerinin Araştırılması
Yükleniyor...
Dosyalar
Tarih
2023
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Selçuk Üniversitesi Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Pankreas Kanseri, hızlı metastaz özelliği ile insidansı ve ölüm oranı yüksek olan ciddi bir
hastalıktır. Pankreas kanserinde temel tedavisel yaklaşım kemoterapi ve radyoterapidir ancak kanser
hücrelerinde oluşan direnç mekanizması tedaviyi başarısız kılmaktadır. Bu nedenle hastalığın
ilerlemesinde ve direnç gelişmesinde etkili olan mekanizmaların incelenmesi, bu mekanizmaların
terapötik hedef olarak kullanılabilirliğinin tespit edilmesi önemlidir. Sisteinil lökotrienler çok çeşitli
farmakolojik ve fizyolojik etkinlikleri olan, 5-lipoksijenaz yoluyla araşidonik asitten sentezlenen
proenflamatuar aracılı sinyal molekülleridir. Sisteinil lökotrien sinyalizasyonu plazma membranındaki
CysLT1 ve CysLT2 reseptörlerine agonist bir molekülün bağlanmasıyla gerçekleşir. Enflamasyondaki
rollerine ek olarak CysLT reseptörlerinin karsinogenezden de sorumlu olduğu, birkaç kanser türünde
normal dokulardan daha fazla eksprese edildikleri belirtilmiştir. CysLT1R antagonist tedavisinin, çeşitli
insan kanser hücre hatlarında apoptozu indükleyerek tümör büyümesini inhibe ettiği gösterilmiştir. Bu
çalışmada CysLT1R antagonisti olan Montelukast’ın in vitro kültür ortamında pankreas kanseri
üzerindeki antikanserojenik etkilerinin belirlenmesi hedeflendi. Bu amaçla ilk olarak Montelukast’ın
hücre canlılığına etkisi hücrelerde MTT testi ile belirlenmiş IC50 değerleri bulunmuştur. Montelukast’ın
kanserli olamayan hücrelere etkisini belirlemek için HEK293 hücreleri kullanılmıştır. Hücrelere IC50
dozlarında 48 saat Montelukast uygulaması yapılmış, ardından qRT-PCR ile CYSLTR1, CYSLTR2,
GPR17, GPR99, ERK1/2, COX-2, MYC, HMGB1, TP53, MTOR, BAX, BCL-2, CASP3 genlerinin
kantitatif ekspresyon analizi yapılmıştır. Western Blot ile BAX, BCL-2 ve CASP3 proteinlerinin
ekspresyon analizi yapılmıştır. Sonuç olarak, çalışmamızda elde ettiğimiz veriler ve literatürde yer alan
sonuçlar birlikte değerlendirildiğinde Montelukast’ın hücresel proliferasyonu inhibe ederek pankreas
karsinogenezisini baskıladığı sonucuna ulaşılabilmektedir. Montelukast bu özelliği ile pankreas
karsinogenezinin tedavisi için umut verici potansiyele sahiptir
Pancreatic Cancer is a serious disease with rapid metastasis and high incidence and mortality. The basic therapeutic approach in pancreatic cancer is chemotherapy and radiotherapy, but the resistance mechanism in cancer cells makes the treatment unsuccessful. For this reason, it is important to examine the mechanisms that are effective in the progression of the disease and the development of resistance, and to determine the usability of these mechanisms as therapeutic targets. Cysteinyl leukotrienes are proinflammatory-mediated signaling molecules synthesized from arachidonic acid via 5-lipoxygenase, with a wide variety of pharmacological and physiological activities. Cysteinyl leukotriene signaling occurs by binding of an agonist molecule to the CysLT1 and CysLT2 receptors on the plasma membrane. In addition to their role in inflammation, it has been stated that CysLT receptors are also responsible for carcinogenesis, and they are expressed more than normal tissues in several cancer types. CysLT1R antagonist therapy has been shown to inhibit tumor growth by inducing apoptosis in various human cancer cell lines. In this study, it was aimed to determine the anticarcinogenic effects of Montelukast, a CysLT1R antagonist, on pancreatic cancer in in vitro culture. For this purpose, firstly, the effect of Montelukast on cell viability was determined by IC50 values determined by MTT test in cells. HEK293 cells were used to determine the effect of Montelukast on non-cancerous cells. Montelukast was applied to the cells at IC50 doses for 48 hours, followed by quantitative expression analysis of CYSLTR1, CYSLTR2, GPR17, GPR99, ERK1/2, COX-2, MYC, HMGB1, TP53, MTOR, BAX, BCL-2, CASP3 genes by qRT-PCR. Expression analysis of BAX, BCL-2 and CASP3 proteins was performed by Western Blot. As a result, when the data we obtained in our study and the results in the literature are evaluated together, it can be concluded that Montelukast suppresses pancreatic carcinogenesis by inhibiting cellular proliferation. With this feature, Montelukast has promising potential for the treatment of pancreatic carcinogenesis.
Pancreatic Cancer is a serious disease with rapid metastasis and high incidence and mortality. The basic therapeutic approach in pancreatic cancer is chemotherapy and radiotherapy, but the resistance mechanism in cancer cells makes the treatment unsuccessful. For this reason, it is important to examine the mechanisms that are effective in the progression of the disease and the development of resistance, and to determine the usability of these mechanisms as therapeutic targets. Cysteinyl leukotrienes are proinflammatory-mediated signaling molecules synthesized from arachidonic acid via 5-lipoxygenase, with a wide variety of pharmacological and physiological activities. Cysteinyl leukotriene signaling occurs by binding of an agonist molecule to the CysLT1 and CysLT2 receptors on the plasma membrane. In addition to their role in inflammation, it has been stated that CysLT receptors are also responsible for carcinogenesis, and they are expressed more than normal tissues in several cancer types. CysLT1R antagonist therapy has been shown to inhibit tumor growth by inducing apoptosis in various human cancer cell lines. In this study, it was aimed to determine the anticarcinogenic effects of Montelukast, a CysLT1R antagonist, on pancreatic cancer in in vitro culture. For this purpose, firstly, the effect of Montelukast on cell viability was determined by IC50 values determined by MTT test in cells. HEK293 cells were used to determine the effect of Montelukast on non-cancerous cells. Montelukast was applied to the cells at IC50 doses for 48 hours, followed by quantitative expression analysis of CYSLTR1, CYSLTR2, GPR17, GPR99, ERK1/2, COX-2, MYC, HMGB1, TP53, MTOR, BAX, BCL-2, CASP3 genes by qRT-PCR. Expression analysis of BAX, BCL-2 and CASP3 proteins was performed by Western Blot. As a result, when the data we obtained in our study and the results in the literature are evaluated together, it can be concluded that Montelukast suppresses pancreatic carcinogenesis by inhibiting cellular proliferation. With this feature, Montelukast has promising potential for the treatment of pancreatic carcinogenesis.
Açıklama
Anahtar Kelimeler
Montelukast, Pankreas Kanseri, Sisteinil Lökotrien, Cysteinyl Leukotriene, Pancreatic Cancer
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Mercan, N., (2023). Si̇stei̇ni̇l Lökotri̇en Reseptör Antagoni̇sti̇ Montelukast’ın Pankreati̇k Duktal Adenokarsi̇nom Hücreleri̇nde Anti̇kanserojeni̇k Etki̇leri̇ni̇n Araştırılması. (Yüksek Lisans Tezi). Selçuk Üniversitesi, Sağlık Bilimleri Enstitüsü, Konya.