Elucidation of anti-inflammatory and anticancer properties of novel nimesulide derivatives
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Tarih
2020
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Çanakkale Onsekiz Mart Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
İnflamasyon, canlı organizmaların patojenler, hasarlı hücreler veya kötü yaşam koşulları gibi zararlı uyaranlara karşı doğal bir bağışıklık tepkisidir. Uzun süreli inflamasyon artrit, diyabet, astım gibi hastalıkların ortaya çıkması ile ilişkilidir. Bu nedenle, kronik inflamasyonun inhibisyonu çeşitli hastalıklar için alternatif bir terapötik ve önleyici strateji olabilir. Steroid olmayan anti-inflamatuar ilaçlar (NSAID'ler), güçlü analjezik ve anti-inflamatuar etkileri nedeniyle ilaç endüstrisinde en çok reçete edilen ilaç sınıfıdır. Etki mekanizmaları, siklooksijenaz (COX) enzim-aracılı prostaglandin üretiminin inhibisyonuna dayanır. Bununla birlikte, NSAID'lerin uzun süreli kullanımı kardiyovasküler, idrar ve gastrointestinal problem riskini artırır. Bu olumsuz etkilerin altında yatan sebep, istenmeyen COX-1 enzim inhibisyonudur. Daha ileri çalışmalar, COX-2 enzimini inhibe ederken COX-1 enzimini sınırlı bir oranda inhibe eden öncelikli COX inhibitörlerinin, geleneksel NSAID'lere kıyasla güvenli terapötikler olabileceğini göstermiştir. İkincil neden, araşidonik asit metabolizmasında homeostazın lipooksijenaz (LOX) yollarına doğru bozulmasıdır. 5-LOX, inflamatuar yanıtta rol oynayan başka bir enzimdir. 5-LOX yolağının aktivasyonu, gastrointestinala zarar veren aşırı miktarda lökotrien üretimine yol açar. Nimesulid, anti-inflamatuar, analjezik ve antipiretik etkilere sahip kanıtlanmış öncelikli COX-2 inhibitörlerden birisidir. Nimesulidin terapötik etkisi, pro-inflamatuar prostaglandin ve sitokin üretimlerinin inhibisyonuna dayanır. Bu farmakolojik etkilerin dışında, nimesulid reaktif oksijen türleri (ROS), nitrik oksit (NO) ve lökotrien B4 (LTB4) seviyelerini de azaltır. Ayrıca, nimesulid kanser hücrelerinin çoğalmasını, serebral iskemiyi ve NSAID'lerin neden olduğu ülseri inhibe eder. Bu çalışmada amid/sülfonamid içeren on yedi adet yeni nimesulid türevlerinin anti-inflamatuar ve antikanser etkilerinin aydınlatılması amaçlanmıştır. Bu amaçla bütün bileşikler COX-2/COX-1 enzim aktivitesi üzerine etkileri açısından taranmıştır. Buna göre, N8 ve N10 bileşikleri, referans ilaç nimesulid ile karşılaştırıldığında COX-2 enzimi üzerinde daha iyi seçicilik göstermiştir. Ayrıca, hem N8 hem de N10, LPS ile uyarılan COX-2 mRNA ekspresyon seviyesini seçici olarak düşürürken, COX-1 seviyesi makrofajlarda stabil kalmıştır. Makrofaj hücrelerinde hem PGE2 salımı hem de nitrik oksit üretimi N8 ve N10 uygulama grubunda önemli ölçüde baskılanmıştır. Ayrıca bu iki bileşik, IL-l? ve TNF-? seviyesini istatistiksel olarak anlamlı ölçüde düşürmüştür. Türevlerin antikanser özelliklerini belirlemek için yapılan tarama çalışmalarına göre, N17 bileşiği kolon (IC50: 9.24 µM) ve meme (IC50: 11.35 µM) kanser hücresi hatlarında önemli sitotok özellik sergiledi. Özetle, bu sonuçlar N8 ve N10 bileşiklerinin umut verici anti-inflamatuar ajanlar olabileceğini, sitotoksik N17 bileşiği ise daha sonraki potansiyel antikanser ilaç gelişimi öncüsü olarak çalışılabileceğini göstermektedir.
The inflammation indicates the innate immune response of organisms against detrimental stimuli including a variety of pathogens, damaged cells, or even worse living conditions. Prolonged-inflammation is associated with the occurrence of diseases such as arthritis, diabetes, asthma. Thus, inhibition of chronic inflammation could be an alternative therapeutic and preventive strategy for several diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most prescribed drug class in the pharmaceutical industry for their strong analgesic and anti-inflammatory effects. Their action mechanism is based on the inhibition of cyclooxygenase enzymes (COXs)-mediated prostaglandin production. Prolonged use of NSAIDs may promote the risk of cardiovascular, urinary, and gastrointestinal problems. The underlying reason for these adverse effects is the undesirable COX-1 enzyme inhibition. Further studies demonstrated that preferential COX inhibitors, which inhibit the COX-2 enzyme eloquently and COX-1 with at a limited rate, might be safe therapeutics as compared to the non-selective classical NSAIDs. The second reason is the deterioration of homeostasis in arachidonic acid metabolism towards lipoxygenases (LOX) pathways. 5-LOX is another enzyme playing a role in the inflammatory response. Over-activation of 5-LOX leads to an excess amount of gastro-damaging leukotrienes. Nimesulide is one of the proven preferential COX-2 inhibitors which have anti-inflammatory analgesic and antipyretic effects. The therapeutic action of nimesulide is based on the inhibition of pro-inflammatory prostaglandin and cytokine productions. Apart from these pharmacological effects, nimesulide reduces the level of reactive oxygen species (ROS), nitric oxide (NO), and leukotriene B4 (LTB4). Besides, nimesulide inhibits cancer cell proliferation, cerebral ischemia, and NSAIDs-induced ulcer. In this study, the anti-inflammatory and anticancer effects of seventeen novel amide/sulfonamide containing nimesulide derivatives were aimed to be elucidated. With this aim, each compound was tested for its selective COX-2/COX-1 enzyme inhibitory properties. Accordingly the compounds N8 and N10 showed better selectivity on the COX-2 enzyme as compared to the reference drug nimesulide. Moreover, both N8 and N10 selectively reduced the LPS-stimulated COX-2 mRNA expression while the level of COX-1 remained stable in macrophages. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed in the N8 and N10 treatment group. Furthermore, these two compounds reduced the mRNA level of IL-1? and TNF-? statistically significant. Screening efforts to identify anticancer properties of derivatives resulted in compound N17 with considerable cytotoxicity in the colon (IC50: 9.24 µM) and breast (IC50:11.35 µM) cancer cell lines. To sum up, these findings suggest that N8 and N10 could be promising agents with anti-inflammatory properties while cytotoxic N17 might be studied as a lead for subsequent potential anticancer drug development.
The inflammation indicates the innate immune response of organisms against detrimental stimuli including a variety of pathogens, damaged cells, or even worse living conditions. Prolonged-inflammation is associated with the occurrence of diseases such as arthritis, diabetes, asthma. Thus, inhibition of chronic inflammation could be an alternative therapeutic and preventive strategy for several diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most prescribed drug class in the pharmaceutical industry for their strong analgesic and anti-inflammatory effects. Their action mechanism is based on the inhibition of cyclooxygenase enzymes (COXs)-mediated prostaglandin production. Prolonged use of NSAIDs may promote the risk of cardiovascular, urinary, and gastrointestinal problems. The underlying reason for these adverse effects is the undesirable COX-1 enzyme inhibition. Further studies demonstrated that preferential COX inhibitors, which inhibit the COX-2 enzyme eloquently and COX-1 with at a limited rate, might be safe therapeutics as compared to the non-selective classical NSAIDs. The second reason is the deterioration of homeostasis in arachidonic acid metabolism towards lipoxygenases (LOX) pathways. 5-LOX is another enzyme playing a role in the inflammatory response. Over-activation of 5-LOX leads to an excess amount of gastro-damaging leukotrienes. Nimesulide is one of the proven preferential COX-2 inhibitors which have anti-inflammatory analgesic and antipyretic effects. The therapeutic action of nimesulide is based on the inhibition of pro-inflammatory prostaglandin and cytokine productions. Apart from these pharmacological effects, nimesulide reduces the level of reactive oxygen species (ROS), nitric oxide (NO), and leukotriene B4 (LTB4). Besides, nimesulide inhibits cancer cell proliferation, cerebral ischemia, and NSAIDs-induced ulcer. In this study, the anti-inflammatory and anticancer effects of seventeen novel amide/sulfonamide containing nimesulide derivatives were aimed to be elucidated. With this aim, each compound was tested for its selective COX-2/COX-1 enzyme inhibitory properties. Accordingly the compounds N8 and N10 showed better selectivity on the COX-2 enzyme as compared to the reference drug nimesulide. Moreover, both N8 and N10 selectively reduced the LPS-stimulated COX-2 mRNA expression while the level of COX-1 remained stable in macrophages. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed in the N8 and N10 treatment group. Furthermore, these two compounds reduced the mRNA level of IL-1? and TNF-? statistically significant. Screening efforts to identify anticancer properties of derivatives resulted in compound N17 with considerable cytotoxicity in the colon (IC50: 9.24 µM) and breast (IC50:11.35 µM) cancer cell lines. To sum up, these findings suggest that N8 and N10 could be promising agents with anti-inflammatory properties while cytotoxic N17 might be studied as a lead for subsequent potential anticancer drug development.
Açıklama
Lisansüstü Eğitim Enstitüsü, Biyomoleküler Bilimler Ana Bilim Dalı
Anahtar Kelimeler
Biyokimya, Biochemistry, Biyoloji
