α-Tomatin`nin Antiproliferatif Aktivitesi ve Moleküler Hedef Tanımlaması

Domates çeşitlerinden elde edilen bir glikoalkaloid olan α-tomatin`nin çeşitli antikanser özelliklere sahip olduğu bildirilmiştir. Fakat, onun epidermal büyüme faktörü reseptörü üzerindeki inhibitör etkileri hala tam olarak anlaşılamamıştır. Bu çalışma, α-tomatin`nin akciğer kanser hücreleri üzerindeki antikanser etkisi ve ilgili mekanizmalarını araştırmayı amaçlamaktadır. α-tomatin`nin sitotoksisitesi ve apoptoz tetiklenmesi sırasıyla MTT ve anneksin V-FITC boyama yöntemleriyle belirlendi. Tirozin kinaz aktivitesi için, sırasıyla TK-1 kinaz seçicilik profil tahlili ve moleküler modelleme çalışmaları yapıldı. α-tomatin`nin DNA parçalanma aktivitesi, agaroz jel elektroforezi yöntemi kullanılarak araştırıldı. α-tomatin`in A549 ve Jurkat hücrelerine karşı üstün bir antiproliferatif aktiviteye sahip olduğu ve PBMC'de gözle görülür toksisitesinin olmadıgı kanıtlandı. Sonuçlar, α-tomatin`nin hem EGFR hem de HER2 kinazların üzerinde önemli bir inhibisyon etkisine sahip olduğunu gösterdi. α-tomatin, EGFR ve HER2'nin ATP bağlayıcı bölgelerine bazı önemli etkileşimler meydana getirdi. Ayrıca, α-tomatin, düşük konsantrasyonlarda, demir(II) kompleksleri varlığında, DNA`yı güçlü bir şekilde parçalamıştır. Mevcut bulgular α-tomatin`nin erlotinib'den ayırt edici bir reseptör tirozin kinaz inhibisyon profiline sahip olduğunu ve KHDAK tedavisi için potansiyel bir ilaç adayı olabileceğini göstermektedir

Anahtar Kelimeler:

α-Tomatin, Akciğer kanseri

Antiproliferative Activity of α-Tomatine and Molecular Target Identification

α-tomatine is a glycoalkaloid derived from tomato varieties that has been reported to possess various anticancer properties. However, its inhibitory effects on epidermal growth factor receptor is still poorly understood. The aim of this study is to investigate the anticancer effect of α-tomatine and its related mechanisms in lung cancer cells. Cytotoxicity and apoptosis induction of α-tomatine were determined by MTT assay and annexin V-FITC staining methods, respectively. For tyrosine kinase activity, TK-1 kinase selectivity profiling assay and molecular modelling study were performed. The DNA cleavage activity of α-tomatine was investigated using agarose gel electrophoretic method. α-tomatine proved to possess an outstanding antiproliferative activity against A549 and Jurkat cells without noticeable toxicity on PBMC. The results indicated that α-tomatine has a significant inhibition effect on both EGFR and HER2. α-tomatine formed some key interaction into ATP binding sites of EGFR and HER2. Furthermore, α-tomatine strongly disintegrated DNA at low concentrations in the presence of iron(II) complexes. The current findings suggest that α-tomatine has a distinguished receptor tyrosine kinase inhibition profile from erlotinib and might be a potential drug candidate for treatment of NSCLC.

Keywords:

α-Tomatine, Lung cancer,

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