HEPATOSELÜLER KARSİNOMDA KUKURBİTASİN D VE I İLE SORAFENİBİN ONKOJENİK SİNYAL YOLAKLARI BAĞLAMINDA ETKİLEŞİMİ
Özet
Hepatoselüler karsinom (HCC), çok sayıda onkojenik sinyal yolağının eş zamanlı olarak düzensizleştiği, yüksek mortalite ve tedavi direnci ile karakterize kompleks bir malignitedir. HCC gelişimi ve progresyonunda özellikle Ras/Raf/MEK/ERK ve PI3K/Akt/mTOR sinyal yolakları; hücre proliferasyonu, sağkalım, apoptoz, anjiyogenez, invazyon ve tedavi direncinin düzenlenmesinde merkezi rol oynamaktadır. Çoklu tirozin kinaz inhibitörü sorafenib, bu sinyal ağlarını ve VEGFR/PDGFR aracılı anjiyogenezi hedefleyen önemli bir sistemik ajan olmakla birlikte, gelişen ilaç direnci ve sınırlı tedavi yanıtı kombinasyon stratejilerine olan ilgiyi artırmıştır. Kukurbitasinler, çoklu moleküler hedefleri modüle edebilen ve antiproliferatif, proapoptotik, antianjiyojenik ve antimetastatik özellikler gösteren doğal triterpenoid bileşiklerdir. Bu derlemede, HCC’nin moleküler patogenezi ve sorafenibin etki mekanizması temelinde, kukurbitasin D ve kukurbitasin I’in antikanser özellikleri ile sorafenib ve diğer antikanser ajanlarla kombinasyon potansiyelleri değerlendirilmiştir. Özellikle EGFR/VEGF aracılı sinyal ile Ras/Raf/MEK/ERK ve PI3K/Akt/mTOR eksenlerinin eş zamanlı hedeflenmesinin, antitümöral etkinliğin artırılması ve tedavi direncinin sınırlandırılması açısından önemi ele alınmıştır. Mevcut bulgular, kukurbitasin D ve I’in sorafenibin antitümöral etkilerini tamamlayabilecek umut verici doğal bileşikler olduğunu düşündürmektedir. Bununla birlikte, bu kombinasyonların terapötik potansiyelinin ortaya konulabilmesi için farklı hücresel modeller, in vivo çalışmalar ve klinik araştırmalarla doğrulanması gerekmektedir.
Anahtar Kelimeler: Hepatoselüler karsinom; kukurbitasin D; kukurbitasin I; sorafenib; Ras/Raf/MEK/ERK; PI3K/Akt/mTOR; kombinasyon tedavisi.
Konu Alanı: Biyoloji -> Biyoloji (diğer) -> Biyokimya
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