Kanser tedavisinde proteozom inhibitörlerinin önemi

Son yıllarda ubikütin-proteozom sistemi, hücre büyümesi ve ölümü arasında denge, insan malignansilerinin ilerlemesi ve kanser hücrelerindeki ilaç direnci gelişimi gibi mekanizmalar için gerekli olarak tanımlanmıştır. Proteozom fonksiyonunun inhibisyonu, anti-kanser terapi için güçlü bir strateji olarak ortaya çıkmıştır. Proteozom’un klinik olarak doğrulanmasının ardından ilk proteozom inhibitörü olan bortezomib, malignant hastalıkların tedavisinde kullanılmaya başlanmış ve farmakolojik olarak geliştirilmiş olan ikinci nesil proteozom inhibitörlerinin keşfedilmesini hızlandırmıştır. Ixazomib, delanzomib, oprozomib ve marizomib gibi ikinci nesil proteozom inhibitörleri, son zamanlarda geliştirilmiş ve klinik olarak test edilmeye başlanmıştır. Bu makale, kanserde terapötik ajan olan proteozom inhibitörinin özelliklerini, yeni nesil proteozom inhibitörlerinin klinikteki ilerlemelerini ve proteozom inhibitörlerinin temel mekanizmasını özellikle NF-?B inhibisyonu yönünden özetlemektedir.

Anahtar Kelimeler:

Bortezomib, Kanser, NF-κB, proteozom inhibitörleri

The importance of proteasome inhibitors in cancer therapy

In recent years the ubiquitin–proteasome system has been identified as essential for maintaining a important balance between cell growth and death, the progression of human malignancies, and the development of drug resistance in cancer. Inhibition of proteasome function has emerged as strong strategy for anti-cancer therapy. Clinical confirmation of the proteasome as a therapeutic target was achieved with bortezomib which is the first proteasome inhibitor to be implemented in the treatment of malignant disease and has prompted the development of a second generation of proteasome inhibitors with improved pharmacological properties. Other novel proteasome inhibitors, such as ixazomib, delanzomib, oprozomib and marizomib, have recently been developed and are being tested in clinical trials. This review summarises the main mechanisms of action of proteasome inhibitors in cancer especially inhibition of NF-?B, the development of proteasome inhibitors as therapeutic agents and the properties and progress of next generation proteasome inhibitors in the clinic.

Keywords:

Bortezomib, cancer, NF-κB, Proteasome inhibitor,

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