Variation in Cellular Responses to Anti-mitotic Drug-Induced Prolonged Mitotic Arrest

Year 2017, , 134 - 143, 01.09.2017

Pınar Buket Atalay Ayşenur Aydın

https://doi.org/10.5505/abantmedj.2017.50103

Abstract

Anti-mitotic drugs, which are successfully used in cancer treatment today, trigger chronic activation of the “Spindle Assembly Checkpoint SAC ” by targeting microtubules. Chronic activation of the SAC induced by anti-mitotic drugs causes a prolonged mitotic arrest in all cancer cell lines tested. However, there is not a single cellular response to the prolonged arrest. In other words, cells can undergo different fates following the prolonged arrest. Therefore, cells from different cancer types, even cells from the same cancer type in different patients may differ greatly by their susceptibilities to anti-mitotic drugs. The variation in cellular responses to these drugs presents a serious problem in cancer treatment. Therefore, understanding the molecular basis of the cell fate determination following the prolonged arrest might provide important information to develop more successful strategies in cancer treatment. Here, we review the SAC as a pathway activated by anti-mitotic drugs as well as its role in cancer. We also discuss the different cell fates following the prolonged arrest induced by these drugs and describe a recently proposed model to explain how cells may commit to a certain cell fate.

Keywords

Anti-mitotic drugs, Spindle assembly checkpoint, Cancer, Cell fate

Anti-mitotik İlaçla Tetiklenen Uzun Süreli Mitotik Areste Hücresel Yanıtın Çeşitliliği

Abstract

Günümüzde kanser tedavisinde başarıyla kullanılan anti-mitotik ilaçlar, mikrotübülleri hedef alarak “İğ İpliği Kontrol Noktası İKN ” nın kronik aktivasyonunu tetikler. Anti-mitotik ilaçlarla tetiklenen kronik İKN aktivasyonu, bu güne kadar test edilen tüm hücre hatlarında uzun süreli mitotik-areste yol açmıştır. Ancak, uzun süreli mitotik areste karşı oluşan tek tip bir hücresel cevap bulunmamaktadır. Diğer bir deyişle, hücreler uzun süreli mitotik aresti takiben farklı post-mitotik kaderlere maruz kalabilirler. Bu nedenle, farklı kanser tiplerindeki hücreler, hatta farklı hastalara ait aynı kanser tipindeki hücreler anti-mitotik ilaçlara gösterdikleri hassasiyet açısından büyük farklılıklar gösterebilirler. Bu ilaçlara karşı gösterilen hücresel cevaplardaki çeşitlilik kanser tedavisinde ciddi bir sorun teşkil etmektedir. Bu nedenle, uzun süreli mitotik aresti takiben hangi hücre kaderine teslim olunacağı kararının moleküler temellerinin iyi anlaşılması kanser tedavisinde daha başarılı stratejiler geliştirebilmek için oldukça önemli bilgiler sağlayabilir. Bu derlemede, İKN’yi antimitotik ilaçlarla aktive olan bir sinyal yolağı olarak ve kanserdeki rolü açısından değerlendirdik. Ayrıca, anti-mitotik ilaçlarla tetiklenen uzun süreli mitotik aresti takip eden farklı hücre kaderlerinin neler olduğunu ve bunların arasından hücrelerin nasıl belirli bir kadere teslim olduğunu açıklayan yeni bir modeli tartıştık.

Keywords

Anti-mitotik ilaçlar, İğ ipliği kontrol noktası, Kanser, Hücre kaderi

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