D/L-Homosistein Tamoksifene Dirençli MCF-7/TAMR-1 Meme Kanseri Hücrelerinin Proliferatif Özelliklerini ER Stresi Aracılı Olarak Baskılayabilir

Tamoksifen meme kanseri tedavisinde sıklıkla kullanılan ancak reseptör ifade profillerindeki değişimlere bağlı olarak kullanımı sınırlanan önemli bir tedavi yaklaşımıdır. Her ne kadar tamoksifen klinikte yoğun bir uygulama alanına sahip olsa da meme kanseri hastalarının %20-30'u çeşitli nedenlerle de novo veya tedavi sonrasında tamoksifene karşı direnç geliştirmektedir. Meme kanseri, dünya genelinde kadınlar arasında kansere bağlı ölümlerin ikinci nedenidir ve her yıl birçok kişi meme kanseri nedeniyle yaşamını yitirmektedir. Bu nedenle meme kanseri hücrelerinin tamoksifen duyarlılığını arttırmak üzerine çok sayıda çalışma sürdürülmektedir. Son çalışmalar, endoplazmik retikulum (ER) stresine ilişkin mekanizmaların meme kanserinin ilerlemesinde ve kazanılmış ilaç direncinde önemli anahtar düzenleyiciler olduğuna işaret etmiştir. Bu nedenle ER stresini modüle eden ajanlar meme kanserine yönelik geliştirilecek yeni tedavi yaklaşımları için yoğun olarak araştırılmaktadır. Çalışmalarımızda D/L-homosistein’in tamoksifen ile kombine uygulamasının in vitro da tamoksifene direnç gelişimini iyi mimik eden MCF-7/TAMR-1 hücrelerinde ER stresi modülasyonu yolu ile tamoksifen duyarlılığını geliştirdiği belirlenmiştir. Çalışmamızdan elde edilen bulgular meme kanserinde ER stresi ile ilişkili süreçlere etki edebilecek yeni moleküllerin tamoksifen ile kombine edilerek tamoksifen direncine karşı uygulanacak alternatif yaklaşımlar açısından umut vaat ettiğini önermektedir.

Anahtar Kelimeler:

ER stresi, MCF-7/TAMR-1, Meme Kanseri, Tamoksifen

D/L-Homocysteine May Suppress Proliferative Properties of Tamoxifen-resistant MCF-7/TAMR-1 Breast Cancer Cells through Modulation of ER Stress

Tamoxifen is an important treatment approach that is frequently used in the treatment of breast cancer, but its usage is limited due to changes in receptor expression profiles of breast cancer cells. Although tamoxifen has an intense clinical application area, 20-30% of breast cancer patients develop resistance to tamoxifen de novo or after treatment for various reasons. Breast cancer is the second cause of cancer-related death among women worldwide, and many people die from breast cancer each year. For this reason, many studies are continuing to increase the sensitivity of breast cancer cells to tamoxifen. Recent studies have pointed out that mechanisms related to endoplasmic reticulum (ER) stress are important key regulators of breast cancer progression and acquired drug resistance. Thus, agents that modulate ER stress are intensively investigated for new treatment approaches to be developed for cancer. In our studies, combined application of D/L-homocysteine with tamoxifen improves tamoxifen sensitivity of MCF-7/TAMR-1 cells, which well-mimic the development of tamoxifen resistance in vitro by ER stress modulation. Our findings suggest that combined treatment of new molecules that can affect the processes associated with ER stress, with tamoxifen, might be promising alternative approaches to be applied against tamoxifen resistance in breast cancer.

Keywords:

ER stress, MCF-7/TAMR-1, Breast Cancer, Tamoxifen,

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