Gamze GÜNEY ESKİLER, Asuman DEVECİ ÖZKAN, Cemil BİLİR, Süleyman KALELİ

Zoledronik Asidin Meme Kanseri Alt Tiplerinde Terapötik Etkisinin Değerlendirilmesi

Amaç: Meme kanseri kadınlarda en sık görülen ve farklı alt tiplere ayrılan heterojen bir kanser türüdür. Bu nedenle, meme kanseri alt tiplerine özgü tedavi yaklaşımları dikkat çekmektedir. Mevcut çalışmada, kemik metastazı görülen kanser tiplerinin tedavisinde klinikte kullanılan ve anti-proliferatif, ve anti-metastatik etkiye sahip olduğu bilinen bir bifosfonat inhibitörü zoledronik asitin (ZOL)’ün, iki farklı meme kanseri alt tipinde [MCF-7 (ER+, PR+, HER2-) ve MDA-MB-231 (ER-, PR-, HER2-)] ve HUVEC kontrol hücrelerinde terapötik etkisinin araştırılması amaçlanmıştır. Gereç ve Yöntem: ZOL’ün (10-100 µM) 24 ve 48 saat boyunca sitotoksik ve apoptotik etkisi WST-1, Annexin V ve hücre siklusu analizleri ile belirlenmiştir. Ayrıca ZOL’ün, hücrelerde ve nukleusda neden olduğu morfolojik değişimler sırasıyla akridin oranj (AO) ve DAPI boyaması ile görüntülenmiştir. Bulgular: ZOL’ün MCF-7 hücrelerine göre, MDA-MB-231 hücrelerinde daha fazla anti-proliferatif etkiye ve erken ve geç apoptotik ölüme neden olduğu analiz edilmiştir (p<0.05). Özellikle 50 ve100 µM ZOL uygulanan hücrelerde G0/G1 fazında hücre miktarının anlamlı bir şekilde arttığı saptanmıştır (p<0.05). Bunun yanı sıra, ZOL uygulanan MCF-7 ve MDA-MB-231 hücrelerinde, hücre membran bütünlüğünde bozulma ve kromatin yoğunlaşması gözlemlenmiştir. Ancak, yüksek konsantrasyonlarda ZOL’ün HUVEC hücrelerinde toksik etkiye neden olduğu belirlenmiştir. Sonuç: Sonuç olarak, ZOL’ün farklı meme kanseri alt tiplerinde potansiyel terapötik etkiye sahip olduğu belirlenmekle birlikte, triple negatif meme kanseri (MDA-MB-231) hücrelerinde, hormon duyarlı (MCF-7) hücrelere göre daha fazla sitotoksik etkiye ve apoptotik ölüme neden olduğu tespit edilmiştir. Ancak, ZOL’ün meme kanseri alt tipine bağlı olarak değişen terapötik etkisine neden olan moleküler mekanizmaların ve ideal uygulama protokolünün belirlenmesine yönelik detaylı çalışmalara ihtiyaç bulunmaktadır.

Anahtar Kelimeler:

Meme kanseri, meme kanseri alt tipleri, zoledronik asit, apoptoz

Assessment of the Therapeutic Effects of Zoledronic Acid on Breast Cancer Subtypes

Objective: Breast cancer is a heterogeneous type of cancer with many subtypes and is the most common cancer among women. It is noteworthy that breast cancer subtype-based treatment options have attracted great attention. In the present study, we aimed to investigate the therapeutic effect of a bisphosphonate inhibitor zoledronic acid (ZOL), which is a clinically used in the treatment of cancer types with bone metastases and has been found to exert anti-proliferative and anti-metastatic effects, on two different subtypes of breast cancer [MCF-7 (ER+, PR+, HER2-) and MDA-MB-231 (ER-, PR-, HER2-)] and HUVEC control cells. Materials and Methods: The cytotoxic and apoptotic effect of ZOL (10-100 uM) for 24 and 48 hours was determined by WST-1, Annexin V and cell cycle analysis. In addition, changes in cell morphology and nucleus after treatment with ZOL observed by acridine orange (AO) and DAPI staining, respectively.Results: ZOL caused more anti-proliferative effect and early and late apoptotic death in MDA-MB-231 cells compared with MCF-7 cells (p<0.05). The cell population in G0/G1 phase was significantly increased after treatment with especially 50 and 100 µM ZOL (p <0.05). Additionally, the loss of cell membrane integrity and chromatin condensation were observed in MCF-7 and MDA-MB-231 cells treated with ZOL. However, ZOL had a toxic effect on HUVEC cells at higher concentrations. Conclusion: In conclusion, although ZOL has a potential therapeutic effect on different subtypes of breast cancer, ZOL causes more cytotoxic effects and apoptotic death in triple negative breast cancer (MDA-MB-231) cells than hormone sensitive (MCF-7) cells. However, further studies are needed to determine the molecular mechanisms underlying the therapeutic effect of ZOL depending on subtypes of breast cancer and the optimal schedule and dose of ZOL.

Keywords:

Breast cancer, Breast cancer subtypes, Zoledronic acid, Apoptosis,

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