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

Year 2019, , 92 - 102, 20.03.2019

Gamze Güney Eskiler , Asuman Deveci Özkan , Cemil Bilir , Süleyman Kaleli

https://doi.org/10.31832/smj.511954

Abstract

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

Zoledronik Asidin Meme Kanseri Alt Tiplerinde Terapötik Etkisinin Değerlendirilmesi

Abstract

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.

Keywords

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

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