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

Year 2019, , 92 - 102, 20.03.2019
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.

References

  • 1. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA oncology 2017; 3(4):524-548.
  • 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6):394-424.
  • 3. Heiser LM, Sadanandam A, Kuo WL, Benz SC, Goldstein TC, Ng S, et al. Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc Natl Acad Sci USA 2012; 109:2724–2729.
  • 4. Sonnenblick A, Fumagalli D, Sotiriou C, Piccart M. Is the differentiation into molecular subtypes of breast cancer important for staging, local and systemic therapy, and follow up? Cancer Treat Rev 2014; 40:1089-1095.
  • 5. Sharp A, Harper-wynne C. Treatment of advanced breast cancer (ABC): The expanding landscape of targeted therapies. J cancer Biol Res 2014; 2:1-5.
  • 6. Weigelt B, Geyer FC, Reis-Filho JS. Histological types of breast cancer: How special are they? Mol Oncol 2010; 4:192-208.
  • 7. Eroglu A, Çiçek E. Meme kanserinde moleküler alt tiplere göre cerrahi tedavi yaklaşımları. Yeni Tıp Dergisi 2014; 31(2): 83-87.
  • 8. Eliyatkin N, Yalcin E, Zengel B, Aktaş S, Vardar E. Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way. J Breast Heal 2015; 11:59-66.
  • 9. Nguyen DX, Bos PD, Massague J. Metastasis: From dissemination to organ-specific colonization. Nat Rev Cancer 2009; 9:274-284.
  • 10. Lan YC, Chang CL, Sung MT, Yin PH, Hsu CC, Wang KC, et al. Zoledronic acid-induced cytotoxicity through endoplasmic reticulum stress triggered REDD1-mTOR pathway in breast cancer cells. Anticancer Res 2013; 33(9):3807-3814.
  • 11. Winter MC, Holen I, Coleman RE. Exploring the antitumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 2008; 34:453-475.
  • 12. McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 2013; 126:13-20.
  • 13. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet 2002; 359:2018-2026.
  • 14. Neville-Webbe HL, Coleman RE. Bisphosphonates and RANK ligand inhibitors for the treatment and prevention of metastatic bone disease. Eur J Cancer 2010; 46:1211-1222.
  • 15. Bosch-Barrera J, Merajver SD, Menendez JA, Van PC. Direct antitumour activity of zoledronic acid: preclinical and clinical data. Clin Transl Oncol 2011; 13:148-155.
  • 16. Guise TA. Antitumor effects of bisphosphonates: promising preclinical evidence. Cancer Treat Rev 2008; 34 Suppl 1:19-24.
  • 17. Green J, Lipton A. Anticancer properties of zoledronic acid. Cancer Invest 2010; 28:944-957.
  • 18. Zekri J, Mansour M, Karim SM. The anti-tumour effects of zoledronic acid. J bone oncol 2014; 3(1):25-35.
  • 19. Senaratne SG, Pirianov G, Mansi JL, Arnett TR, Colston KW. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 2000; 82(8):1459-1468.
  • 20. Busch M, Rave-Frank M, Hille A, Duhmke E. Influence of clodronate on breast cancer cells in vitro. Eur J Med Res 1998; 3(9):427-431.
  • 21. Ibrahim T, Mercatali L, Sacanna E, Tesei A, Carloni S, Ulivi P, et al. Inhibition of breast cancer cell proliferation in repeated and non-repeated treatment with zoledronic acid. Cancer Cell Int 2012; 12(1):48.
  • 22. Almubarak H, Jones A, Chaisuparat R, Zhang M, Meiller TF, Scheper MA. Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers. J Carcinog 2011; 10: 2.
  • 23. Senaratne SG, Colston KW. Direct effects of bisphosphonates on breast cancer cells. Breast Cancer Res 2012; 4:18-23.
  • 24. Santini D, Virzi V, Fratto ME, Bertoldo F, Sabbatini R, Berardi R, et al. Can we consider zoledronic acid a new antitumor agent? Recent evidence in clinical setting. Curr Cancer Drug Targets 2010; 10(1):46-54.
  • 25. Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, et al. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. The lancet oncology 2014; 15(9): 997-1006.
  • 26. Steinman RA, Brufsky AM, Oesterreich S.Zoledronic acid effectiveness against breast cancer metastases-a role for estrogen in the microenvironment?. Breast Cancer Res 2012; 14(5): 213.
  • 27. Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month followup from the ABCSG-12 randomised trial. Lancet Oncol 2011; 12:631-641.
  • 28. Coleman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011; 365:1396-1405.
  • 29. Hershman DL, McMahon DJ, Crew KD, Cremers S, Irani D, Cucchiara G, et al. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 2008; 26(29):4739-4745.
  • 30. Zhao X, Xu X, Guo L, Ragaz J, Guo H, Wu J, et al. Biomarker alterations with metronomic use of low-dose zoledronic acid for breast cancer patients with bone metastases and potential clinical significance. Breast Cancer Res Treat 2010; 124(3):733-743.
  • 31. Wilson C, Ottewell, P, Coleman RE, Holen I. The differential anti-tumour effects of zoledronic acid in breast cancer–evidence for a role of the activin signaling pathway. BMC cancer 2015; 15(1):55.
  • 32. Jagdev SP, Coleman RE, Shipman CM, Rostami-H A, Croucher PI. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 2001; 84(8):1126.
  • 33. Gschwantler-Kaulich D, Weingartshofer S, Grunt TW, Mairhofer M, Tan Y, Gamper J, et al. Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro. PloS one 2017; 12(9): e0185566.
  • 34. Mani J, Vallo S, Barth K, Makarević J, Juengel E, Bartsch G, et al. Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro. Prostate Cancer Prostatic Dis 2012; 15(3):250.

Zoledronik Asidin Meme Kanseri Alt Tiplerinde Terapötik Etkisinin Değerlendirilmesi

Year 2019, , 92 - 102, 20.03.2019
https://doi.org/10.31832/smj.511954

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.

References

  • 1. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study. JAMA oncology 2017; 3(4):524-548.
  • 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6):394-424.
  • 3. Heiser LM, Sadanandam A, Kuo WL, Benz SC, Goldstein TC, Ng S, et al. Subtype and pathway specific responses to anticancer compounds in breast cancer. Proc Natl Acad Sci USA 2012; 109:2724–2729.
  • 4. Sonnenblick A, Fumagalli D, Sotiriou C, Piccart M. Is the differentiation into molecular subtypes of breast cancer important for staging, local and systemic therapy, and follow up? Cancer Treat Rev 2014; 40:1089-1095.
  • 5. Sharp A, Harper-wynne C. Treatment of advanced breast cancer (ABC): The expanding landscape of targeted therapies. J cancer Biol Res 2014; 2:1-5.
  • 6. Weigelt B, Geyer FC, Reis-Filho JS. Histological types of breast cancer: How special are they? Mol Oncol 2010; 4:192-208.
  • 7. Eroglu A, Çiçek E. Meme kanserinde moleküler alt tiplere göre cerrahi tedavi yaklaşımları. Yeni Tıp Dergisi 2014; 31(2): 83-87.
  • 8. Eliyatkin N, Yalcin E, Zengel B, Aktaş S, Vardar E. Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way. J Breast Heal 2015; 11:59-66.
  • 9. Nguyen DX, Bos PD, Massague J. Metastasis: From dissemination to organ-specific colonization. Nat Rev Cancer 2009; 9:274-284.
  • 10. Lan YC, Chang CL, Sung MT, Yin PH, Hsu CC, Wang KC, et al. Zoledronic acid-induced cytotoxicity through endoplasmic reticulum stress triggered REDD1-mTOR pathway in breast cancer cells. Anticancer Res 2013; 33(9):3807-3814.
  • 11. Winter MC, Holen I, Coleman RE. Exploring the antitumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 2008; 34:453-475.
  • 12. McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, et al. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 2013; 126:13-20.
  • 13. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet 2002; 359:2018-2026.
  • 14. Neville-Webbe HL, Coleman RE. Bisphosphonates and RANK ligand inhibitors for the treatment and prevention of metastatic bone disease. Eur J Cancer 2010; 46:1211-1222.
  • 15. Bosch-Barrera J, Merajver SD, Menendez JA, Van PC. Direct antitumour activity of zoledronic acid: preclinical and clinical data. Clin Transl Oncol 2011; 13:148-155.
  • 16. Guise TA. Antitumor effects of bisphosphonates: promising preclinical evidence. Cancer Treat Rev 2008; 34 Suppl 1:19-24.
  • 17. Green J, Lipton A. Anticancer properties of zoledronic acid. Cancer Invest 2010; 28:944-957.
  • 18. Zekri J, Mansour M, Karim SM. The anti-tumour effects of zoledronic acid. J bone oncol 2014; 3(1):25-35.
  • 19. Senaratne SG, Pirianov G, Mansi JL, Arnett TR, Colston KW. Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer 2000; 82(8):1459-1468.
  • 20. Busch M, Rave-Frank M, Hille A, Duhmke E. Influence of clodronate on breast cancer cells in vitro. Eur J Med Res 1998; 3(9):427-431.
  • 21. Ibrahim T, Mercatali L, Sacanna E, Tesei A, Carloni S, Ulivi P, et al. Inhibition of breast cancer cell proliferation in repeated and non-repeated treatment with zoledronic acid. Cancer Cell Int 2012; 12(1):48.
  • 22. Almubarak H, Jones A, Chaisuparat R, Zhang M, Meiller TF, Scheper MA. Zoledronic acid directly suppresses cell proliferation and induces apoptosis in highly tumorigenic prostate and breast cancers. J Carcinog 2011; 10: 2.
  • 23. Senaratne SG, Colston KW. Direct effects of bisphosphonates on breast cancer cells. Breast Cancer Res 2012; 4:18-23.
  • 24. Santini D, Virzi V, Fratto ME, Bertoldo F, Sabbatini R, Berardi R, et al. Can we consider zoledronic acid a new antitumor agent? Recent evidence in clinical setting. Curr Cancer Drug Targets 2010; 10(1):46-54.
  • 25. Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, et al. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. The lancet oncology 2014; 15(9): 997-1006.
  • 26. Steinman RA, Brufsky AM, Oesterreich S.Zoledronic acid effectiveness against breast cancer metastases-a role for estrogen in the microenvironment?. Breast Cancer Res 2012; 14(5): 213.
  • 27. Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month followup from the ABCSG-12 randomised trial. Lancet Oncol 2011; 12:631-641.
  • 28. Coleman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med 2011; 365:1396-1405.
  • 29. Hershman DL, McMahon DJ, Crew KD, Cremers S, Irani D, Cucchiara G, et al. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 2008; 26(29):4739-4745.
  • 30. Zhao X, Xu X, Guo L, Ragaz J, Guo H, Wu J, et al. Biomarker alterations with metronomic use of low-dose zoledronic acid for breast cancer patients with bone metastases and potential clinical significance. Breast Cancer Res Treat 2010; 124(3):733-743.
  • 31. Wilson C, Ottewell, P, Coleman RE, Holen I. The differential anti-tumour effects of zoledronic acid in breast cancer–evidence for a role of the activin signaling pathway. BMC cancer 2015; 15(1):55.
  • 32. Jagdev SP, Coleman RE, Shipman CM, Rostami-H A, Croucher PI. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 2001; 84(8):1126.
  • 33. Gschwantler-Kaulich D, Weingartshofer S, Grunt TW, Mairhofer M, Tan Y, Gamper J, et al. Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro. PloS one 2017; 12(9): e0185566.
  • 34. Mani J, Vallo S, Barth K, Makarević J, Juengel E, Bartsch G, et al. Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro. Prostate Cancer Prostatic Dis 2012; 15(3):250.
There are 34 citations in total.

Details

Primary Language Turkish
Journal Section Articles
Authors

Gamze Güney Eskiler 0000-0002-2088-9914

Asuman Deveci Özkan

Cemil Bilir

Süleyman Kaleli

Publication Date March 20, 2019
Submission Date January 11, 2019
Published in Issue Year 2019

Cite

AMA Güney Eskiler G, Deveci Özkan A, Bilir C, Kaleli S. Zoledronik Asidin Meme Kanseri Alt Tiplerinde Terapötik Etkisinin Değerlendirilmesi. Sakarya Tıp Dergisi. March 2019;9(1):92-102. doi:10.31832/smj.511954

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