DEBIO 1143’ün tek başına veya tamoksifenle kombinasyonunun östrojen reseptörü pozitif meme kanseri hücre hatlarındaki etkisi.

Öz

Amaç: Tamoxifen (TAM) ve DEBIO 1143 (AT-406)’ün artan konsantrasyonlarının tek başına veya birlikte uygulanmasının, MCF-7 ve BT-474 östrojen reseptörü pozitif (ER+) meme kanseri hücre hatlarındaki etkisini araştırmak.

Gereç ve Yöntem: XTT testi, Tamoxifen ve DEBIO 1143’ün tek başına veya birlikte kullanımın 72 saatlik MCF-7 ve BT-474 hücre hatlarındaki hücre canlılığı üzerine olan etkisini belirlemek için kullanıldı. TAM ve DEBIO 1143'ün tek başına / kombinasyonunun her iki hücre hattı üzerindeki etkisini göstermek için çok parametreli apoptoz analiz kiti kullanıldı ve floresan mikroskobik görüntüleme yapıldı.

Bulgular: TAM'ın IC₅₀ değeri MCF-7 ve BT-474 hücre hatlarında sırasıyla 3,8±0,6 mikromolar (µM) ve 18,9±6,7 µM idi. DEBIO 1143'ün IC₅₀ değeri, MCF-7 hücre hattında 15±0,5 uM idi. İlaç kombinasyonuna bağlı sonuçlar her iki hücre hattı için istatistiksel olarak anlamlıydı (p<0,001). Hücre canlılığının azalması apoptozis ile ilişkili bulunmadı.

Sonuç: ER+ meme kanseri hücre hatlarında, kombinasyon halinde uygulanan TAM ve DEBIO 1143 dozlarının, tek başına uygulanmalarına göre hücre canlılığını daha fazla azalttığı belirlenmiştir. Her iki hücre hattında kombinasyon dozlarının uygulanması sinerjik bir etki göstermiştir. Kombine uygulamanın sebep olduğu hücre canlılığındaki azalmanın, apoptoz dışındaki hangi hücre ölüm tipi ile olduğunu belirlemek için ileri araştırmalara ihtiyaç vardır.

Anahtar Kelimeler

• DEBIO 1143,ER + meme kanseri,SMAC mimetik,Tamoxifen

The effect of DEBIO 1143 usage alone or in combination with Tamoxifen on estrogen receptor positive breast cancer cell lines.

Öz

Purpose: To investigate the effect of increased concentrations of Tamoxifen (TAM) and DEBIO 1143 (AT-406) administered alone or in combination on cells in MCF-7 and BT-474 estrogen receptor positive (ER +) breast cancer cell lines.

Materials and Methods: The effect of Tamoxifen and DEBIO 1143 administered alone or in combination on cell viability in MCF-7 and BT-474 cell lines at the 72nd hour was assessed by the XTT test. Multi-parameter apoptosis assay kit was used to display the effect of the alone/combination of TAM and DEBIO 1143 on both cell lines. Fluorescence microscobic analysis was performed.

Results: The IC₅₀ value of TAM was 3.8±0.6 micromolar (µM) and 18.9±6.7 µM in the MCF-7 and BT-474 cell lines, respectively. The IC₅₀ value of DEBIO 1143 was 15±0.5 µM in the MCF-7 cell line. The results related to drug combination were statistically significant for both cell lines (p<0.001). The decrease in cell viability was not associated with apoptosis.

Conclusion: In ER + breast cancer cell lines, the combined doses of the TAM and DEBIO 1143 reduced cell viability more than their administration alone. Combined administrations in both cell lines were concluded in a synergistic effect. Further research is needed to determine which cell death type other than apoptosis is associated with a reduction in cell viability caused by combined administration.

Anahtar Kelimeler

• DEBIO 1143,ER + breast cancer,SMAC mimetic,Tamoxifen

Kaynakça

1. 1. Abotaleb M, Kubatka P, Caprnda M, et al. Chemotherapeutic agents for the treatment of metastatic breast cancer: an update. Biomed Pharmacother 2018 May;101:458-477. doi: 10.1016/j.biopha.2018.02.108.
2. 2. Chen B, Wang Y, Kane SE, Chen S. Improvement of sensitivity to tamoxifen in estrogen receptor-positive and Herceptin-resistant breast cancer cells. J Mol Endocrinol 2008 Nov;41(5):367-377. doi: 10.1677/JME-08-0026.
3. 3. Sun H, Nikolovska-Coleska Z, Yang CY, et al. Design of small-molecule peptidic and nonpeptidic Smac mimetics. Acc Chem Res 2008 Oct;41(10):1264-1277. doi: 10.1021/ar8000553.
4. 4. Brunckhorst MK, Lerner D, Wang S, Yu Q. AT-406, an orally active antagonist of multiple inhibitor of apoptosis proteins, inhibits progression of human ovarian cancer. Cancer Biol Ther 2012 Jul;13(9):804-811.
5. 5.Tuğrul B, İşseven M. SMAC mimetiği olarak AT-406’nın kanserdeki rolü (Role of AT-406 as a SMAC mimetic in cancer). Akd Med J 2018;2:114-119. doi: 10.17954/amj.2018.132.
6. 6. Subik K, Lee JF, Baxter L, et al. The expression patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines. Breast Cancer (Auckl) 2010 May 20;4:35-41. Erratum in: Breast Cancer (Auckl) 2018 Oct 16;12:1178223418806626. PubMed PMID: 20697531.
7. 7. Lasfargues EY, Coutinho WG, Redfield ES. Isolation of two human tumor epithelial cell lines from solid breast carcinomas. J Natl Cancer Inst 1978 Oct;61(4):967-978. PubMed PMID: 212572.
8. 8. Karami-Tehrani F, Salami S. Cell kinetic study of tamoxifen treated MCF-7 and MDA-MB 468 breast cancer cell lines Iranian Biomedical Journal 2003;7(2):51-56.

9. 9. Wang C, Wu P, Shi JF, Jiang ZH, Wei XY. Synthesis and cancer cell growth inhibitory activity of icaritin derivatives. Eur J Med Chem 2015 Jul 15;100:139-150. doi: 10.1016/j.ejmech.2015.06.006.
10. 10. Barrett I, Meegan MJ, Hughes RB, et al. Synthesis, biological evaluation, structural-activity relationship, and docking study for a series of benzoxepin-derived estrogen receptor modulators. Bioorg Med Chem 2008 Nov 1;16(21):9554-9573. doi:10.1016/j.bmc.2008.09.035.
11. 11. Yenigun VB, Ozpolat B, Kose GT. Response of CD44+/CD24-/low breast cancer stem/progenitor cells to tamoxifen‑ and doxorubicin‑induced autophagy. Int J Mol Med 2013 Jun;31(6):1477-1483. doi: 10.3892/ijmm.2013.1342.
12. 12. Kharbanda A, Rajabi H, Jin C, Raina D, Kufe D. Oncogenic MUC1-C promotes tamoxifen resistance in human breast cancer. Mol Cancer Res. 2013 Jul;11(7):714-723. doi: 10.1158/1541-7786.MCR-12-0668.
13. 13. Fernandez-Cuesta L, Anaganti S, Hainaut P, Olivier M. p53 status influences response to tamoxifen but not to fulvestrant in breast cancer cell lines. Int J Cancer 2011 Apr 15;128(8):1813-1821. doi: 10.1002/ijc.25512.
14. 14. Chessari G, Buck IM, Day JE, et al. Fragment-based drug discovery targeting ınhibitor of apoptosis proteins: discovery of a non-alanine lead series with dual activity against cIAP1 and XIAP. J Med Chem 2015 Aug 27;58(16):6574-6588. doi:10.1021/acs.jmedchem.5b00706.
15. 15. Sah NK, Khan Z, Khan GJ, Bisen PS. Structural, functional and therapeutic biology of survivin. Cancer Lett 2006 Dec 8;244(2):164-171. Epub 2006 Apr 18. Review. PubMed PMID: 16621243.
16. 16. Ma L, Huang Y, Song Z, et al. Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway. Cell Death Differ 2006 Dec;13(12):2079-2788. Epub 2006 May 26. PubMed PMID: 16729033.
17. 17. Fandy TE, Shankar S, Srivastava RK. Smac/DIABLO enhances the therapeutic potential of chemotherapeutic drugs and irradiation, and sensitizes TRAIL-resistant breast cancer cells. Mol Cancer 2008 Jun 30;7:60. doi:10.1186/1476-4598-7-60.
18. 18. Stanculescu A, Bembinster LA, Borgen K, Bergamaschi A, Wiley E, Frasor J. Estrogen promotes breast cancer cell survival in an inhibitor of apoptosis (IAP)-dependent manner. Horm Cancer. 2010 Jun;1(3):127-35. doi:10.1007/s12672-010-0018-6.
19. 19. Cai Q, Sun H, Peng Y, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem 2011 Apr 28;54(8):2714-2726. doi: 10.1021/jm101505d.
20. 20. Fristedt Duvefelt C, Lub S, Agarwal P, et al. Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2--implications for a combinatorial treatment. Oncotarget 2015 Aug 21;6(24):20621-20635. PubMed PMID: 26036313.
21. 21. Matzinger O, Viertl D, Tsoutsou P, et al. The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma. Radiother Oncol. 2015 Sep;116(3):495-503. doi:10.1016/j.radonc.2015.05.017.
22. 22. Langdon CG, Wiedemann N, Held MA, et al. SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells. Oncotarget. 2015 Nov 10;6(35):37410-37425. doi: 10.18632/oncotarget.6138.
23. 23. Bursch W, Ellinger A, Kienzl H, et al. Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis. 1996 Aug;17(8):1595-1607. PubMed PMID: 8761415.
24. 24. Paglin S, Hollister T, Delohery T, et al. A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 2001 Jan 15;61(2):439-444. PubMed PMID: 11212227.
25. 25. Zhang GJ, Kimijima I, Onda M, et al. Tamoxifen-induced apoptosis in breast cancer cells relates to down-regulation of bcl-2, but not bax and bcl-X(L), without alteration of p53 protein levels. Clin Cancer Res 1999 Oct;5(10):2971-2977. PubMed PMID: 10537367.
26. 26. Cho KS, Yoon YH, Choi JA, Lee SJ, Koh JY. Induction of autophagy and cell death by tamoxifen in cultured retinal pigment epithelial and photoreceptor cells. Invest Ophthalmol Vis Sci 2012 Aug 9;53(9):5344-5353. doi:10.1167/iovs.12-9827.
27. 27. Graham CD, Kaza N, Klocke BJ, et al. Tamoxifen induces cytotoxic autophagy in glioblastoma. J Neuropathol Exp Neurol 2016 Oct;75(10):946-954. Epub 2016 Aug 11. PubMed PMID: 27516117.
28. 28. Li C, Ip KW, Man WL, et al. Cytotoxic (salen)ruthenium(iii) anticancer complexes exhibit different modes of cell death directed by axial ligands. Chem Sci 2017 Oct 1;8(10):6865-6870. doi:10.1039/c7sc02205k.
29. 29. Hwang JJ, Kim HN, Kim J, et al. Zinc(II) ion mediates tamoxifen-induced autophagy and cell death in MCF-7 breast cancer cell line. Biometals 2010 Dec;23(6):997-1013. doi:10.1007/s10534-010-9346-9.
30. 30. Cekay MJ, Roesler S, Frank T, Knuth AK, Eckhardt I, Fulda S. Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines. Cancer Lett. 2017 Dec 1;410:228-237. doi: 10.1016/j.canlet.2017.09.002.
31. 31. Chen D, Yu J, Zhang L. Necroptosis: an alternative cell death program defending against cancer. Biochim Biophys Acta 2016 Apr;1865(2):228-236. doi: 10.1016/j.bbcan.2016.03.003.
32. 32. Laukens B, Jennewein C, Schenk B, et al. Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor α-induced necroptosis. Neoplasia 2011 Oct;13(10):971-9. PubMed PMID: 22028622.
33. 33. Belz K, Schoeneberger H, Wehner S, et al. Smac mimetic and glucocorticoids synergize to induce apoptosis in childhood ALL by promoting ripoptosome assembly. Blood 2014 Jul 10;124(2):240-250. doi: 10.1182/blood-2013-05-500918.
34. 34. Rohde K, Kleinesudeik L, Roesler S, et al. A Bak-dependent mitochondrial amplification step contributes to Smac mimetic/glucocorticoid-induced necroptosis. Cell Death Differ 2017 Jan;24(1):83-97. doi: 10.1038/cdd.2016.102.
35. 35. Hannes S, Abhari BA, Fulda S. Smac mimetic triggers necroptosis in pancreatic carcinoma cells when caspase activation is blocked. Cancer Lett 2016 Sep28;380(1):31-38. doi: 10.1016/j.canlet.2016.05.036.
36. 36. Bai L, Smith DC, Wang S. Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol Ther 2014 Oct;144(1):82-95. doi: 10.1016/j.pharmthera. 2014.05.007.
37. 37. Jin G, Lan Y, Han F, et al. Smac mimetic‑induced caspase‑independent necroptosis requires RIP1 in breast cancer. Mol Med Rep 2016 Jan;13(1):359-366. doi: 10.3892/mmr.2015.4542.