Year 2020, Volume 6 , Issue 1, Pages 19 - 25 2020-01-04

Reversal effect of quercetin on talazoparib resistance in BRCA1 mutant triple negative breast cancer

Gamze GÜNEY ESKİLER [1] , Gülşah ÇEÇENER [2] , Ünal EGELİ [3] , Berrin TUNCA [4]


Objectives: Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated an outstanding activity in patients with BRCA-mutated and wild-type breast cancer. However, the identification of resistance mechanisms to PARP inhibitors is a significant clinical challenge in effective treatment. Thus, new therapeutic strategies are urgently needed to overcome resistance. The aim of the current study was to explore the potential effect of quercetin on HCC1937 (BRCA1 mutant) and talazoparib (BMN 673), a PARP inhibitor, resistant HCC1937 (HCC1937-R) triple negative breast cancer cells (TNBC).

Methods: We firstly generated BMN 673 resistance HCC1937 cells by continuous exposure to BMN 673 during 6 months. Then, cells were exposed to the different concentration (0-100 µM) of quercetin and the cytotoxic and apoptotic effects of quercetin on these cells were evaluated by WST-1, Annexin V and dual acridine orange-ethidiumbromide (Et-BR) staining.

Results: The cell viability of HCC1937 and HCC1937-R cells reduced to 37.1% and 44.2% at a concentration of 100 μM, respectively for 48 h (p < 0.01). Apoptotic rates of HCC1937 and HCC1937-R cells treated with 100 μM quercetin were nearly 56.0% and 46.0%, respectively (p < 0.01). Additionally, theapoptotic morphologicalchanges were observed in these cells.

Conclusions: In conclusion, the obtained results suggest that quercetin could potentially be used as an alternative therapeutic strategy in BRCA1 mutant TNBC to overcome acquired BMN 673-resistance. 

Triple negative breast cancer, PARP inhibitors, talazoparib (BMN 673), quercetin, apoptosis, BRCA1
  • 1. Curtin NJ, Sharma R. eds. PARP inhibitors for cancer therapy. Humana Press: Cham, 2015.
  • 2. Weil MK, Chen AP. PARP inhibitor treatment in ovarian and breast Ccncer. Curr Probl Cancer 2011;35:7-50.
  • 3. Naipal KAT, van Gent DC. PARP inhibitors : the journey from research hypothesis to clinical approval. Per Med 2015;12:139-54.
  • 4. Lord CJ, Ashworth A. Targeted therapy for cancer using PARP inhibitors. Curr Opin Pharmacol 2008;8:363-9.
  • 5. Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors? Nat Rev Clin Oncol 2018;15:564-76.
  • 6. Sonnenblick A, de Azambuja E, Azim HA Jr, Piccart M. An update on PARP inhibitors -- moving to the adjuvant setting. Nat Rev Clin Oncol 2015;12:27-41.
  • 7. Lim JSJ, Tan DSP. Understanding resistance mechanisms and expanding the therapeutic utility of PARP inhibitors. Cancers (Basel) 2017;9:1-14.
  • 8. Sedukhina AS, Sundaramoorthy E, Hara M, Kumai T, Sato K. Beyond resistance to PARP inhibition: Mechanisms and effective treatment options. Cancer Cell Microenviron 2015;31:14-7.
  • 9. Lord CJ, Ashworth A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat Med 2013;19:1381-8.
  • 10. Murai J, Huang SY, Renaud A, Zhang Y, Ji J, Takeda S, et al. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014;13:433-43.
  • 11. Shen Y, Rehman FL, Feng Y, Boshuizen J, Bajrami I, Elliott R, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res 2013;19:5003-15.
  • 12. de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov 2017;7:620-9.
  • 13. Wainberg ZA, de Bono JS, Mina L, Sachdev J, Byers LA, Chugh R, et al. Update on first-in-man trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. Mol Cancer Ther 2013;12:C295.
  • 14. Engert F, Kovac M, Baumhoer D, Nathrath M, Fulda S. Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics. Oncotarget 2017;8:48794-806.
  • 15. Cardnell RJ, Feng Y, Diao L, Fan YH, Masrorpour F, Wang J, et al. Proteomic markers of DNA repair and PI3K pathway activation predict response to the PARP inhibitor BMN 673 in small cell lung cancer. Clin Cancer Res 2013;19:6322-8.
  • 16. Murai J, Feng Y, Yu GK, Ru Y, Tang S. Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition. Oncotarget 2016;7:76534-550.
  • 17. Kim HJ, Kim SK, Kim BS, Lee SH, Park YS, Park BK, et al. Apoptotic effect of quercetin on HT-29 colon cancer cells via the AMPK signaling pathway. J Agric Food Chem 2010;58:8643-50.
  • 18. Zhang L. Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Mol Med Rep 2012:1453-6.
  • 19. Nguyen LT, Lee YH, Sharma AR, Park JB, Jagga S, Sharma G, et al. Quercetin induces apoptosis and cell cycle arrest in triple-negative breast cancer cells through modulation of Foxo3a activity. Korean J Physiol Pharmacol 2017;21:205-13.
  • 20. Khan F, Niaz K, Maqbool F, Hassan FI, Abdollahi M, Nagulapalli Venkata KC, et al. Molecular targets underlying the anticancer effects of quercetin: an update. Nutrients 2016;8(9). pii:E529.
  • 21. Wang K, Liu R, Li J, Mao J, Lei Y, Wu J, et al. Quercetin induces protective autophagy in gastric cancer cells: Involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling. Autophagy 2011;7:966-78.
  • 22. Lan H, Hong W, Fan P, Qian D, Zhu J, Bai B. Quercetin inhibits cell migration and invasion in human osteosarcoma cells. Cell Physiol Biochem 2017;43:553-67.
  • 23. Hashemzaei M, Far AD, Yari A, Heravi RE, Tabrizian K, Taghdisi SM, et al. Anticancer and apoptosis-inducing effects of quercetin in vitro and in vivo. Oncol Rep 2017;38:819-28.
  • 24. Gong C, Yang Z, Zhang L, Wang Y, Gong W, Liu Y. Quercetin suppresses DNA double-strand break repair and enhances the radiosensitivity of human ovarian cancer cells via p53-dependent endoplasmic reticulum stress pathway. Onco Targets Ther 2017;11:17-27.
  • 25. Srivastava S, Somasagara RR, Hegde M, Nishana M, Tadi SK, Srivastava M, et al. Quercetin, a natural flavonoid interacts with DNA, arrests cell cycle and causes tumor regression by activating mitochondrial pathway of apoptosis. Sci Rep 2016;6:24049.
  • 26. Wang H, Tao L, Qi K, Zhang H, Feng D, Wei W, et al. Quercetin reverses tamoxifen resistance in breast cancer cells. J BUON 2015;20:707-13.
  • 27. Hyun HB, Moon JY, Cho SK. Quercetin suppresses CYR61-mediated multidrug resistance in human gastric adenocarcinoma AGS cells. Molecules 2018;23(2). pii: E209.
  • 28. Tummala R, Lou W, Gao AC, Nadiminty N. Quercetin targets hnRNPA1 to overcome enzalutamide resistance in prostate cancer cells. Mol Cancer Ther 2017;16:2770-9.
  • 29. Oh SJ, Kim O, Lee JS, Kim JA, Kim MR, Choi HS, et al. Inhibition of angiogenesis by quercetin in tamoxifen-resistant breast cancer cells. Food Chem Toxicol 2010;48:3227-34.
  • 30. Xavier CPR, Lima CF, Rohde M, Pereira-Wilson C. Quercetin enhances 5-fluorouracil-induced apoptosis in MSI colorectal cancer cells through p53 modulation. Cancer Chemother Pharmacol 2011;68:1449-57.
  • 31. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 2008;26:3785-90.
  • 32. Rehman FL, Lord CJ, Ashworth A. Synthetic lethal approaches to breast cancer therapy. Nat Rev Clin Oncol 2010;7:718-24.
  • 33. Gelmon K, Dent R, Mackey JR, Laing K, Mcleod D, Verma S. Targeting triple-negative breast cancer: optimising therapeutic outcomes. Ann Oncol 2012;23:2223-34.
  • 34. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382-92.
  • 35. Sinha G. Downfall of iniparib: a PARP inhibitor that doesn’t inhibit PARP after all. J Natl Cancer Inst 2014;106:djt447.
  • 36. Sinha G. Downfall of iniparib: a PARP inhibitor that doesn’t inhibit PARP after all. J Natl Cancer Inst 2014;106:1-2.
  • 37. Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: A phase 1 dose-escalation trial. Lancet Oncol 2013;14:882-92.
  • 38. Drew Y, Ledermann J, Hall G, Rea D, Glasspool R, Highley M, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly (ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer 2016;114:723-30.
  • 39. LoRusso PM, Li J, Burger A, Heilbrun LK, Sausville EA, Boerner SA, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) in combination with irinotecan in patients with advanced solid tumors. Clin Cancer Res 2016;22:3227-37.
  • 40. Rodler ET, Kurland BF, Griffin M, Gralow JR, Porter P, Yeh RF, et al. Phase I study of veliparib (ABT-888) combined with cisplatin and vinorelbine in advanced triple-negative breast cancer and/or BRCA mutation-associated breast cancer. Clin Cancer Res 2016;22:2855-64.
  • 41. Herriott A, Tudhope SJ, Junge G, Rodrigues N, Patterson MJ, Woodhouse L, et al. PARP1 expression, activity and ex vivo sensitivity to the PARP inhibitor, talazoparib (BMN 673), in chronic lymphocytic leukaemia. Oncotarget 2015;6:43978-91.
  • 42. Huang J, Wang L, Cong Z, Amoozgar Z, Kiner E, Xing D, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1−/− murine model of ovarian cancer. Biochem Biophys Res Commun 2015;463:551-6.
  • 43. Koppensteiner R, Samartzis EP, Noske A, von Teichman A, Dedes I, Gwerder M, et al. Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PLoS One 2014;9:e100041.
  • 44. Postel-Vinay S, Bajrami I, Friboulet L, Elliott R, Fontebasso Y, Dorvault N, et al. A high-throughput screen identifies PARP1/2 inhibitors as a potential therapy for ERCC1-deficient non-small cell lung cancer. Oncogene 2013;32:5377-87.
  • 45. Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 2008;451:1111-5.
  • 46. Fojo T, Bates S. Mechanisms of resistance to PARP inhibitors-three and counting. Cancer Discov 2013;3:20-3.
  • 47. Nakagawa Y, Sedukhina AS, Okamoto N, Nagasawa S. NF- κ B signaling mediates acquired resistance after PARP inhibition. Oncotarget 2015;6:3825-39.
  • 48. Montoni A, Robu M, Pouliot E, Shah GM. Resistance to PARP-inhibitors in cancer therapy. Front Pharmacol 2013;4:18.
  • 49. Eskiler GG, Cecener G, Egeli U, Tunca B. A potential therapeutic effects of BMN673, a novel PARP inhibitor, on triple negative breast cancer. The 16th European Microscopy Congress, Lyon, France, 2016. Proceedings 2016:Abstract no.5883.
  • 50. Guney Eskiler G. Investigation of the role of PARP inhibitors loaded solid lipid nanoparticles on overcoming drug resistance mechanisms in triple negative breast cancer treatment. PhD Thesis. Uludag University, Bursa, 2017.
  • 51. Su C, Haskins AH, Omata C, Aizawa Y, Kato TA. PARP inhibition by flavonoids induced selective cell killing to BRCA2-deficient cells. Pharmaceuticals (Basel) 2017;10(4). pii: E80.
  • 52. Maeda J, Roybal EJ, Brents CA, Uesaka M, Aizawa Y, Kato TA. Natural and glucosyl flavonoids inhibit poly(ADP-ribose) polymerase activity and induce synthetic lethality in BRCA mutant cells. Oncol Rep 2014;31:551-6.
Primary Language en
Subjects Biochemistry and Molecular Biology, Oncology, Cell Biology
Journal Section Original Articles
Authors

Orcid: 0000-0002-2088-9914
Author: Gamze GÜNEY ESKİLER (Primary Author)
Institution: Department of Medical Biology, Sakarya University School of Medicine, Sakarya, Turkey
Country: Turkey


Orcid: 0000-0002-3820-424X
Author: Gülşah ÇEÇENER
Institution: Department of Medical Biology, Uludağ University School of Medicine, Bursa, Turkey
Country: Turkey


Orcid: 0000-0001-7904-883X
Author: Ünal EGELİ
Institution: Department of Medical Biology, Uludağ University School of Medicine, Bursa, Turkey
Country: Turkey


Orcid: 0000-0002-1619-6680
Author: Berrin TUNCA
Institution: Department of Medical Biology, Uludağ University School of Medicine, Bursa, Turkey
Country: Turkey


Dates

Publication Date : January 4, 2020

EndNote %0 The European Research Journal Reversal effect of quercetin on talazoparib resistance in BRCA1 mutant triple negative breast cancer %A Gamze GÜNEY ESKİLER , Gülşah ÇEÇENER , Ünal EGELİ , Berrin TUNCA %T Reversal effect of quercetin on talazoparib resistance in BRCA1 mutant triple negative breast cancer %D 2020 %J The European Research Journal %P -2149-3189 %V 6 %N 1 %R doi: 10.18621/eurj.454176 %U 10.18621/eurj.454176