Synergistic combination of doxorubicin with hydralazine, and disulfiram against MCF-7 breast cancer cell line.

Zainab Lafi, Walhan Alshaer, Lobna Gharaibeh, Dana A Alqudah, Baidaa AlQuaissi, Banan Bashaireh, Abed Alqader Ibrahim
Author Information
  1. Zainab Lafi: Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan.
  2. Walhan Alshaer: Cell Therapy Center, The University of Jordan, Amman, Jordan. ORCID
  3. Lobna Gharaibeh: Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan.
  4. Dana A Alqudah: Cell Therapy Center, The University of Jordan, Amman, Jordan.
  5. Baidaa AlQuaissi: Cell Therapy Center, The University of Jordan, Amman, Jordan.
  6. Banan Bashaireh: Cell Therapy Center, The University of Jordan, Amman, Jordan.
  7. Abed Alqader Ibrahim: Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, University of North Carolina at Greensboro, Greensboro, NC, United States of America.

Abstract

Disulfiram and hydralazine have recently been reported to have anti-cancer action, and repositioned to be used as adjuvant in cancer therapy. Chemotherapy combined with other medications, such as those that affect the immune system or epigenetic cell profile, can overcome resistance with fewer adverse effects compared to chemotherapy alone. In the present study, a combination of doxorubicin (DOX) with hydrazine (Hyd) and disulfiram (Dis), as a triple treatment, was evaluated against wild-type and DOX-resistant MCF-7 breast cancer cell line. Both wild-type MCF-7 cell line (MCF-7_WT) and DOX-resistant MCF-7 cell line (MCF-7_DoxR) were treated with different combination ratios of DOX, Dis, and Hyd followed by measuring the cell viability using the MTT assay. Synergism was determined using a combination index, isobologram analysis, and dose-reducing index. The anti-proliferation activity and mechanism of the triple combination were investigated by apoptosis analysis. The results showed a reduction in the IC50 values of DOX in MCF-7_WT cells (from 0.24 μM to 0.012 μM) and MCF-7_DoxR cells (from 1.13 μM to 0.44 μM) when treated with Dis (0.03μM), and Hyd (20μM) combination. Moreover, The triple combination DOX/Hyd/Dis induced significant apoptosis in both MCF-7_WT and MCF-7_DoxR cells compared to DOX alone. The triple combination of DOX, Dis, and Hyd showed a synergistic drugs combination to decrease the DOX dose needed to kill both MCF-7_WT and MCF-7_DoxR cancer cells and enhanced chemosensitivity to DOX.

References

  1. Proc Am Thorac Soc. 2005;2(4):282-9; discussion 290-1 [PMID: 16267349]
  2. Int J Mol Sci. 2019 Sep 26;20(19): [PMID: 31561494]
  3. Cold Spring Harb Perspect Biol. 2016 Sep 01;8(9): [PMID: 27194046]
  4. PLoS One. 2014 Feb 10;9(2):e87366 [PMID: 24520330]
  5. Trends Pharmacol Sci. 2019 Oct;40(10):774-789 [PMID: 31515079]
  6. Oncol Rep. 2017 Nov;38(5):2587-2596 [PMID: 29048620]
  7. Oncotarget. 2017 Jun 6;8(23):38022-38043 [PMID: 28410237]
  8. Cancer Drug Resist. 2019;2:141-160 [PMID: 34322663]
  9. Int J Mol Sci. 2021 May 10;22(9): [PMID: 34068765]
  10. Cancers (Basel). 2020 Jan 09;12(1): [PMID: 31936526]
  11. Nature. 2004 May 27;429(6990):457-63 [PMID: 15164071]
  12. Int J Breast Cancer. 2013;2013:137414 [PMID: 23864953]
  13. Clin Epigenetics. 2019 Dec 2;11(1):174 [PMID: 31791394]
  14. Exp Mol Med. 2017 Apr 28;49(4):e321 [PMID: 28450735]
  15. Exp Mol Med. 2020 Feb;52(2):192-203 [PMID: 32060354]
  16. Front Pharmacol. 2022 Dec 16;13:1072651 [PMID: 37077808]
  17. Methods Mol Biol. 2010;596:467-88 [PMID: 19949937]
  18. Mar Drugs. 2019 Sep 16;17(9): [PMID: 31527453]
  19. Cancers (Basel). 2018 Dec 04;10(12): [PMID: 30518036]
  20. Ann Oncol. 2007 Sep;18(9):1529-38 [PMID: 17761710]
  21. Nat Med. 2012 Nov;18(11):1639-42 [PMID: 23104132]
  22. Biomed Pharmacother. 2016 Oct;83:397-406 [PMID: 27424321]
  23. Front Pharmacol. 2013 Aug 01;4:89 [PMID: 23914174]
  24. CA Cancer J Clin. 2021 May;71(3):209-249 [PMID: 33538338]
  25. Cell. 1994 Aug 26;78(4):539-42 [PMID: 8069905]
  26. PLoS One. 2022 Apr 6;17(4):e0265497 [PMID: 35385506]
  27. Sci Rep. 2020 Feb 26;10(1):3470 [PMID: 32103105]
  28. Cancer Drug Resist. 2020 Mar 19;3(1):113-116 [PMID: 35582041]
  29. Anticancer Agents Med Chem. 2016;16(11):1378-1384 [PMID: 27141876]
  30. Cell Cycle. 2013 Sep 15;12(18):3013-24 [PMID: 23974104]
  31. Br J Cancer. 2013 Oct 1;109(7):1876-85 [PMID: 24008666]
  32. Asia Pac J Clin Oncol. 2022 Feb;18(1):19-27 [PMID: 32964588]
  33. Nucleic Acids Res. 2023 Jan 6;51(D1):D638-D646 [PMID: 36370105]
  34. Biochem J. 2019 Apr 10;476(7):1083-1104 [PMID: 30971458]
  35. Anticancer Res. 2016 Jan;36(1):1-4 [PMID: 26722021]
  36. Cell Biosci. 2019 Jun 18;9:50 [PMID: 31244991]
  37. Int J Mol Sci. 2020 May 02;21(9): [PMID: 32370233]
  38. Front Oncol. 2020 Nov 18;10:605386 [PMID: 33312959]
  39. PLoS One. 2006 Dec 20;1:e98 [PMID: 17183730]
  40. J Exp Clin Cancer Res. 2019 Apr 8;38(1):150 [PMID: 30961642]
  41. Int J Mol Sci. 2019 Jul 28;20(15): [PMID: 31357721]
  42. J Transl Med. 2006 Feb 28;4:10 [PMID: 16507100]
  43. Oncotarget. 2016 Apr 19;7(16):21875-86 [PMID: 26942461]
  44. Breast. 2022 Dec;66:15-23 [PMID: 36084384]
  45. Cancer Drug Resist. 2019 Jun 19;2(2):297-312 [PMID: 35582717]
  46. Mol Cancer Ther. 2007 Mar;6(3):1089-98 [PMID: 17363502]
  47. Front Oncol. 2020 Mar 05;10:265 [PMID: 32195185]
  48. JAMA. 2019 Jan 22;321(3):288-300 [PMID: 30667505]
  49. Mol Cancer Ther. 2002 Jan;1(3):197-204 [PMID: 12467214]
  50. BMC Cell Biol. 2011 Jan 13;12:2 [PMID: 21226962]
  51. Ann Transl Med. 2016 Dec;4(24):518 [PMID: 28149880]
  52. J Transl Med. 2006 Aug 07;4:32 [PMID: 16893460]
  53. Signal Transduct Target Ther. 2023 Feb 17;8(1):70 [PMID: 36797231]
  54. Biomater Sci. 2020 Jun 21;8(12):3310-3319 [PMID: 32400782]
  55. Drug Discov Today. 2020 Jun;25(6):1099-1108 [PMID: 32320854]
  56. Adv Exp Med Biol. 2017;1026:59-104 [PMID: 29282680]
  57. Biomed Pharmacother. 2020 Jun;126:110048 [PMID: 32145587]
  58. Front Oncol. 2022 Jun 23;12:891652 [PMID: 35814435]
  59. Int J Pharm. 2020 Apr 30;580:119191 [PMID: 32142738]
  60. Sci Rep. 2016 Mar 10;6:22847 [PMID: 26961701]
  61. Ann Oncol. 2009 May;20(5):816-27 [PMID: 19153118]
  62. Biochim Biophys Acta Rev Cancer. 2023 May;1878(3):188866 [PMID: 36842765]
  63. Redox Biol. 2021 Oct;46:102122 [PMID: 34482117]
  64. Oncotarget. 2015 Dec 1;6(38):40907-19 [PMID: 26517513]
  65. Front Cell Dev Biol. 2021 Apr 20;9:645518 [PMID: 33959607]

Word Cloud

Created with Highcharts 10.0.0combinationDOXcellcancerHydDistripleMCF-7lineMCF-7_WTMCF-7_DoxRcells0μMhydralazinecomparedalonedoxorubicindisulfiramwild-typeDOX-resistantbreasttreatedusingindexanalysisapoptosisshowedDisulfiramrecentlyreportedanti-canceractionrepositionedusedadjuvanttherapyChemotherapycombinedmedicationsaffectimmunesystemepigeneticprofilecanovercomeresistancefeweradverseeffectschemotherapypresentstudyhydrazinetreatmentevaluateddifferentratiosfollowedmeasuringviabilityMTTassaySynergismdeterminedisobologramdose-reducinganti-proliferationactivitymechanisminvestigatedresultsreductionIC50values240121134403μM20μMMoreoverDOX/Hyd/DisinducedsignificantsynergisticdrugsdecreasedoseneededkillenhancedchemosensitivitySynergistic

Similar Articles

Cited By