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Wu L, Chatla S, Lin Q, et al. Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia. Nat Commun. 2021;12(1):6936doi: 10.1038/s41467-021-27300-w.
Wu, L., Chatla, S., Lin, Q., Chowdhury, F. A., Geldenhuys, W., & Du, W. (2021). Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia. Nature communications, 12(1), 6936. https://doi.org/10.1038/s41467-021-27300-w
Wu, Limei, et al. "Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia." Nature communications vol. 12,1 (2021): 6936. doi: https://doi.org/10.1038/s41467-021-27300-w
Wu L, Chatla S, Lin Q, Chowdhury FA, Geldenhuys W, Du W. Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia. Nat Commun. 2021 Nov 26;12(1):6936. doi: 10.1038/s41467-021-27300-w. PMID: 34836965; PMCID: PMC8626516.
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Nat Commun. 2021 Nov 26;12(1):6936. doi: 10.1038/s41467-021-27300-w.

Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia.

Nature communications

Limei Wu, Srinivas Chatla, Qiqi Lin, Fabliha Ahmed Chowdhury, Werner Geldenhuys, Wei Du

Affiliations

  1. Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, USA.
  2. Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA.
  3. Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA.
  4. Molecular Pharmacology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, USA.
  5. Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, USA. [email protected].
  6. Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, 26506, USA. [email protected].
  7. Molecular Pharmacology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, USA. [email protected].
  8. UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA. [email protected].

PMID: 34836965 PMCID: PMC8626516 DOI: 10.1038/s41467-021-27300-w

Abstract

Chemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of Cdc42 Activity Specific Inhibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.

© 2021. The Author(s).

References

  1. PeerJ. 2015 Oct 06;3:e1314 - PubMed
  2. Clin Cancer Res. 2011 May 15;17(10):3248-58 - PubMed
  3. Oncotarget. 2015 Nov 3;6(34):36354-69 - PubMed
  4. Cancer Res. 1979 Jan;39(1):42-9 - PubMed
  5. Cell Death Dis. 2013 Oct 10;4:e838 - PubMed
  6. J Hematol Oncol. 2016 Oct 24;9(1):114 - PubMed
  7. J Exp Clin Cancer Res. 2018 Nov 1;37(1):266 - PubMed
  8. Genes Dev. 1997 Sep 15;11(18):2295-322 - PubMed
  9. Signal Transduct Target Ther. 2020 Dec 18;5(1):288 - PubMed
  10. J Biol Chem. 2010 Jun 18;285(25):19162-72 - PubMed
  11. Leukemia. 2010 Oct;24(10):1785-8 - PubMed
  12. Oncotarget. 2020 May 05;11(18):1603-1617 - PubMed
  13. Cell Death Dis. 2018 May 22;9(6):589 - PubMed
  14. Ann Hematol. 2006 Oct;85(10):717-22 - PubMed
  15. Leuk Lymphoma. 2003 Mar;44(3):391-409 - PubMed
  16. Nature. 2002 Dec 12;420(6916):629-35 - PubMed
  17. Blood. 2011 Apr 21;117(16):4243-52 - PubMed
  18. Oncotarget. 2015 Dec 8;6(39):41600-19 - PubMed
  19. Eur J Cancer. 1998 Feb;34(3):296-306 - PubMed
  20. Cancer Discov. 2017 Jul;7(7):716-735 - PubMed
  21. Blood. 2015 Jan 29;125(5):767-74 - PubMed
  22. Blood. 2020 Jan 23;135(4):252-260 - PubMed
  23. React Oxyg Species (Apex). 2016;2(5):361-370 - PubMed
  24. Cell Chem Biol. 2016 Mar 17;23(3):415-25 - PubMed
  25. Cancer. 1997 May 15;79(10):2045-51 - PubMed
  26. JAMA. 1982 Nov 19;248(19):2481-6 - PubMed
  27. Int J Oncol. 2011 Apr;38(4):911-9 - PubMed
  28. Leukemia. 2017 Feb;31(2):423-433 - PubMed
  29. Blood Cancer J. 2015 Apr 17;5:e307 - PubMed
  30. Clin Cancer Res. 2013 Apr 1;19(7):1637-43 - PubMed
  31. Oncotarget. 2017 Feb 14;8(7):12234-12246 - PubMed
  32. Antimicrob Agents Chemother. 2019 Aug 23;63(9): - PubMed
  33. Oncol Lett. 2019 Oct;18(4):4317-4327 - PubMed
  34. Leukemia. 2019 Mar;33(3):749-761 - PubMed
  35. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5091-6 - PubMed
  36. Toxicol Appl Pharmacol. 2015 Apr 1;284(1):33-41 - PubMed
  37. Leukemia. 2016 Aug;30(8):1691-700 - PubMed
  38. Leuk Res. 2017 Dec;63:41-46 - PubMed
  39. Sci Rep. 2020 Nov 2;10(1):18850 - PubMed
  40. Leukemia. 2020 Nov;34(11):3028-3041 - PubMed
  41. Leukemia. 2018 Sep;32(9):2041-2046 - PubMed
  42. Curr Drug Targets. 2003 Aug;4(6):443-60 - PubMed
  43. Leukemia. 2014 Jan;28(1):203-6 - PubMed
  44. Cancer Discov. 2011 Nov;1(6):469-71 - PubMed
  45. Anticancer Res. 2015 Oct;35(10):5667-70 - PubMed
  46. Nat Commun. 2017 Nov 22;8(1):1679 - PubMed
  47. Blood. 2012 May 3;119(18):4162-73 - PubMed
  48. Nat Commun. 2018 Aug 30;9(1):3535 - PubMed
  49. Mutat Res. 2001 Jul 25;494(1-2):41-53 - PubMed
  50. Semin Oncol. 1992 Dec;19(6):695-706 - PubMed
  51. Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17448-53 - PubMed
  52. Stem Cells Transl Med. 2014 Apr;3(4):520-9 - PubMed
  53. Eur J Haematol. 2006 Oct;77(4):293-9 - PubMed
  54. Exp Hematol. 2013 Jul;41(7):597-603.e2 - PubMed
  55. Blood. 2007 Mar 1;109(5):2256-62 - PubMed
  56. Blood. 2002 Sep 1;100(5):1828-34 - PubMed
  57. Front Oncol. 2013 May 16;3:120 - PubMed
  58. Curr Med Chem. 2001 Nov;8(13):1543-72 - PubMed
  59. Blood. 2017 Mar 16;129(11):e26-e37 - PubMed
  60. Cancer Treat Rep. 1977 Sep;61(6):1109-16 - PubMed
  61. BMC Infect Dis. 2004 Nov 29;4:53 - PubMed
  62. Klin Padiatr. 1999 Jul-Aug;211(4):239-44 - PubMed
  63. Leukemia. 2001 Dec;15(12):1892-7 - PubMed
  64. J Immunol. 2013 Sep 1;191(5):2806-17 - PubMed
  65. Blood. 2007 Dec 1;110(12):3853-61 - PubMed
  66. Toxicol Appl Pharmacol. 2017 Nov 1;334:35-46 - PubMed
  67. Leuk Res. 2000 Jun;24(6):535-41 - PubMed
  68. Expert Opin Pharmacother. 2017 Aug;18(11):1081-1099 - PubMed
  69. Biochem Pharmacol. 2005 Aug 1;70(3):426-32 - PubMed
  70. Cancer Chemother Pharmacol. 2007 May;59(6):771-9 - PubMed
  71. Blood. 2005 Sep 1;106(5):1867-74 - PubMed

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