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Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia

Author

Listed:
  • Limei Wu

    (University of Pittsburgh School of Medicine
    West Virginia University)

  • Srinivas Chatla

    (Lewis Katz School of Medicine at Temple University)

  • Qiqi Lin

    (West Virginia University)

  • Fabliha Ahmed Chowdhury

    (West Virginia University
    University of Pittsburgh School of Medicine)

  • Werner Geldenhuys

    (West Virginia University)

  • Wei Du

    (University of Pittsburgh School of Medicine
    West Virginia University
    University of Pittsburgh School of Medicine
    UPMC Hillman Cancer Center)

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.

Suggested Citation

  • Limei Wu & Srinivas Chatla & Qiqi Lin & Fabliha Ahmed Chowdhury & Werner Geldenhuys & Wei Du, 2021. "Quinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27300-w
    DOI: 10.1038/s41467-021-27300-w
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    1. Cedric S. Tremblay & Jesslyn Saw & Sung Kai Chiu & Nicholas C. Wong & Kirill Tsyganov & Sarah Ghotb & Alison N. Graham & Feng Yan & Andrew A. Guirguis & Stefan E. Sonderegger & Nicole Lee & Paul Kalit, 2018. "Restricted cell cycle is essential for clonal evolution and therapeutic resistance of pre-leukemic stem cells," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    2. Alessandro Di Tullio & Kevin Rouault-Pierre & Ander Abarrategi & Syed Mian & William Grey & John Gribben & Aengus Stewart & Elizabeth Blackwood & Dominique Bonnet, 2017. "The combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    3. Sandrine Etienne-Manneville & Alan Hall, 2002. "Rho GTPases in cell biology," Nature, Nature, vol. 420(6916), pages 629-635, December.
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