Echinomycin Protects Mice Against Relapsed Acute Myeloid Leukemia Without Adverse Effect on Hematopoietic Stem Cells

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2014 Jul 5

PMID 24994068

Citations 32

Authors

Yin Wang

Yan Liu

Fei Tang

Kelsie M Bernot

Reuven Schore

Guido Marcucci

Michael A Caligiuri

Pan Zheng

Yang Liu

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukemia (AML) often relapses following chemotherapy-induced remission and is generally chemo-resistant. Given the potential role for cancer stem cells in relapse, targeting of the leukemia-initiating cell (LIC) in AML may provide improved outcome following remission induction. However, due to overlap in their self-renewal program with normal hematopoietic stem cells (HSCs), therapeutic targeting of the LIC may have an adverse effect on long-term hematopoietic recovery. Here we used a mouse model of relapsed AML to explore whether the hypoxia-inducible factor (HIF)1α inhibitor echinomycin can be used to treat relapsed AML without affecting host HSCs. We show that echinomycin cured 40% to 60% of mice transplanted with relapsed AML. Bone marrow cells from the cured mice displayed normal composition of HSCs and their progenitors and were as competent as those isolated from nonleukemic mice in competitive repopulation assays. Importantly, in mice with complete remission, echinomycin appeared to completely eliminate LICs because no leukemia could be propagated in vivo following serial transplantation. Taken together, our data demonstrate that in a mouse model of relapsed AML, low-dose echinomycin selectively targets LICs and spares normal hematopoiesis.

Citing Articles

Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent.

Kojima K, Konishi H, Momosaki K, Komatani Y, Katsuyama A, Nakagawa K Sci Rep. 2024; 14(1):7628.

PMID: 38561454 PMC: 10985088. DOI: 10.1038/s41598-024-58196-3.

Liu X, Wang L, Kang Q, Feng C, Wang J Front Pharmacol. 2024; 15:1339465.

PMID: 38482057 PMC: 10933109. DOI: 10.3389/fphar.2024.1339465.

Acriflavine, a HIF-1 inhibitor, preserves vision in an experimental autoimmune encephalomyelitis model of optic neuritis.

Anders J, Elwood B, Kardon R, Gramlich O Front Immunol. 2023; 14:1271118.

PMID: 37942317 PMC: 10628762. DOI: 10.3389/fimmu.2023.1271118.

Genetic and pharmaceutical targeting of HIF1α allows combo-immunotherapy to boost graft vs. leukemia without exacerbation graft vs. host disease.

Bailey C, Wei Y, Yan J, Huang D, Zhang P, Qi C Cell Rep Med. 2023; 4(11):101236.

PMID: 37827154 PMC: 10694596. DOI: 10.1016/j.xcrm.2023.101236.

Endophytic Microbes from Medicinal Plants in Fenghuang Mountain as a Source of Antibiotics.

Yang A, Hong Y, Zhou F, Zhang L, Zhu Y, Wang C Molecules. 2023; 28(17).

PMID: 37687129 PMC: 10488465. DOI: 10.3390/molecules28176301.

References

Chang A, Kim K, Boucher H, Bonomi P, Stewart J, Karp D . A randomized phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma: an Eastern Cooperative Oncology Group Study (E1587). Cancer. 1998; 82(2):292-300. DOI: 10.1002/(SICI)1097-0142(19980115)82:2<301::AID-CNCR8>3.0.CO;2-T. View

Quintana E, Shackleton M, Sabel M, Fullen D, Johnson T, Morrison S . Efficient tumour formation by single human melanoma cells. Nature. 2008; 456(7222):593-8. PMC: 2597380. DOI: 10.1038/nature07567. View

Kelly P, Dakic A, Adams J, Nutt S, Strasser A . Tumor growth need not be driven by rare cancer stem cells. Science. 2007; 317(5836):337. DOI: 10.1126/science.1142596. View

Whitman S, Caligiuri M, Maharry K, Radmacher M, Kohlschmidt J, Becker H . The MLL partial tandem duplication in adults aged 60 years and older with de novo cytogenetically normal acute myeloid leukemia. Leukemia. 2012; 26(7):1713-7. PMC: 3565839. DOI: 10.1038/leu.2012.34. View

Jin L, Lee E, Ramshaw H, Busfield S, Peoppl A, Wilkinson L . Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell. 2009; 5(1):31-42. DOI: 10.1016/j.stem.2009.04.018. View

Taylor S, Crowley J, Townsend J, Vogel F, Eyre H, Braun J . Phase II evaluation of echinomycin (NSC-526417) in patients with central nervous system malignancies. A Southwest Oncology Group study. J Neurooncol. 1993; 15(2):181-4. DOI: 10.1007/BF01053939. View

Park I, Qian D, Kiel M, Becker M, Pihalja M, Weissman I . Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003; 423(6937):302-5. DOI: 10.1038/nature01587. View

Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A . Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol. 2010; 28(3):275-80. PMC: 3857633. DOI: 10.1038/nbt.1607. View

Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller K . HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007; 11(5):407-20. DOI: 10.1016/j.ccr.2007.04.001. View

10.

Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H . TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell. 2010; 7(6):708-17. DOI: 10.1016/j.stem.2010.11.014. View

11.

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C . let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007; 131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054. View

12.

Guzman M, Rossi R, Neelakantan S, Li X, Corbett C, Hassane D . An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood. 2007; 110(13):4427-35. PMC: 2234793. DOI: 10.1182/blood-2007-05-090621. View

13.

Jin L, Hope K, Zhai Q, Smadja-Joffe F, Dick J . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006; 12(10):1167-74. DOI: 10.1038/nm1483. View

14.

Chang A, Tu Z, Bryan G, Kirkwood J, Oken M, Trump D . Phase II study of echinomycin in the treatment of renal cell carcinoma ECOG study E2885. Invest New Drugs. 1994; 12(2):151-3. DOI: 10.1007/BF00874447. View

15.

MARSHALL M, Wolf M, Crawford E, Taylor S, Blumenstein B, Flanigan R . Phase II trial of echinomycin for the treatment of advanced renal cell carcinoma. A Southwest Oncology Group study. Invest New Drugs. 1993; 11(2-3):207-9. DOI: 10.1007/BF00874157. View

16.

Gradishar W, Vogelzang N, Kilton L, Leibach S, Rademaker A, French S . A phase II clinical trial of echinomycin in metastatic soft tissue sarcoma. An Illinois Cancer Center Study. Invest New Drugs. 1995; 13(2):171-4. DOI: 10.1007/BF00872868. View

17.

Chen C, Liu Y, Liu Y, Zheng P . mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal. 2009; 2(98):ra75. PMC: 4020596. DOI: 10.1126/scisignal.2000559. View

18.

Phillips T, McBride W, Pajonk F . The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006; 98(24):1777-85. DOI: 10.1093/jnci/djj495. View

19.

Beachy P, Karhadkar S, Berman D . Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004; 432(7015):324-31. DOI: 10.1038/nature03100. View

20.

Dean M, Fojo T, Bates S . Tumour stem cells and drug resistance. Nat Rev Cancer. 2005; 5(4):275-84. DOI: 10.1038/nrc1590. View