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Cited by 49Retinoids in leukemia and cellular processesAcute Myeloid Leukemia ResearchHepatocellular Carcinoma Treatment and Prognosis

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Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα–Driven Leukemia

Coltella, Nadia, Valsecchi, Roberta, Ponente, Manfredi, Ponzoni, Maurilio, Bernardi, Rosa·2015·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-14-3022

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Abstract

Purpose Retinoic acid-arsenic trioxide (ATRA-ATO) combination therapy is the current standard of care for patients with acute promyelocytic leukemia (APL) carrying the oncogenic fusion protein PML-RARα. Despite the high cure rates obtained with this drug combination, resistance to arsenic is recently emerging. Moreover, patients with APL carrying the PLZF-RARα fusion protein are partially resistant to ATRA treatment. Hypoxia-inducible factor-1α (HIF-1α) activation has been recently reported in APL, and EZN-2208 (PEG-SN38) is a compound with HIF-1α inhibitory function currently tested in clinical trials. This study investigates the effect of EZN-2208 in different preclinical APL models, either alone or in combination with ATRA. Experimental design Efficacy of EZN-2208 in APL was measured in vitro by assessing expression of HIF-1α target genes, cell migration, clonogenicity, and differentiation, vis a vis the cytotoxic and cytostatic effects of this compound. In vivo, EZN-2208 was used in mouse models of APL driven by PML-RARα or PLZF-RARα, either alone or in combination with ATRA. Results Treatment of APL cell lines with noncytotoxic doses of EZN-2208 causes dose-dependent downregulation of HIF-1α bona fide target genes and affects cell migration and clonogenicity in methylcellulose. In vivo, EZN-2208 impairs leukemia progression and prolongs mice survival in APL mouse models. More importantly, when used in combination with ATRA, EZN-2208 synergizes in debulking leukemia and e…

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References 29 · Cited by 49

Research works printed but not linked: 27

  1. Ablain, 2011, Revisiting the differentiation paradigm in acute promyelocytic leukemia, Blood, 117, 5795, 10.1182/blood-2011-02-329367 · DOI
  2. Du, 1999, Overexpression of wild-type retinoic acid receptor alpha (RARalpha) recapitulates retinoic acid-sensitive transformation of primary myeloid progenitors by acute promyelocytic leukemia RARalpha-fusion genes, Blood, 94, 793, 10.1182/blood.V94.2.793 · DOI
  3. Wang, 2008, Acute promyelocytic leukemia: from highly fatal to highly curable, Blood, 111, 2505, 10.1182/blood-2007-07-102798 · DOI
  4. Zhou, 2002, Frequent mutations in the ligand-binding domain of PML-RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo, Blood, 99, 1356, 10.1182/blood.V99.4.1356 · DOI
  5. Goto, 2011, Missense mutations in PML-RARA critical for the lack of responsiveness to arsenic trioxide treatment, Blood, 118, 1600, 10.1182/blood-2011-01-329433 · DOI
  6. Zhu, 2014, Resistance to arsenic therapy in acute promyelocytic leukemia, N Engl J Med, 370, 1864, 10.1056/NEJMc1316382 · DOI
  7. Licht, 1995, Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17), Blood, 85, 1083, 10.1182/blood.V85.4.1083.bloodjournal8541083 · DOI
  8. Koken, 1999, Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARalpha fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient, Oncogene, 18, 1113, 10.1038/sj.onc.1202414 · DOI
  9. Nasr, 2008, Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation, Nat Med, 14, 1333, 10.1038/nm.1891 · DOI
  10. Lee, 2012, From stem cells to cancer stem cells: HIF takes the stage, Curr Opin Cell Biol, 24, 232, 10.1016/j.ceb.2012.01.005 · DOI
  11. Coltella, 2014, HIF factors cooperate with PML-RARalpha to promote acute promyelocytic leukemia progression and relapse, EMBO Mol Med, 6, 640, 10.1002/emmm.201303065 · DOI
  12. Percio, 2014, A HIF-1 network reveals characteristics of epithelial-mesenchymal transition in acute promyelocytic leukemia, Genome Med, 6, 84, 10.1186/s13073-014-0084-4 · DOI
  13. Zheng, 2007, Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RARalpha-positive leukemic stem cells, Haematologica, 92, 323, 10.3324/haematol.10541 · DOI
  14. Rapisarda, 2004, Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications, Cancer Res, 64, 1475, 10.1158/0008-5472.CAN-03-3139 · DOI · Paper page
  15. Xia, 2012, Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors, Eur J Med Chem, 49, 24, 10.1016/j.ejmech.2012.01.033 · DOI · Paper page
  16. Sapra, 2008, Novel delivery of SN38 markedly inhibits tumor growth in xenografts, including a camptothecin-11-refractory model, Clin Cancer Res, 14, 1888, 10.1158/1078-0432.CCR-07-4456 · DOI · Paper page
  17. Pastorino, 2010, Tumor regression and curability of preclinical neuroblastoma models by PEGylated SN38 (EZN-2208), a novel topoisomerase I inhibitor, Clin Cancer Res, 16, 4809, 10.1158/1078-0432.CCR-10-1354 · DOI · Paper page
  18. Grignani, 1998, Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia, Nature, 391, 815, 10.1038/35901 · DOI
  19. He, 2000, Two critical hits for promyelocytic leukemia, Mol Cell, 6, 1131, 10.1016/S1097-2765(00)00111-8 · DOI
  20. Guarnerio, 2014, Bone marrow endosteal mesenchymal progenitors depend on HIF factors for maintenance and regulation of hematopoiesis, Stem Cell Reports, 2, 794, 10.1016/j.stemcr.2014.04.002 · DOI
  21. Pommier, 2006, Topoisomerase I inhibitors: camptothecins and beyond, Nat Rev Cancer, 6, 789, 10.1038/nrc1977 · DOI
  22. Minucci, 2002, PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors, Blood, 100, 2989, 10.1182/blood-2001-11-0089 · DOI
  23. Guibal, 2009, Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia, Blood, 114, 5415, 10.1182/blood-2008-10-182071 · DOI · Paper page
  24. Wojiski, 2009, PML-RARalpha initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors, Leukemia, 23, 1462, 10.1038/leu.2009.63 · DOI
  25. Sapra, 2009, Marked therapeutic efficacy of a novel polyethylene glycol-SN38 conjugate, EZN-2208, in xenograft models of B-cell non-Hodgkin's lymphoma, Haematologica, 94, 1456, 10.3324/haematol.2009.008276 · DOI
  26. Ablain, 2014, Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure, Nat Med, 20, 167, 10.1038/nm.3441 · DOI
  27. Park, 2011, Treatment of acute promyelocytic leukemia without cytotoxic chemotherapy, Oncology, 25, 733

Metadata

Authors
Coltella, N., Valsecchi, R., Ponente, M., Ponzoni, M., & Bernardi, R.
Affiliations
  • IRCCS Ospedale San Raffaele (IT)
  • University of Modena and Reggio Emilia (IT)
  • Vita-Salute San Raffaele University (IT)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2015-08-13
Volume
21
Issue
16
Pages
3685-3694
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-14-3022
OpenAlex
W2152442601
Cited by
49
References
29
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 6 · 2018: 1 · 2017: 3 · 2016: 5
FWCI
1.30
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
acute promyelocytic leukemia, PML-RARα, PLZF-RARα, HIF-1α inhibition, retinoic acid, arsenic trioxide, combination therapy, drug resistance, leukemia-initiating cells, hypoxia, cell migration, clonogenicity
MeSH terms
Arsenic Trioxide, Animals, Arsenicals, Camptothecin, Cell Differentiation, Cell Movement, Disease Models, Animal, Drug Synergism, Humans, Mutation, Neoplasm Proteins, Oxides, Polyethylene Glycols, Tretinoin, Leukemia, Promyelocytic, Acute, Oncogene Proteins, Fusion, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Mice, Hypoxia-Inducible Factor 1, alpha Subunit

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CoChat. (2026). Citation check: Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα–Driven Leukemia. https://app.cochat.ai/papers/10.1158/1078-0432.ccr-14-3022
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Coltella, N., Valsecchi, R., Ponente, M., Ponzoni, M., & Bernardi, R. (2015). Synergistic Leukemia Eradication by Combined Treatment with Retinoic Acid and HIF Inhibition by EZN-2208 (PEG-SN38) in Preclinical Models of PML-RARα and PLZF-RARα–Driven Leukemia. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.ccr-14-3022