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EZN-2208 treatment suppresses chronic lymphocytic leukaemia by interfering with environmental protection and increases response to fludarabine
Open accessAbstract
The transcription factor HIF-1α is overexpressed in chronic lymphocytic leukaemia (CLL), where it promotes leukaemia progression by favouring the interaction of leukaemic cells with protective tissue microenvironments. Here, we tested the hypothesis that a pharmacological compound previously shown to inhibit HIF-1α may act as a chemosensitizer by interrupting protective microenvironmental interactions and exposing CLL cells to fludarabine-induced cytotoxicity. We found that the camptothecin-11 analogue EZN-2208 sensitizes CLL cells to fludarabine-induced apoptosis in cytoprotective in vitro cultures; in vivo EZN-2208 improves fludarabine responses, especially in early phases of leukaemia expansion, and exerts significant anti-leukaemia activity, thus suggesting that this or similar compounds may be considered as effective CLL therapeutic approaches.
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In murine models of chronic lymphocytic leukemia, EZN-2208 enhanced the therapeutic efficacy of fludarabine.
“In murine models of chronic lymphocytic leukemia (CLL), EZN-2208 - a water-soluble polyethylene glycol conjugate of SN-38, the active metabolite of irinotecan was reported to enhance the therapeutic efficacy of fludarabine, providing early in vivo support for combinatorial strategies targeting hypoxia-associated pathways [325].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [325]
The Eμ-TCL1 mouse-model passage reports that combined treatment reduced leukaemia burden after the first cycle when either drug alone had little effect; the MEC-1 model also showed a further reduction in bone-marrow involvement. But the paper says sensitization in vivo was only partial: the combination did not improve survival over EZN-2208 alone, and its benefit was not sustained after a second cycle. (LLM, conf=0.86)
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HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies
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“…leukemia (CLL), EZN-2208 - a water-soluble polyethylene glycol conjugate of SN-38, the active metabolite of irinotecan was reported to enhance the therapeutic efficacy of fludarabine, providing early in vivo support for combinatorial strategies targeting hypoxia-associated pathways [325].”
Huang, X., Huang, J., Huang, D., Huang, T., & Deng, G. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.125814 · Cited by 2
The Role of Intra-tumor Hypoxia in Cancer Cells Immune Escape Mechanism
Farhangnia, P., Delbandi, A., Aghamohamadi, N., Safdarian, A. R., & Akbarpour, M. (2025) · Springer eBooks · doi:10.1007/978-3-032-00759-9_61 · Cited by 1
Metadata
- Authors
- Valsecchi, R., Coltella, N., Magliulo, D., Bongiovanni, L., Scarfò, L., Ghia, P., Ponzoni, M., & Bernardi, R.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Vita-Salute San Raffaele University (IT)
- Corresponding author
- Bernardi, Rosa
- ORCID
- Venue
- Open Biology
- Publisher
- The Royal Society
- Published
- 2020-05
- Volume
- 10
- Issue
- 5
- Pages
- 190262
- ISSN
- 2046-2441 (ISSN-L)
- PMC
- PMC7276525
- OpenAlex
- W3025162315
- Cited by
- 12
- References
- 13
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 1
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Open Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- CLL Global Research Foundation
- Associazione Italiana per la Ricerca sul Cancro (9965)
- Lady Tata Memorial Trust
- Topics
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- chronic lymphocytic leukemia, HIF-1α, fludarabine, chemosensitization, tumor microenvironment, apoptosis, transcription factor inhibition
- MeSH terms
- Adult, Aged, Animals, Camptothecin, Cell Survival, Drug Synergism, Female, Humans, Male, Middle Aged, Neoplasm Transplantation, Polyethylene Glycols, Vidarabine, Leukemia, Lymphocytic, Chronic, B-Cell, Gene Expression Regulation, Leukemic, Treatment Outcome, Cell Line, Tumor, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Tumor Microenvironment
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