Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers
Abstract Background Anti-angiogenic tyrosine kinase inhibitors (TKIs) have become major drugs for the treatment of various cancer types, but with an overall high incidence of severe toxicities, particularly haematological toxicities including severe anemia. Methods We treated C57BL6 mice continuousl...
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2025-04-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-025-00640-9 |
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| author | Tai Van Nguyen Eurydice Angeli Diaddin Hamdan Morad El Bouchtaoui Oanh T. Bui Feriel Azibani Rong Shen He Lu Kien Hung Do Anne Janin Quang Van Le Guilhem Bousquet |
| author_facet | Tai Van Nguyen Eurydice Angeli Diaddin Hamdan Morad El Bouchtaoui Oanh T. Bui Feriel Azibani Rong Shen He Lu Kien Hung Do Anne Janin Quang Van Le Guilhem Bousquet |
| author_sort | Tai Van Nguyen |
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| description | Abstract Background Anti-angiogenic tyrosine kinase inhibitors (TKIs) have become major drugs for the treatment of various cancer types, but with an overall high incidence of severe toxicities, particularly haematological toxicities including severe anemia. Methods We treated C57BL6 mice continuously by gavage for 14 days with either sunitinib, pazopanib, or axitinib. In this study, we set out to decipher the pathophysiological mechanisms of anti-angiogenic TKI haematological toxicity. Results We demonstrated that anti-angiogenic TKIs induced a broad range of toxic effects on normal tissues through a cytotoxic effect on normal endothelial cells. Haematological toxicities were particulary marked with sunitinib. Sunitinib-induced hypoxia through the destruction of normal vessels in the bone marrow mainly affected erythrocyte and myeloid lineages, and this was associated with a blockage in erythrocyte maturation. Althought sunitinib-induced anemia was associated with an adaptative response to systemic hypoxia, we demonstrated that erythropoietin (EPO) concentrations in the total bone marrow of sunitinib-treated mice were significantly lower than in untreated mice. This is coherent with the destruction of microvessels in the bone marrow under sunitinib treatment, preventing circulating EPO from reaching the bone marrow at relevant concentrations. However, we demonstrated an additional effect specific to sunitinib that induced autophagy flux inhibition in erythroid progenitors, with a blockage of erythrocyte maturation, leading to more severe anemia. Conclusions We deciphered the pathophysiology of anti-angiogenic TKI-induced anemia, which we observed to be mainly linked to a direct effect on normal bone-marrow vessels and to autophagy flux inhibition in erythroid progenitors under sunitinib. |
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| issn | 2162-3619 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Experimental Hematology & Oncology |
| spelling | doaj-art-92bc65bdcfea49ffb13e49e3a5fd1df72025-08-20T02:17:49ZengBMCExperimental Hematology & Oncology2162-36192025-04-011411610.1186/s40164-025-00640-9Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancersTai Van Nguyen0Eurydice Angeli1Diaddin Hamdan2Morad El Bouchtaoui3Oanh T. Bui4Feriel Azibani5Rong Shen6He Lu7Kien Hung Do8Anne Janin9Quang Van Le10Guilhem Bousquet11Université de Paris, INSERM, MASCOTUniversité de Paris, INSERM, MASCOTUniversité de Paris, INSERM, MASCOTUniversité de Paris, INSERM, MASCOTUniversité de Paris, INSERM, MASCOTUniversité de Paris, INSERM, MASCOTDepartment of Hematology, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineUniversité de Paris, INSERM, MASCOTVietnam National Cancer Hospital – K HospitalUniversité de Paris, INSERM, MASCOTVietnam National Cancer Hospital – K HospitalUniversité de Paris, INSERM, MASCOTAbstract Background Anti-angiogenic tyrosine kinase inhibitors (TKIs) have become major drugs for the treatment of various cancer types, but with an overall high incidence of severe toxicities, particularly haematological toxicities including severe anemia. Methods We treated C57BL6 mice continuously by gavage for 14 days with either sunitinib, pazopanib, or axitinib. In this study, we set out to decipher the pathophysiological mechanisms of anti-angiogenic TKI haematological toxicity. Results We demonstrated that anti-angiogenic TKIs induced a broad range of toxic effects on normal tissues through a cytotoxic effect on normal endothelial cells. Haematological toxicities were particulary marked with sunitinib. Sunitinib-induced hypoxia through the destruction of normal vessels in the bone marrow mainly affected erythrocyte and myeloid lineages, and this was associated with a blockage in erythrocyte maturation. Althought sunitinib-induced anemia was associated with an adaptative response to systemic hypoxia, we demonstrated that erythropoietin (EPO) concentrations in the total bone marrow of sunitinib-treated mice were significantly lower than in untreated mice. This is coherent with the destruction of microvessels in the bone marrow under sunitinib treatment, preventing circulating EPO from reaching the bone marrow at relevant concentrations. However, we demonstrated an additional effect specific to sunitinib that induced autophagy flux inhibition in erythroid progenitors, with a blockage of erythrocyte maturation, leading to more severe anemia. Conclusions We deciphered the pathophysiology of anti-angiogenic TKI-induced anemia, which we observed to be mainly linked to a direct effect on normal bone-marrow vessels and to autophagy flux inhibition in erythroid progenitors under sunitinib.https://doi.org/10.1186/s40164-025-00640-9Anti-angiogenic agentsTyrosine kinase inhibitorAnemiaSunitinibAutophagyErythropoietin |
| spellingShingle | Tai Van Nguyen Eurydice Angeli Diaddin Hamdan Morad El Bouchtaoui Oanh T. Bui Feriel Azibani Rong Shen He Lu Kien Hung Do Anne Janin Quang Van Le Guilhem Bousquet Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers Experimental Hematology & Oncology Anti-angiogenic agents Tyrosine kinase inhibitor Anemia Sunitinib Autophagy Erythropoietin |
| title | Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers |
| title_full | Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers |
| title_fullStr | Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers |
| title_full_unstemmed | Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers |
| title_short | Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers |
| title_sort | anti angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects revisiting the treatment of anemia in metastatic cancers |
| topic | Anti-angiogenic agents Tyrosine kinase inhibitor Anemia Sunitinib Autophagy Erythropoietin |
| url | https://doi.org/10.1186/s40164-025-00640-9 |
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