PUBLICATION
A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
- Authors
- Zeng, Y., Zhang, X., Lin, D., Feng, X., Liu, Y., Fang, Z., Zhang, W., Chen, Y., Zhao, M., Wu, J., Jiang, L.
- ID
- ZDB-PUB-211110-2
- Date
- 2021
- Source
- Journal of Hematology & Oncology 14: 189 (Journal)
- Registered Authors
- Jiang, Linjia
- Keywords
- Chemotherapy, Doxorubicin, Hypoxia, Lysosome, Myeloid leukemia
- MeSH Terms
-
- Animals
- Antibiotics, Antineoplastic/administration & dosage*
- Antibiotics, Antineoplastic/therapeutic use
- Cell Line, Tumor
- Delayed-Action Preparations/chemistry*
- Dextrans/chemistry*
- Doxorubicin/administration & dosage*
- Doxorubicin/therapeutic use
- Drug Delivery Systems
- Drug Resistance, Neoplasm
- Humans
- Leukemia, Myeloid/drug therapy*
- Leukemia, Myeloid/metabolism
- Lysosomes/metabolism*
- Zebrafish
- PubMed
- 34749790 Full text @ J. Hematol. Oncol.
Citation
Zeng, Y., Zhang, X., Lin, D., Feng, X., Liu, Y., Fang, Z., Zhang, W., Chen, Y., Zhao, M., Wu, J., Jiang, L. (2021) A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia. Journal of Hematology & Oncology. 14:189.
Abstract
The hypoxic microenvironment is presumed to be a sanctuary for myeloid leukemia cells that causes relapse following chemotherapy, but the underlying mechanism remains elusive. Using a zebrafish xenograft model, we observed that the hypoxic hematopoietic tissue preserved most of the chemoresistant leukemic cells following the doxorubicin (Dox) treatment. And hypoxia upregulated TFEB, a master regulator of lysosomal biogenesis, and increased lysosomes in leukemic cells. Specimens from relapsed myeloid leukemia patients also harbored excessive lysosomes, which trapped Dox and prevented drug nuclear influx leading to leukemia chemoresistance. Pharmaceutical inhibition of lysosomes enhanced Dox-induced cytotoxicity against leukemic cells under hypoxia circumstance. To overcome lysosome associated chemoresistance, we developed a pH-sensitive dextran-doxorubicin nanomedicine (Dex-Dox) that efficiently released Dox from lysosomes and increased drug nuclear influx. More importantly, Dex-Dox treatment significantly improved the chemotherapy outcome in the zebrafish xenografts transplanted with cultured leukemic cells or relapsed patient specimens. Overall, we developed a novel lysosome targeting nanomedicine that is promising to overcome the myeloid leukemia chemoresistance.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping