A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia

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 chemores...

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Autores principales:	Yunxin Zeng, Xinyu Zhang, Dongjun Lin, Xiaohui Feng, Yuye Liu, Zhengwen Fang, Weijian Zhang, Yu Chen, Meng Zhao, Jun Wu, Linjia Jiang
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Myeloid leukemia Chemotherapy Doxorubicin Hypoxia Lysosome Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/396da4126a384433b841fd512a89988f
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spelling	oai:doaj.org-article:396da4126a384433b841fd512a89988f2021-11-14T12:05:41ZA lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia10.1186/s13045-021-01199-81756-8722https://doaj.org/article/396da4126a384433b841fd512a89988f2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13045-021-01199-8https://doaj.org/toc/1756-8722Abstract 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.Yunxin ZengXinyu ZhangDongjun LinXiaohui FengYuye LiuZhengwen FangWeijian ZhangYu ChenMeng ZhaoJun WuLinjia JiangBMCarticleMyeloid leukemiaChemotherapyDoxorubicinHypoxiaLysosomeDiseases of the blood and blood-forming organsRC633-647.5Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-6 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Myeloid leukemia Chemotherapy Doxorubicin Hypoxia Lysosome Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Myeloid leukemia Chemotherapy Doxorubicin Hypoxia Lysosome Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yunxin Zeng Xinyu Zhang Dongjun Lin Xiaohui Feng Yuye Liu Zhengwen Fang Weijian Zhang Yu Chen Meng Zhao Jun Wu Linjia Jiang A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
description	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.
format	article
author	Yunxin Zeng Xinyu Zhang Dongjun Lin Xiaohui Feng Yuye Liu Zhengwen Fang Weijian Zhang Yu Chen Meng Zhao Jun Wu Linjia Jiang
author_facet	Yunxin Zeng Xinyu Zhang Dongjun Lin Xiaohui Feng Yuye Liu Zhengwen Fang Weijian Zhang Yu Chen Meng Zhao Jun Wu Linjia Jiang
author_sort	Yunxin Zeng
title	A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
title_short	A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
title_full	A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
title_fullStr	A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
title_full_unstemmed	A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
title_sort	lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia
publisher	BMC
publishDate	2021
url	https://doaj.org/article/396da4126a384433b841fd512a89988f
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A lysosome-targeted dextran-doxorubicin nanodrug overcomes doxorubicin-induced chemoresistance of myeloid leukemia

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