The Oxygen-Generating Calcium Peroxide-Modified Magnetic Nanoparticles Attenuate Hypoxia-Induced Chemoresistance in Triple-Negative Breast Cancer

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Title:	The Oxygen-Generating Calcium Peroxide-Modified Magnetic Nanoparticles Attenuate Hypoxia-Induced Chemoresistance in Triple-Negative Breast Cancer
Authors:	Cheng, FY (Cheng, Fong-Yu) Chan, CH (Chan, Chia-Hsin) Wang, B (Wang, Bour-, Jr.) Yeh, YL (Yeh, Ya-Ling) Wang, YJ (Wang, Ying-Jan) Chiu, HW (Chiu, Hui-Wen)
Contributors:	化學系
Keywords:	hypoxia nanocarriers chemoresistance triple-negative breast cancer autophagy
Date:	2021-02
Issue Date:	2021-04-14 16:09:57 (UTC+8)
Abstract:	Tumor hypoxia is known to increase the resistance of cancer cells to chemotherapy. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lack of target. Therefore, chemotherapy is the only approved systemic treatment in TNBC. Here, we synthesized the calcium peroxide-modified magnetic nanoparticles (CaO2-MNPs) with the function of oxygen generation to improve and enhance the therapeutic efficiency of doxorubicin treatment in the hypoxia microenvironment of TNBC. CaO2-MNPs promoted ubiquitination and protein degradation of hypoxia-inducible factor 1 alpha (HIF-1 alpha). Furthermore, CaO2-MNPs inhibited autophagy and induced apoptosis in TNBC cells. CaO2-MNPs in combination with doxorubicin showed a stronger tumor-suppressive effect on TNBC compared to the doxorubicin treatment alone in an orthotopic mouse model. Our findings suggest that combined with CaO2-MNPs and doxorubicin attenuates HIF-1 alpha expression to improve the efficiency of chemotherapy in TNBC. Cancer response to chemotherapy is regulated not only by intrinsic sensitivity of cancer cells but also by tumor microenvironment. Tumor hypoxia, a condition of low oxygen level in solid tumors, is known to increase the resistance of cancer cells to chemotherapy. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Due to lack of target in TNBC, chemotherapy is the only approved systemic treatment. We evaluated the effect of hypoxia on chemotherapy resistance in TNBC in a series of in vitro and in vivo experiments. Furthermore, we synthesized the calcium peroxide-modified magnetic nanoparticles (CaO2-MNPs) with the function of oxygen generation to improve and enhance the therapeutic efficiency of doxorubicin treatment in the hypoxia microenvironment of TNBC. The results of gene set enrichment analysis (GSEA) software showed that the hypoxia and autophagy gene sets are significantly enriched in TNBC patients. We found that the chemical hypoxia stabilized the expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein and increased doxorubicin resistance in TNBC cells. Moreover, hypoxia inhibited the induction of apoptosis and autophagy by doxorubicin. In addition, CaO2-MNPs promoted ubiquitination and protein degradation of HIF-1 alpha. Furthermore, CaO2-MNPs inhibited autophagy and induced apoptosis in TNBC cells. Our animal studies with an orthotopic mouse model showed that CaO2-MNPs in combination with doxorubicin exhibited a stronger tumor-suppressive effect on TNBC, compared to the doxorubicin treatment alone. Our findings suggest that combined with CaO2-MNPs and doxorubicin attenuates HIF-1 alpha expression to improve the efficiency of chemotherapy in TNBC.
Relation:	CANCERS 卷冊: 13 期: 4 文獻號碼: 606
Appears in Collections:	[Department of Chemistry & Graduate Institute of Applied Chemistry ] journal articles

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