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Icaritin Exacerbates Mitophagy and Synergizes with Doxorubicin to Induce Immunogenic Cell Death in Hepatocellular Carcinoma
journal contribution
posted on 2020-03-23, 12:43 authored by Zhuo Yu, Jianfeng Guo, Mengying Hu, Yueqiu Gao, Leaf HuangHepatocellular
carcinoma (HCC) resistant to both chemotherapy and
immunotherapy is among the deadliest malignancies. Doxorubicin widely
used in transarterial chemotherapy in HCC can induce immunogenic cell
death (ICD), but the resulting immunogenicity is still weak. We aim
to seek a strategy for improving the efficacy of ICD in HCC based
on an immunoregulatory drug called icaritin. Icaritin induced mitophagy
and apoptosis to provoke ICD both in mouse Hepa1–6 and human
Huh7 HCC cells. A combination of icaritin and doxorubicin with a molar
ratio of 1:2 played a synergistic role in ICD induction. The poly
lactic-co-glycolic acid (PLGA)-polyethylene glycol
(PEG)-aminoethyl anisamide (AEAA) nanoparticle (NP) targeted codelivery
of icaritin and doxorubicin remodeled the immunosuppressive tumor
microenvironment and triggered a robust immune memory response, which
efficiently improved anti-HCC effect at an early stage in mouse HCC
model. In addition, the combo PLGA-PEG-AEAA NP together with lenvatinib
significantly prolonged survival time of mice at the advanced stage
of HCC. Collectively, our findings reveal an anti-HCC mechanism of
icaritin on mitophagy and provide an effective immune-based therapeutic
strategy for HCC.
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Huh 7 HCC cellsglycolic acidpoly lacticsurvival timeHepatocellular Carcinoma Hepatocellular carcinomatumor microenvironmenttransarterial chemotherapyIcaritin Exacerbates MitophagyICD inductionInduce Immunogenic Cell Deathimmunogenic cell deathicaritinmouse HCC modelmemory responsecombo PLGA-PEG-AEAA NPanti-HCC mechanismmolar ratioimmunoregulatory druganti-HCC effect
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