Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics

Wu, Huifeng; Wu, Xiaodong; Zhao, Mengdan; Yan, Jingjing; Li, Chaoqun; Zhang, Zhewei; Tang, Sangsang; Wang, Rong; Fei, Weidong

doi:10.2147/ijn.s439828

Cited by 6 publications

(1 citation statement)

References 107 publications

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“…This is the result of the activation of genes involved in the synthesis of cholesterol and an increase in its absorption by cells mediated by low-density lipoprotein receptors and abnormal cholesterol metabolism (reviewed in [ 166 ]). Ultimately, one potential anti-cancer strategy is the use of substances that reduce the cholesterol content in the tumor (reviewed in [ 167 ]).…”

Section: Mammalian Mitochondrial (Peripheral) Benzodiazepine Receptormentioning

confidence: 99%

Targeting Mitochondria for Cancer Treatment

Zorova,

Abramicheva,

Andrianova

et al. 2024

Pharmaceutics

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There is an increasing accumulation of data on the exceptional importance of mitochondria in the occurrence and treatment of cancer, and in all lines of evidence for such participation, there are both energetic and non-bioenergetic functional features of mitochondria. This analytical review examines three specific features of adaptive mitochondrial changes in several malignant tumors. The first feature is characteristic of solid tumors, whose cells are forced to rebuild their energetics due to the absence of oxygen, namely, to activate the fumarate reductase pathway instead of the traditional succinate oxidase pathway that exists in aerobic conditions. For such a restructuring, the presence of a low-potential quinone is necessary, which cannot ensure the conventional conversion of succinate into fumarate but rather enables the reverse reaction, that is, the conversion of fumarate into succinate. In this scenario, complex I becomes the only generator of energy in mitochondria. The second feature is the increased proliferation in aggressive tumors of the so-called mitochondrial (peripheral) benzodiazepine receptor, also called translocator protein (TSPO) residing in the outer mitochondrial membrane, the function of which in oncogenic transformation stays mysterious. The third feature of tumor cells is the enhanced retention of certain molecules, in particular mitochondrially directed cations similar to rhodamine 123, which allows for the selective accumulation of anticancer drugs in mitochondria. These three features of mitochondria can be targets for the development of an anti-cancer strategy.

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Section: Mammalian Mitochondrial (Peripheral) Benzodiazepine Receptormentioning

confidence: 99%

Targeting Mitochondria for Cancer Treatment

Zorova,

Abramicheva,

Andrianova

et al. 2024

Pharmaceutics

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Cholesterol Depletion‐Enhanced Ferroptosis and Immunotherapy via Engineered Nanozyme

Bai,

Xue,

Shao

et al. 2024

Advanced Science

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Ferroptosis, an iron‐ and reactive oxygen species (ROS)‐dependent cell death, holds significant promise for tumor therapy due to its ability to induce lipid peroxidation (LPO) and trigger antitumor immune responses. However, elevated cholesterol levels in cancer cells impede ferroptosis and compromise immune function. Here, a novel nanozyme, Fe‐MOF/CP, composed of iron metal‐organic framework (Fe‐MOF) nanoparticles loaded with cholesterol oxidase and PEGylation for integrated ferroptosis and immunotherapy is introduced. Fe‐MOF/CP depletes cholesterol and generates hydrogen peroxide, enhancing ROS levels and inducing LPO, thereby promoting ferroptosis. This process disrupts lipid raft integrity and downregulates glutathione peroxidase 4 and ferroptosis suppressor protein 1, further facilitating ferroptosis. Concurrently, Fe‐MOF/CP augments immunogenic cell death, reduces programmed death‐ligand 1 expression, and revitalizes exhausted CD8+ T cells. In vivo studies demonstrate significant therapeutic efficacy in abscopal, metastasis, and recurrent tumor models, highlighting the robust antitumor immune responses elicited by Fe‐MOF/CP. This study underscores the potential of Fe‐MOF/CP as a multifunctional therapeutic agent that combines ferroptosis and immunotherapy, offering a promising strategy for effective and durable cancer treatment.

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Cupric Doping Hollow Prussian Blue Nanoplatform for Enhanced Cholesterol Depletion: a Promising Strategy for Breast Cancer Therapy and Metastasis Inhibition

Yan,

Xue,

Sun

et al. 2024

Advanced Science

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The dysregulated cholesterol metabolism in breast cancer cells drives malignancy, invasion, and metastasis, emphasizing the significance of reducing abnormal cholesterol accumulation for effective cancer treatment and metastasis inhibition. Despite its promise, cholesterol oxidase (ChOx) encounters challenge due to limited catalytic efficiency and susceptibility to harsh conditions. To overcome these hurdles, biocompatible nanoplatforms (Cu‐HPB/C) tailored for efficient cholesterol depletion are introduced. Cu2+‐doped hollow Prussian blue (Cu‐HPB) acts as a carrier, shelter, and enhancer for ChOx, bolstering tumor‐targeting ability, stability, and enzymatic activity. Tumor‐responsive released Cu2+ notably augments ChOx activity, facilitating cholesterol depletion and disrupting lipid rafts, thereby impeding cell invasion and migration. Additionally, H2O2 generated from the oxidase reaction enhances Cu‐HPB's chemo dynamic therapeutic efficacy. Transcriptomic analysis validates Cu‐HPB/C's impact on cholesterol homeostasis and reveals cell death mechanisms including oxidative stress, ferroptosis, cuproptosis, and apoptosis. Demonstrating therapeutic efficacy in both 4T1 tumor subcutaneous and metastasis mouse models, the study presents a direct and effective strategy for tumor therapy and metastasis inhibition through enhanced cholesterol depletion.

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Regulating Cholesterol in Tumorigenesis: A Novel Paradigm for Tumor Nanotherapeutics

Cited by 6 publications

References 107 publications

Targeting Mitochondria for Cancer Treatment

Targeting Mitochondria for Cancer Treatment

Cholesterol Depletion‐Enhanced Ferroptosis and Immunotherapy via Engineered Nanozyme

Cupric Doping Hollow Prussian Blue Nanoplatform for Enhanced Cholesterol Depletion: a Promising Strategy for Breast Cancer Therapy and Metastasis Inhibition

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