Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma.
Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma.
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DOI：
10.3390/antiox12030741
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发表时间：
2023-03-17
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影响因子：
--
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中科院分区：
文献类型：
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头颈鳞状细胞癌 (HNSCC) 细胞的代谢具有高度异质性，通常在肿瘤微环境中经历较高的活性氧 (ROS) 水平，例如超氧化物和过氧化氢 (H2O2)。肿瘤细胞通过上调抗氧化系统在这些慢性氧化条件下生存。为了研究肿瘤和健康组织中细胞对化疗 H2O2 产生的反应的异质性，我们利用单细胞 RNA 测序 (scRNA-seq) 数据对醌循环 β-拉帕酮治疗进行氧化还原系统级模拟，作为 NQO1 依赖性快速超氧化物和过氧化氢 (H2O2) 产生的来源。来自 10 个 HNSCC 患者肿瘤的转录组数据被用来填充 4000 多个药物代谢的单细胞抗氧化酶网络模型。这些模拟反映了健康细胞和癌细胞氧化还原状态之间的显着系统级差异，在一些患者样本中证明了可靶向的癌细胞群，或在其他样本中证明了非恶性细胞和恶性细胞之间在统计上无法区分的影响。随后对健康和恶性细胞模型进行的多变量分析指出了这些表型之间氧化还原反应的不同贡献者。该模型框架为解释 NAD(P)H:醌氧化还原酶 1 (NQO1) 生物激活疗法的混合结果提供了机制基础，尽管这些药物具有由 NQO1/过氧化氢酶表达定义的肿瘤特异性，并强调了替代抗氧化剂成分在决定药物诱导的氧化应激中的作用。
Head and neck squamous cell carcinoma (HNSCC) cells are highly heterogeneous in their metabolism and typically experience elevated reactive oxygen species (ROS) levels such as superoxide and hydrogen peroxide (H2O2) in the tumor microenvironment. Tumor cells survive under these chronic oxidative conditions by upregulating antioxidant systems. To investigate the heterogeneity of cellular responses to chemotherapeutic H2O2 generation in tumor and healthy tissue, we leveraged single-cell RNA-sequencing (scRNA-seq) data to perform redox systems-level simulations of quinone-cycling β-lapachone treatment as a source of NQO1-dependent rapid superoxide and hydrogen peroxide (H2O2) production. Transcriptomic data from 10 HNSCC patient tumors was used to populate over 4000 single-cell antioxidant enzymatic network models of drug metabolism. The simulations reflected significant systems-level differences between the redox states of healthy and cancer cells, demonstrating in some patient samples a targetable cancer cell population or in others statistically indistinguishable effects between non-malignant and malignant cells. Subsequent multivariate analyses between healthy and malignant cellular models pointed to distinct contributors of redox responses between these phenotypes. This model framework provides a mechanistic basis for explaining mixed outcomes of NAD(P)H:quinone oxidoreductase 1 (NQO1)-bioactivatable therapeutics despite the tumor specificity of these drugs as defined by NQO1/catalase expression and highlights the role of alternate antioxidant components in dictating drug-induced oxidative stress.
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过氧化氢酶消除了NQO1阳性乳腺癌中的β-拉帕酮诱导的PARP1过度激活导向的坏死。
影响因子：
5.7
作者：
Bey EA;Reinicke KE;Srougi MC;Varnes M;Anderson VE;Pink JJ;Li LS;Patel M;Cao L;Moore Z;Rommel A;Boatman M;Lewis C;Euhus DM;Bornmann WG;Buchsbaum DJ;Spitz DR;Gao J;Boothman DA
通讯作者：
Boothman DA
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
4.8
作者：
Bienert, Gerd P.;Moller, Anders L. B.;Jahn, Thomas P.
通讯作者：
Jahn, Thomas P.
影响因子：
12.3
作者：
Kim, Tae Hyun;Zhou, Xiang;Chen, Mengjie
通讯作者：
Chen, Mengjie
影响因子：
5.9
作者：
Chakrabarti G;Moore ZR;Luo X;Ilcheva M;Ali A;Padanad M;Zhou Y;Xie Y;Burma S;Scaglioni PP;Cantley LC;DeBerardinis RJ;Kimmelman AC;Lyssiotis CA;Boothman DA
通讯作者：
Boothman DA