β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death globally. Currently there is a lack of tumor-selective and efficacious therapies for hepatocellular carcinoma. β-Lapachone (ARQ761 in clinical form) selectively kill NADPH: quinone oxidoreductase 1 (NQO1)-overexpressi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.747282/full |
| _version_ | 1818586905881608192 |
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| author | Wenxiu Zhao Wenxiu Zhao Lingxiang Jiang Ting Fang Fei Fang Yingchun Liu Ye Zhao Yuting You Hao Zhou Xiaolin Su Jiangwei Wang Sheng Liu Yaomin Chen Jun Wan Jun Wan Xiumei Huang |
| author_facet | Wenxiu Zhao Wenxiu Zhao Lingxiang Jiang Ting Fang Fei Fang Yingchun Liu Ye Zhao Yuting You Hao Zhou Xiaolin Su Jiangwei Wang Sheng Liu Yaomin Chen Jun Wan Jun Wan Xiumei Huang |
| author_sort | Wenxiu Zhao |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death globally. Currently there is a lack of tumor-selective and efficacious therapies for hepatocellular carcinoma. β-Lapachone (ARQ761 in clinical form) selectively kill NADPH: quinone oxidoreductase 1 (NQO1)-overexpressing cancer cells. However, the effect of β-Lapachone on HCC is virtually unknown. In this study, we found that relatively high NQO1 and low catalase levels were observed in both clinical specimens collected from HCC patients and HCC tumors from the TCGA database. β-Lapachone treatment induced NQO1-selective killing of HCC cells and caused ROS formation and PARP1 hyperactivation, resulting in a significant decrease in NAD+ and ATP levels and a dramatic increase in double-strand break (DSB) lesions over time in vitro. Administration of β-Lapachone significantly inhibited tumor growth and prolonged survival in a mouse xenograft model in vivo. Our data suggest that NQO1 is an ideal potential biomarker, and relatively high NQO1:CAT ratios in HCC tumors but low ratios in normal tissues offer an optimal therapeutic window to use β-Lapachone. This study provides novel preclinical evidence for β-Lapachone as a new promising chemotherapeutic agent for use in NQO1-positive HCC patients. |
| first_indexed | 2024-12-16T09:00:24Z |
| format | Article |
| id | doaj.art-b6644f8b793e46278c14dc25851e6d0e |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-16T09:00:24Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-b6644f8b793e46278c14dc25851e6d0e2022-12-21T22:37:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-10-011110.3389/fonc.2021.747282747282β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 HyperactivationWenxiu Zhao0Wenxiu Zhao1Lingxiang Jiang2Ting Fang3Fei Fang4Yingchun Liu5Ye Zhao6Yuting You7Hao Zhou8Xiaolin Su9Jiangwei Wang10Sheng Liu11Yaomin Chen12Jun Wan13Jun Wan14Xiumei Huang15Department of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesFujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Xiamen, ChinaDepartment of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesFujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Xiamen, ChinaFujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Xiamen, ChinaDepartments of Biochemistry and Molecular Biology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartments of Biochemistry and Molecular Biology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesFujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Zhongshan Hospital, Xiamen University, Xiamen, ChinaDepartment of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartments of Biochemistry and Molecular Biology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United StatesIndiana University Health Pathology Laboratory, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United StatesCenter for Computational Biology and Bioinformatics, Indiana University, School of Medicine, Indianapolis, IN, United StatesDepartment of Radiation Oncology, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United StatesHepatocellular carcinoma (HCC) is the second leading cause of cancer-related death globally. Currently there is a lack of tumor-selective and efficacious therapies for hepatocellular carcinoma. β-Lapachone (ARQ761 in clinical form) selectively kill NADPH: quinone oxidoreductase 1 (NQO1)-overexpressing cancer cells. However, the effect of β-Lapachone on HCC is virtually unknown. In this study, we found that relatively high NQO1 and low catalase levels were observed in both clinical specimens collected from HCC patients and HCC tumors from the TCGA database. β-Lapachone treatment induced NQO1-selective killing of HCC cells and caused ROS formation and PARP1 hyperactivation, resulting in a significant decrease in NAD+ and ATP levels and a dramatic increase in double-strand break (DSB) lesions over time in vitro. Administration of β-Lapachone significantly inhibited tumor growth and prolonged survival in a mouse xenograft model in vivo. Our data suggest that NQO1 is an ideal potential biomarker, and relatively high NQO1:CAT ratios in HCC tumors but low ratios in normal tissues offer an optimal therapeutic window to use β-Lapachone. This study provides novel preclinical evidence for β-Lapachone as a new promising chemotherapeutic agent for use in NQO1-positive HCC patients.https://www.frontiersin.org/articles/10.3389/fonc.2021.747282/fullbeta-lapachoneNQO1hepatocellular carcinomaDNA damage/reactive oxygen speciesNAD+/ATP depletion |
| spellingShingle | Wenxiu Zhao Wenxiu Zhao Lingxiang Jiang Ting Fang Fei Fang Yingchun Liu Ye Zhao Yuting You Hao Zhou Xiaolin Su Jiangwei Wang Sheng Liu Yaomin Chen Jun Wan Jun Wan Xiumei Huang β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation Frontiers in Oncology beta-lapachone NQO1 hepatocellular carcinoma DNA damage/reactive oxygen species NAD+/ATP depletion |
| title | β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation |
| title_full | β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation |
| title_fullStr | β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation |
| title_full_unstemmed | β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation |
| title_short | β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation |
| title_sort | β lapachone selectively kills hepatocellular carcinoma cells by targeting nqo1 to induce extensive dna damage and parp1 hyperactivation |
| topic | beta-lapachone NQO1 hepatocellular carcinoma DNA damage/reactive oxygen species NAD+/ATP depletion |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.747282/full |
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