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A Novel NQO1 Bioactivatable Drug β‐Lapachone Efficiently Inhibits Cancer Cell Growth in Hepatocellular Carcinoma
Purpose: Hepaotocellular carcinoma (HCC) is one of the most lethal human malignancies. The majority of HCC patients are diagnosed at an advanced stage, leading to systemic therapy as the primary treatment. However, lack of efficacious approaches and resistance to cytotoxic chemotherapy result in low...
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Published in: | The FASEB journal 2021-05, Vol.35 (S1), p.n/a, Article fasebj.2021.35.S1.04949 |
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Main Authors: | , , , , , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Purpose:
Hepaotocellular carcinoma (HCC) is one of the most lethal human malignancies. The majority of HCC patients are diagnosed at an advanced stage, leading to systemic therapy as the primary treatment. However, lack of efficacious approaches and resistance to cytotoxic chemotherapy result in low survival rate among these patients. Therefore, exploiting novel and efficacious therapies is impervious. This study aims to determine whether β‐Lapachone (β‐Lap) could be a potential chemotherapeutic agent for HCC.
Experimental Design
We firstly analyzed the expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) and Catalase (CAT) in HCC patients using data from The Cancer Genome Atlas (TCGA), then examined their expression levels in our collected clinical patient samples and cell lines. Cell cytotoxicity and mechanism of of ß‐Lap were evaluated in wild type HCC cell line cells, stable NQO1 overexpression and knockout of SK‐HEP‐1 and PLC/PRF/5 cells, respectively. Preclinical therapeutic efficacious of ß‐Lap was finally validated in subcutaneous and orthotopic xenograft in vivo.
Results
Concomitant high NQO1 and low CAT levels were observed in HCC patient samples, offering an ideal target for NQO1 bioactivatable drug β‐Lap. Treatment of β‐Lap hold great promise in NQO1‐selective killing of HCC cells, causing ROS accumulation and PARP1 hyperactivation, together with a greatly decrease of NAD+ and ATP levels and an increase of double‐strand break (DSB) lesions over time in vitro. Administration of β‐Lap in orthotopic xenograftin vivo, as well as subcutaneous, significantly inhibited tumor growth and prolonged mice survival.
Conclusions
Our data suggest that NQO1 is an ideal potential biomarker and NQO1:CAT is a therapeutic window for NQO1 bioactivatable drugs in HCC and offers preclinical proof‐of‐concept for β‐Lap as a promising new chemotherapeutic agent for NQO1‐postive HCC patients regardless of oncogenic driver or passenger mutations. |
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ISSN: | 0892-6638 1530-6860 |
DOI: | 10.1096/fasebj.2021.35.S1.04949 |