β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation.

Wenxiu Zhao,Yuting You,Fei Fang,Yaomin Chen,Xiaolin Su,Lingxiang Jiang,Jiangwei Wang,Ting Fang,Hao Zhou,Yingchun Liu,Jun Wan,Ye Zhao,Xiumei Huang,Sheng Liu

doi:10.3389/fonc.2021.747282

Abstract

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.

Highlights

As the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide [1], hepatocellular carcinoma (HCC) patients are usually diagnosed with advanced disease, resulting in only 15% of Hepatocellular carcinoma (HCC) patients being eligible for surgical resection or liver transplantation and the median survival time for HCC patients in intermediate to advanced stages being only 1-2 years [2]
These results indicate that the NADPH:quinone oxidoreductase 1 (NQO1):CAT ratio is an ideal therapeutic window in liver cancer for NQO1 bioactivatable drugs
Except the expression and activity of NQO1, the cytotoxicity of b-lap is driven by reactive oxygen species (ROS)-metabolizing enzymes catalase and SOD1 expression and activity. catalase is an important resistance factor in b-lap-induced cytotoxicity and this resistance could be enhanced by superoxide dismutase (SOD) [37]

Summary

Introduction

As the most common primary liver cancer and the second leading cause of cancer-related deaths worldwide [1], hepatocellular carcinoma (HCC) patients are usually diagnosed with advanced disease, resulting in only 15% of HCC patients being eligible for surgical resection or liver transplantation and the median survival time for HCC patients in intermediate to advanced stages being only 1-2 years [2]. The first-line drug used for patients with advanced HCC, has been used for over 10 years, but the overall outcomes are unsatisfactory [3]. These have led to more extensive research focusing on personalized medicine with increased selectivity and efficacy. It has been reported that NQO1 was increased 18-fold in HCC versus normal livers [12]. NQO1 overexpression was reported to be a potent independent biomarker for prognostic evaluation of HCC [13] and enhanced apoptosis inhibition of liver cancer cells via the SIRT6/AKT/XIAP signaling pathway [14, 15]. NQO1 overexpression in tumors has the advantage of preferentially killing cancer cells and sparing normal cells when anticancer drugs that are bioreductively activated by NQO1, such as b-Lapachone (b-lap), are used [5]

Methods

Results

Conclusion