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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) is a leading global cause of cancer mortality.
• Existing therapies for HCC lack tumor selectivity and efficacy.
• β-Lapachone is a compound known to selectively target cancer cells overexpressing NADPH: quinone oxidoreductase 1 (NQO1).

Purpose of the Study:

• To investigate the efficacy of β-Lapachone against HCC.
• To determine the role of NQO1 and catalase in HCC response to β-Lapachone.
• To evaluate β-Lapachone as a potential chemotherapeutic agent for HCC.

Main Methods:

• Analysis of NQO1 and catalase levels in HCC patient specimens and TCGA data.
• In vitro studies assessing β-Lapachone's effect on HCC cell lines, including ROS formation, PARP1 activation, NAD+/ATP levels, and DNA damage.
• In vivo evaluation of β-Lapachone efficacy using a mouse xenograft model.

Main Results:

• HCC tumors exhibited high NQO1 and low catalase levels.
• β-Lapachone induced NQO1-dependent cancer cell death, increased reactive oxygen species (ROS), and PARP1 hyperactivation.
• Significant reductions in NAD+ and ATP levels and increased DNA double-strand breaks (DSB) were observed.
• β-Lapachone treatment inhibited tumor growth and improved survival in vivo.
• High NQO1:CAT ratios in tumors versus normal tissues suggest a therapeutic window.

Conclusions:

• NQO1 is a potential biomarker for HCC treatment selection.
• β-Lapachone demonstrates significant preclinical efficacy against HCC by exploiting high NQO1 expression.
• The findings support β-Lapachone as a promising chemotherapeutic agent for NQO1-positive HCC patients.