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Synergistic Lethality between Beta‐lapachone and Proliferating Cell Nuclear Antigen (PCNA) Inhibitor in NQO1‐positive Cancer Cells
Author(s) -
Su Xiaolin,
Wang Jiangwei,
Jiang Lingxiang,
Huang Xiumei
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04956
Subject(s) - proliferating cell nuclear antigen , chemistry , cancer cell , cancer , antigen , beta (programming language) , synthetic lethality , lethality , cancer research , microbiology and biotechnology , biology , cell growth , dna repair , dna , biochemistry , immunology , genetics , computer science , programming language
β‐Lapachone is a classical quinone‐containing anti‐tumor NQO1 bioactivatable drug which directly kills NQO1 overexpressing cancer cells. However, the clinical applications of β‐lapachone are major limited by its high toxicity and modest lethality. To overcome this side effect and expand the therapeutic utility of β‐lapachone, we here demonstrate a novel combination therapy of β‐lapachone with proliferating cell nuclear antigen (PCNA) inhibitor T2 amino alcohol (T2AA) in various NQO1 + cancer cells. PCNA has a DNA clamp processivity by encircling the DNA double strands to recruit proteins involved in DNA replication and DNA repair. In this study, we found that non‐toxic dose of PCNA inhibitor T2AA synergized with sublethal dose of β‐lapachone in an NQO1‐dependent manner, and combination of T2AA with β‐lapachone prevented DNA repair, increased DSB formation and PARP1 hyperactivation, and induced catastrophic energy loss compared to monotherapy. We further defined that T2AA promoted programmed necrosis and S‐phase cell cycle arrest in β‐lapachone‐treated NQO1 + cancer cells.