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Visualization and Quantitative Analysis of Genotoxin-Induced PARP1/PARP2 Activation in Cells Using a Fluorescent Fusion Protein-Based Reporter
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Prostate cancer radiosensitization through poly(ADP-Ribose) polymerase-1 hyperactivation.
Ying Dong1, Erik A Bey, Long-Shan Li
1Departments of Pharmacology, Radiation Oncology, Pathology, Biostatistics and Clinical Sciences, and Urology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8807, USA.
Cancer Research
|October 14, 2010
Summary
Beta-lapachone (β-lap) enhances radiation therapy for prostate cancer by targeting NQO1-positive cells. It induces DNA damage and cell death, showing promise for clinical use with radiation.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Beta-lapachone (β-lap) is a potential radiosensitizer with an unclear mechanism.
- NAD(P)H:quinone oxidoreductase 1 (NQO1) is implicated in β-lap's cytotoxic effects.
Purpose of the Study:
- To elucidate the mechanism of β-lap as a radiosensitizer.
- To evaluate β-lap's potential for clinical use in prostate cancer treatment.
Main Methods:
- Investigated β-lap's effects on prostate cancer cells, including DNA damage and cell death pathways.
- Assessed the combination of β-lap with ionizing radiation (IR) in vitro and in a mouse xenograft model.
- Utilized NQO1 and poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors to block radiosensitization.
Main Results:
- β-lap induced reactive oxygen species, DNA single-strand breaks (SSBs), PARP-1 hyperactivation, and programmed necrosis via NQO1 bioactivation.
- Combination therapy with β-lap and IR synergistically increased SSBs, γ-H2AX foci, and PARP-1 poly(ADP-ribosylation), leading to ATP depletion and cell death.
- Radiosensitization was dependent on NQO1 and PARP-1 activity, as confirmed by inhibitor studies.
- β-lap and IR demonstrated synergistic antitumor efficacy in a prostate cancer xenograft model.
Conclusions:
- β-lap acts as a radiosensitizer by inducing NQO1-dependent DNA damage and cell death pathways.
- Combination therapy with β-lap and IR shows significant antitumor activity.
- β-lap is a promising radiosensitizer for NQO1-overexpressing prostate cancers, potentially enhancing radiation therapy efficacy.
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