NAD(P)H:Quinone Oxidoreductase Functionality in Cancer Therapy

NAD(P)H:quinone oxidoreductase enzymes (principally NQO1 and NQO2) serve as crucial redox regulators by catalysing the two-electron reduction of quinones to hydroquinones, thereby preventing one-electron redox cycling and excessive reactive oxygen species formation. In healthy tissues these flavoproteins contribute to antioxidant defence, coenzyme Q10 metabolism and stabilisation of tumour suppressors. Paradoxically, many solid tumours overexpress NQO1, rendering cancer cells vulnerable to quinone-based prodrugs that exploit the enzyme’s catalytic cycle to generate cytotoxic reactive oxygen species and deplete cellular NAD(P)H and ATP. This dual nature—protective in normal cells, pro-oxidant in tumours—underpins a therapeutic window for selective cancer cell killing. The dysregulated activity of NQO1 also influences hypoxic adaptation through stabilisation of key transcription factors, modulates proteasomal degradation pathways and impacts sensitivity to radiotherapy and chemotherapy. Recent advances have focused on elucidating the structural basis of enzyme variants, defining the redox-switch function of NQO1 in cellular stress responses and designing combination strategies that harness enzyme-activated quinones alongside complementary agents to overcome drug resistance in aggressive malignancies.

Research from Nature Portfolio

A seminal study revealed that NQO1 directly binds to the oxygen-dependent degradation domain of hypoxia-inducible factor-1α, shielding it from proteasome-mediated turnover. By preventing prolyl hydroxylase engagement, NQO1 stabilises HIF-1α under normoxic conditions, thus promoting angiogenesis, metabolic adaptation and survival of solid tumours. Genetic or pharmacological inhibition of NQO1 in colorectal and breast cancer models suppressed HIF-1α signalling, reduced tumour growth and improved outcome measures, highlighting a non-catalytic role for NQO1 as an oxygen-sensing modulator with implications for targeted therapy.

NAD(P)H:Quinone Oxidoreductase Functionality in Cancer Therapy publication trend

The graph below shows the total number of articles in nad(p)h:quinone oxidoreductase functionality in cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

NAD(P)H:quinone oxidoreductase (NQO1): Flavoprotein enzyme that catalyses the two-electron reduction of quinones, preventing reactive oxygen species formation and modulating cellular redox balance.

Quinone: Aromatic compound capable of redox cycling, which can generate reactive oxygen species through one-electron reduction pathways.

Redox cycling: Continuous process of electron transfer between a compound and molecular oxygen, leading to oxidative stress in cells.

β-Lapachone: Quinone-based chemotherapeutic prodrug bioactivated by NQO1 to induce tumour-selective oxidative damage and cell death.

Hypoxia-inducible factor-1α (HIF-1α): Oxygen-responsive transcription factor that regulates genes involved in angiogenesis, metabolism and survival under low-oxygen conditions; stabilised by NQO1 interaction.

References

1. Unlocking the effective alliance of β-lapachone and hydroxytyrosol against triple-negative breast cancer cells. Biomedicine & Pharmacotherapy (2024).
2. Functions of NQO1 in Cellular Protection and CoQ10 Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. Frontiers in Physiology (2017).
3. NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nature Communications (2016).
4. Phase 1 study of ARQ 761, a β-lapachone analogue that promotes NQO1-mediated programmed cancer cell necrosis. British Journal of Cancer (2018).