PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage

Su, Xiaolin; Wang, Jiangwei; Jiang, Lingxiang; Chen, Yaomin; Lü, Tao; Mendonca, Marc S.; Huang, Xiumei

doi:10.1016/j.canlet.2021.07.040

Cited by 14 publications

(18 citation statements)

References 49 publications

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“…Although these two extensively used NSCLC cell lines were highly consistent in their results, there are likely cell line specific responses to β-Lapachone that reflect distinct biology and cell of origin. Finally, β-Lapachone induced acute toxicity in red blood cells [ [56] , [57] , [58] ] preclude us from further assessing SOD2 inhibition in vivo. It will be fascinating to assess SOD2 inhibition whenever a tolerable version of a β-Lapachone analog becomes available.…”

Section: Discussionmentioning

confidence: 99%

A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer

et al. 2022

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Section: Discussionmentioning

confidence: 99%

A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer

et al. 2022

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“…Although these two extensively used NSCLC cell lines were highly consistent in their results, there are likely cell line specific responses to β-Lapachone that reflect distinct biology and cell of origin. Finally, β-Lapachone induced acute toxicity in red blood cells [50][51][52] preclude us from further assessing SOD2 inhibition in vivo. It will be fascinating to assess SOD2 inhibition whenever a tolerable version of β-Lapachone analog becomes available.…”

Section: Discussionmentioning

confidence: 99%

A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer

Jiang

Ward

Prieto-Farigua

et al. 2022

Preprint

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The redox regulator NRF2 is hyperactivated in a large percentage of non-small cell lung cancer (NSCLC) cases, which is associated with chemotherapy and radiation resistance. To identify redox vulnerabilities for KEAP1/NRF2 mutant NSCLC, we conducted a CRISPR-Cas9-based negative selection screen for antioxidant enzyme genes whose loss sensitized cells to sub-lethal concentrations of the superoxide-generating drug β-Lapachone. While our screen identified expected hits in the pentose phosphate pathway, the thioredoxin-dependent antioxidant system, and glutathione reductase, we also identified the mitochondrial superoxide dismutase 2 (SOD2) as one of the top hits. Surprisingly, β-Lapachone did not generate mitochondrial superoxide, but rather SOD2 loss enhanced the efficacy of β-Lapachone due to loss of iron-sulfur protein function, loss of mitochondrial ATP maintenance and deficient NADPH production. Importantly, inhibition of mitochondrial electron transport activity sensitized to β-Lapachone, demonstrating these effects may be translated to increase ROS sensitivity therapeutically.

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“…β-Lapachone (β-Lap, 1, Figure 1), an ortho-naphthoquinone natural product isolated from the lapacho tree in South America, is a promising anticancer agent because of its extensive anticancer activity. [26][27][28][29] Specifically, β-lap has entered multiple clinical trials as a potential candidate for the treatment of pancreatic and lung cancers. [26,28,30] Detailed mechanistic studies have revealed that 1 exerts anticancer efficacy mainly through NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling owing to the orthoquinone moiety of 1.…”

Section: Introductionmentioning

confidence: 99%

“…β‐Lapachone (β‐Lap, 1 , Figure 1), an ortho ‐naphthoquinone natural product isolated from the lapacho tree in South America, is a promising anticancer agent because of its extensive anticancer activity [26–29] . Specifically, β‐lap has entered multiple clinical trials as a potential candidate for the treatment of pancreatic and lung cancers [26, 28, 30] .…”

Section: Introductionmentioning

confidence: 99%

A Carbon‐Carbon Bond Cleavage‐Based Prodrug Activation Strategy Applied to β‐Lapachone for Cancer‐Specific Targeting

Gong

et al. 2022

Angewandte Chemie

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Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (CÀ C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of β-lapachone (β-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of CÀ N/CÀ O bond cleavage-based prodrugs. The designed β-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing β-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1rich cancer cells over normal cells both in vitro and in vivo. This significantly amplified the therapeutic window of β-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.

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PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage

Cited by 14 publications

References 49 publications

A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer

A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer

A CRISPR screen identifies redox vulnerabilities for KEAP1/NRF2 mutant non-small cell lung cancer

A Carbon‐Carbon Bond Cleavage‐Based Prodrug Activation Strategy Applied to β‐Lapachone for Cancer‐Specific Targeting

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