β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation

Zhao, Wenxiu; Jiang, Lingxiang; Fang, Ting; Fang, Fei; Liu, Yingchun; Zhao, Ye; You, Yuting; Zhou, Hao; Su, Xiaolin; Wang, Jiangwei; Liu, Sheng; Chen, Yaomin; Wan, Jun; Huang, Xiumei

doi:10.3389/fonc.2021.747282

Cited by 16 publications

(17 citation statements)

References 42 publications

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“…Additionally, while NQO1:CAT was not directly measured, inhibition of catalase and GSH did not lead to a sensitization of KEAP1-mutated NSCLC during −lapachone treatment while inhibition of TXNRD and SOD1 sensitized cancers (28). A recent TCGA analysis revealed higher NQO1:CAT levels in hepatocellular carcinoma (HCC) than in matched healthy tissue, and the authors reported that the high NQO1 patient cohort had lower survival (37).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, while NQO1:CAT was not directly measured, inhibition of catalase and GSH did not lead to a sensitization of KEAP1-mutated NSCLC during β–lapachone treatment while inhibition of TXNRD and SOD1 sensitized cancers (28). A recent TCGA analysis revealed higher NQO1:CAT levels in hepatocellular carcinoma (HCC) than in matched healthy tissue, and the authors reported that the high NQO1 patient cohort had lower survival (37). These studies serve to highlight the complexity of the antioxidant system in the context of NQO1-activatable drugs like β–lapachone, and suggest the current approach for identifying how well a cancer would respond to the treatment is underdeveloped.…”

Section: Discussionmentioning

confidence: 99%

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Single cell kinetic modeling of redox-based drug metabolism in head and neck squamous cell carcinoma

Raddatz

Furdui

Bey

et al. 2022

Preprint

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Head and neck squamous cell carcinoma (HNSCC) cells are highly heterogeneous in their metabolism and typically experience elevated reactive oxygen species (ROS) levels in the tumor microenvironment. The tumor cells survive under these chronic oxidative conditions by upregulating antioxidant systems compared to healthy cells. Radiation and the majority of chemotherapies used clinically for treatment of HNSCC rely directly or indirectly upon the generation of short-lived ROS to induce cancer cell death. To investigate the heterogeneity of cellular responses to chemotherapeutic ROS generation in tumor and healthy tissue, we leveraged single cell RNA-sequencing (scRNA-seq) data to perform redox systems-level simulations of quinone-cycling β-lapachone treatment as a source of NQO1-dependent rapid superoxide and hydrogen peroxide (H2O2) production. Transcriptomic data from 10 HNSCC patient tumors was used to populate over 4000 single cell antioxidant enzymatic models. The simulations reflected significant systems-level differences between the redox states of healthy and cancer cells, demonstrating in some patient samples a targetable cancer cell population or in others statistically indistinguishable effects between non-malignant and malignant cells. Subsequent multivariate analyses between healthy and malignant cellular models point to distinct contributors of redox responses between these phenotypes. This model framework provides a mechanistic basis for explaining mixed outcomes of NQO1-bioactivatable therapeutics despite the tumor specificity of these drugs as defined by NQO1/catalase expression.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Single cell kinetic modeling of redox-based drug metabolism in head and neck squamous cell carcinoma

Raddatz

Furdui

Bey

et al. 2022

Preprint

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“…The overexpression of Nqo1 has been observed in HCC and enhances the vulnerability of cells to oxidative stress-induced injury. Nqo1 is also involved in regulating the proliferative and aggressive characteristics of HCC [ 45 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype

Neuckermans

Lequeue

Claes

et al. 2023

Genes

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Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.

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“…Manganese porphyrin enhances NRF2 in the normal tissue only (Shrishrimal et al, 2017;Chatterjee et al, 2020), which helps to sustain the natural anticancer activity of normal cells and increase anticancer treatment efficacy. β-Lapachone senses the NQO1 levels in the tissue and inhibits NRF2 signaling to maintain homeostasis (Gong Q et al, 2021;Wu et al, 2021;Zhao et al, 2021). As the advanced PCa tissue harbors enhanced NRF2-NQO1 levels as compared to the normal prostate tissue, to cope with increased oxidative stress, β-Lapachone may have a better efficacy to reduce NRF2 selectively in cancer tissue.…”

Section: Nrf2 Modulators In Anticancer Clinical Trialsmentioning

confidence: 99%

NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression

et al. 2022

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Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer. In agreement, the blanket use of NRF2 inducers or inhibitors along with anticancer therapies cause adverse effects in some preclinical cancer models. In this review, we have summarized the levels of oxidative stress, metabolic preferences and NRF2 activity in the different stages of prostate cancer. We also propose condition specific ways to use NRF2 inducers or inhibitors along with conventional prostate cancer therapies. The significance of this review is not only to provide a detailed understanding of the mechanism of action of NRF2 to regulate oxidative stress-mediated metabolic switching by prostate cancer cells to escape the radiation, chemo, or hormonal therapies, and to grow aggressively, but also to provide a potential therapeutic method to control aggressive prostate cancer growth by stage specific proper use of NRF2 regulators.

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β-Lapachone Selectively Kills Hepatocellular Carcinoma Cells by Targeting NQO1 to Induce Extensive DNA Damage and PARP1 Hyperactivation

Cited by 16 publications

References 42 publications

Single cell kinetic modeling of redox-based drug metabolism in head and neck squamous cell carcinoma

Single cell kinetic modeling of redox-based drug metabolism in head and neck squamous cell carcinoma

Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype

NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression

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