Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone

Torrente, Laura; Prieto-Farigua, Nicolas; Falzone, Aimee; Elkins, Cody M; Boothman, David A.; Haura, Eric B.; DeNicola, Gina M.

doi:10.1016/j.redox.2020.101440

Cited by 36 publications

(39 citation statements)

References 65 publications

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“…Intriguingly, these quinones, along with emodin (Mischitelli et al, 2016b) and NSC-95397 (Mischitelli et al, 2016a), cause redox imbalance in RBCs, which LAP does not (Figure 5). This is in contrast to the oxidative properties of LAP observed in nucleated cells (Bey et al, 2007;Han et al, 2019;Li et al, 2014;Park et al, 2011;Torrente et al, 2020), which may be accounted for by differences in metabolic demands between normal and cancer cells. Notably, we have previously shown that N,N-diethyl-3-methylbenzamide (DEET) and triclosan, two other pro-eryptotic compounds, similarly do not elicit oxidative stress in RBCs .…”

Section: Discussionmentioning

confidence: 69%

Reprogramming of erythrocyte lifespan by NFκB‐TNFα naphthoquinone antagonist β‐lapachone is regulated by calcium overload and CK1α

2021

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The pathophysiology of chemotherapy-associated anemia, prevalent in at least 75% of patients, remains difficult to establish. Chemotherapy-related anemia is attributed in part to eryptosis, and it is therefore of considerable interest to interrogate the toxicity of investigative anticancer compounds to red blood cells (RBCs). Beta-lapachone (LAP), an anthraquinone extracted from the bark of Lapacho tree (Tabebuia avellanedae), is effective against a myriad of cancer cells. However, the toxicity of LAP to RBCs remains unexplored. Hemoglobin leakage as a surrogate for hemolysis was photometrically measured, while flow cytometry was employed to capture phosphatidylserine (PS) exposure with Annexin-V-FITC, calcium levels with Fluo4/AM, cell size by forward scatter (FSC), and oxidative stress by H2DCFDA. Our results show that LAP, at antitumor levels (10-30 µM), induces dose-dependent hemolysis secondary to calcium influx from the extracellular space. Moreover, LAP stimulates eryptosis, as evident from PS exposure, which is associated with reduced cell volume and intracellular calcium overload. Importantly, it is also revealed that the cytotoxicity of LAP is mediated through casein kinase 1α. Altogether, this report shows, for the first time, that LAP possesses both hemolytic and eryptotic potential against RBCs that necessitates careful application in chemotherapy. Practical applicationsLapacho is a widely consumed herbal tea with origins in the Tabebuia avellanedae tree endogenous to South America. LAP is one of the active ingredients in lapacho with promising antitumor potential. We show that LAP is cytotoxic to human RBCs by virtue of eryptosis and hemolysis, and we identify associated molecular mechanisms.Given that these two manifestations are known to contribute to chemotherapyinduced anemia, our study provides invaluable insights into the suitability of LAP in cancer management and sheds some light on possible strategies to limit its undesirable side effects.

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Section: Discussionmentioning

confidence: 69%

Reprogramming of erythrocyte lifespan by NFκB‐TNFα naphthoquinone antagonist β‐lapachone is regulated by calcium overload and CK1α

2021

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“…Logically, based on the known mechanism of action, the cytotoxicity of β-lap is expected to be driven by the expression and activity of NQO1, the expression and activity of ROS-metabolizing enzymes (e.g., catalase, SOD1, etc.) ( 11 , 14 ), and the availability of NAD(P)H, which is needed to support both the NQO1-catalyzed generation of ROS and the activity of key ROS-suppressing redox regulatory enzymes [e.g., thioredoxin reductase ( 14 )]. In this context, the localization of NAD(P)H may also become important considering the predominant cytoplasmic localization of NQO1.…”

Section: Introductionmentioning

confidence: 99%

MTHFD2 Blockade Enhances the Efficacy of β-Lapachone Chemotherapy With Ionizing Radiation in Head and Neck Squamous Cell Cancer

et al. 2020

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Head and Neck Squamous Cell Cancer (HNSCC) presents with multiple treatment challenges limiting overall survival rates and affecting patients' quality of life. Amongst these, resistance to radiation therapy constitutes a major clinical problem in HNSCC patients compounded by origin, location, and tumor grade that limit tumor control. While cisplatin is considered the standard radiosensitizing agent for definitive or adjuvant radiotherapy, in recurrent tumors or for palliative care other chemotherapeutics such as the antifolates methotrexate or pemetrexed are also being utilized as radiosensitizers. These drugs inhibit the enzyme dihydrofolate reductase, which is essential for DNA synthesis and connects the 1-C/folate metabolism to NAD(P)H and NAD(P) + balance in cells. In previous studies, we identified MTHFD2, a mitochondrial enzyme involved in folate metabolism, as a key contributor to NAD(P)H levels in the radiation-resistant cells and HNSCC tumors. In the study presented here, we investigated the role of MTHFD2 in the response to radiation alone and in combination with β-lapachone, a NQO1 bioactivatable drug, which generates reactive oxygen species concomitant with NAD(P)H oxidation to NAD(P) + . These studies are performed in a matched HNSCC cell model of response to radiation: the radiation resistant rSCC-61 and radiation sensitive SCC-61 cells reported earlier by our group. Radiation resistant rSCC-61 cells had increased sensitivity to β-lapachone compared to SCC-61 and knockdown of MTHFD2 in rSCC-61 cells further potentiated the cytotoxicity of β-lapachone with radiation in a dose and time-dependent manner. rSCC-61 MTHFD2 knockdown cells irradiated and treated with β-lapachone showed increased PARP1 activation, inhibition of mitochondrial respiration, decreased respiration-linked ATP production, and increased mitochondrial superoxide and protein oxidation as compared to control rSCC-61 scrambled shRNA. Thus, these studies point to MTHFD2 as a potential target for development of radiosensitizing chemotherapeutics and potentiator of β-lapachone cytotoxicity.

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“…Except the expression and activity of NQO1, the cytotoxicity of β-lap is also driven by ROS-metabolizing enzymes catalase and SOD1 expression and activity. catalase is an important resistance factor in β-lap-induced cytotoxicity and this resistance could be enhanced by superoxide dismutase (SOD) ( 37 ). The NQO1:CAT ratios are suggested to be a therapeutic window in NSCLC, pancreatic and breast cancers ( 11 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death globally. Currently there is a lack of tumor-selective and efficacious therapies for hepatocellular carcinoma. β-Lapachone (ARQ761 in clinical form) selectively kill NADPH: quinone oxidoreductase 1 (NQO1)-overexpressing cancer cells. However, the effect of β-Lapachone on HCC is virtually unknown. In this study, we found that relatively high NQO1 and low catalase levels were observed in both clinical specimens collected from HCC patients and HCC tumors from the TCGA database. β-Lapachone treatment induced NQO1-selective killing of HCC cells and caused ROS formation and PARP1 hyperactivation, resulting in a significant decrease in NAD+ and ATP levels and a dramatic increase in double-strand break (DSB) lesions over time in vitro. Administration of β-Lapachone significantly inhibited tumor growth and prolonged survival in a mouse xenograft model in vivo. Our data suggest that NQO1 is an ideal potential biomarker, and relatively high NQO1:CAT ratios in HCC tumors but low ratios in normal tissues offer an optimal therapeutic window to use β-Lapachone. This study provides novel preclinical evidence for β-Lapachone as a new promising chemotherapeutic agent for use in NQO1-positive HCC patients.

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Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone

Cited by 36 publications

References 65 publications

Reprogramming of erythrocyte lifespan by NFκB‐TNFα naphthoquinone antagonist β‐lapachone is regulated by calcium overload and CK1α

Reprogramming of erythrocyte lifespan by NFκB‐TNFα naphthoquinone antagonist β‐lapachone is regulated by calcium overload and CK1α

MTHFD2 Blockade Enhances the Efficacy of β-Lapachone Chemotherapy With Ionizing Radiation in Head and Neck Squamous Cell Cancer

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

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