Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

Li, Jason Z.; Ke, Yuebin; Misra, Hara P.; Trush, Michael A.; Li, Y. Robert; Zhu, Hong; Jia, Zhenquan

doi:10.1016/j.taap.2014.10.012

Cited by 44 publications

(23 citation statements)

References 43 publications

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“…It is the main non-mitochondrial enzyme responsible for the reduction of CoQ10 in cells. Thus, NQO1 may “boost” mitochondrial metabolism by providing increased reduced CoQ10 species to facilitate oxidative mitochondrial metabolism [25, 26]. …”

Section: Discussionmentioning

confidence: 99%

Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

et al. 2017

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Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007).

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Section: Discussionmentioning

confidence: 99%

Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

et al. 2017

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“…Studies are currently underway in our laboratories to apply this novel method to investigate the redox mechanisms of cancer cell metastasis and the therapeutic effects of novel anticancer drugs, including the redox active beta-lapachone and other natural quinones that generate reactive oxygen species (ROS). In this context, our previous studies showed beta-lapachone as a potent killer of B16-F10 melanoma cells via the mitochondrial electron transport chain-mediated redox activation to form tumoricidal ROS [10]. …”

Section: Resultsmentioning

confidence: 99%

Innovative Bioluminometric Quantification of Cancer Cell Load in Target Organs: Implications for Studying Anticancer Drugs, Including ROS Enhancers

Zhu

Kauffman

et al. 2016

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Animal models are essential for developing effective drugs for treating human cancer. Examination of the formation of lung surface foci of B16-F10 melanoma cells is a widely used animal model for studying cancer metastasis and drug intervention. This model, however, suffers from several drawbacks, including its non-quantitative nature and inability to yield information on cancer cell load inside the target organ. Here we report the development of a highly sensitive, bioluminescence-based method for quantifying melanoma cell load in mouse lungs following intravenous injection of luciferase-expressing B16-F10 melanoma cells. This method could readily detect as few as 1–10 cells in the samples and enable quantification of cancer cell load before the formation of surface foci in mouse lungs following metastasis of intravenously inoculated B16-F10 melanoma cells. This innovative bioluminometry-based method has important implications for studying anticancer drugs, including naturally occurring redox-active quinones that generate reactive oxygen species to kill cancer cells.

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“…In addition, β-lapachone exhibited an anti-cancer effect in various types of cancer, including liver, breast, prostate, and colon cancer [16–19]. In particular, it induced cytotoxicity in melanoma cells through reactive oxygen species, and NAD(P)H:quinone acceptor oxidoreductase (NQO) 1-mediated redox activation [20]. However, the anti-metastatic effects of β-lapachone on melanoma cells were rarely reported.…”

Section: Introductionmentioning

confidence: 99%

β-Lapachone suppresses the lung metastasis of melanoma via the MAPK signaling pathway

et al. 2017

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β-Lapachone is a natural quinone compound from Lapacho trees, which has various pharmacological effects such as anti-bacterial, anti-fungal, anti-viral, and anti-inflammatory activities. However, the effect of β-lapachone on metastasis of melanoma cells is unclear. In this study, β-lapachone reduced cell viability of metastatic melanoma cancer cell lines B16F10 and B16BL6 through induction of apoptosis via the mitogen-activated protein kinase (MAPK) pathway. Additionally, flow cytometry results showed that β-lapachone increased DNA content in the G0/G1 phase of the cell cycle. Analysis of the mechanisms of these events indicated that β-lapachone regulated the expression of Bcl-2, Bcl-xL, and Bax, resulting in the activation of caspase-3, -8, -9, and poly-ADP-ribose polymerase (PARP). Moreover, the β-lapachone-administered group showed significantly decreased lung metastasis in the experimental mouse model. In conclusion, our study demonstrates the inhibitory effect of β-lapachone on lung metastasis of melanoma cells and provides a new insight into the role of β-lapachone as a potential antitumor agent.

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Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent

Cited by 44 publications

References 43 publications

Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

Innovative Bioluminometric Quantification of Cancer Cell Load in Target Organs: Implications for Studying Anticancer Drugs, Including ROS Enhancers

β-Lapachone suppresses the lung metastasis of melanoma via the MAPK signaling pathway

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