Bezielle (BZL101)‐induced oxidative stress damage followed by redistribution of metabolic fluxes in breast cancer cells: A combined proteomic and metabolomic study

Klawitter, Jelena; Klawitter, Jost; Gurshtein, Jennifer; Corby, Kyler; Fong, Sylvia; Tagliaferri, Mary; Quattrochi, Linda C.; Cohen, Isaac; Shtivelman, Emma; Christians, Uwe

doi:10.1002/ijc.25965

Cited by 24 publications

(16 citation statements)

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“…Previously published analysis of the transcriptional changes induced by Bezielle in tumor cells [8] indicated that the glutathione redox system is engaged in the cellular response to Bezielle, a conclusion supported by the recent proteomic and metabolomic analyses [24]. Thus, elevated expression of cystathionine-beta-synthase and glutamate cysteine ligase modifier GCLM were observed in Bezielle treated tumor cells but not in non-transformed cells.…”

Section: Resultsmentioning

confidence: 76%

“…Indeed, our results show that Bezielle induces mainly necrotic death [8] that is known to be associated with the hyperactivation of PARP-1 [21], [22], [23]. A recent detailed combined proteomic and metabolomic analysis of breast cancer cells treated with Bezielle revealed induction of oxidative stress damage followed by redistribution of metabolic fluxes [24]. Specifically, three families of enzymes involved in maintenance of redox potential were affected by Bezielle: glutathione- and thioredoxin-related proteins and peroxiredoxins.…”

Section: Introductionmentioning

confidence: 62%

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Bezielle Selectively Targets Mitochondria of Cancer Cells to Inhibit Glycolysis and OXPHOS

et al. 2012

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Bezielle (BZL101) is a candidate oral drug that has shown promising efficacy and excellent safety in the early phase clinical trials for advanced breast cancer. Bezielle is an aqueous extract from the herb Scutellaria barbata. We have reported previously that Bezielle was selectively cytotoxic to cancer cells while sparing non-transformed cells. In tumor, but not in non-transformed cells, Bezielle induced generation of ROS and severe DNA damage followed by hyperactivation of PARP, depletion of the cellular ATP and NAD, and inhibition of glycolysis. We show here that tumor cells' mitochondria are the primary source of reactive oxygen species induced by Bezielle. Treatment with Bezielle induces progressively higher levels of mitochondrial superoxide as well as peroxide-type ROS. Inhibition of mitochondrial respiration prevents generation of both types of ROS and protects cells from Bezielle-induced death. In addition to glycolysis, Bezielle inhibits oxidative phosphorylation in tumor cells and depletes mitochondrial reserve capacity depriving cells of the ability to produce ATP. Tumor cells lacking functional mitochondria maintain glycolytic activity in presence of Bezielle thus supporting the hypothesis that mitochondria are the primary target of Bezielle. The metabolic effects of Bezielle towards normal cells are not significant, in agreement with the low levels of oxidative damage that Bezielle inflicts on them. Bezielle is therefore a drug that selectively targets cancer cell mitochondria, and is distinguished from other such drugs by its ability to induce not only inhibition of OXPHOS but also of glycolysis. This study provides a better understanding of the mechanism of Bezielle's cytotoxicity, and the basis of its selectivity towards cancer cells.

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Section: Resultsmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 62%

Bezielle Selectively Targets Mitochondria of Cancer Cells to Inhibit Glycolysis and OXPHOS

et al. 2012

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“…Storage at 280°C is the recommended condition for long-term LC-MS/MS-based metabolomic analyses (17) and samples have been shown to be stable across time and freeze thaw cycles with this storage method (18). These technologies are well established in our laboratory (19)(20)(21)(22) and utilize a positive/negative ion switching, targeted mass spectrometry-based metabolomics platform on an AB Sciex 5500 QTRAP system (AB Sciex, Concord, ON, Canada) that was established by Yuan et al (23) and further extended and improved within our laboratory. This method utilizes compound-specific multiple reaction monitoring transitions.…”

Section: Urine Metabolomicsmentioning

confidence: 99%

Effect of Dietary Sodium Restriction on Human Urinary Metabolomic Profiles

Jablonski

Klawitter

Chonchol

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Metabolomics is a relatively new field of "-omics" research, focusing on highthroughput identification of small molecular weight metabolites. Diet has both acute and chronic effects on metabolic profiles; however, alterations in response to dietary sodium restriction (DSR) are completely unknown. The goal of this study was to explore changes in urine metabolites in response to DSR, as well as their association with previously reported improvements in vascular function with DSR.Design, setting, participants, & measurements Using stored urine samples from a 10-week randomized placebo-controlled crossover study of DSR in 17 middle-aged/older adults (six men and 11 women; mean age 6268 years) who had moderately elevated systolic BP (130-159 mmHg) and were otherwise healthy, a liquid chromatography/mass spectrometry-based analysis of 289 metabolites was performed. This study identified metabolites that were significantly altered between the typical (153629 mmol/d) and low (70629 mmol/d) sodium conditions, as well as their baseline (typical sodium) association with responsiveness to previously reported improvements in vascular endothelial function (brachial artery flow-mediated dilation) and large elastic artery stiffness (aortic pulse wave velocity).Results Of the 289 metabolites surveyed, 10 were significantly altered (nine were upregulated and one was downregulated) during the low sodium condition, and eight of these exceeded our prespecified clinically significant threshold of a .40% change. These metabolites were involved in biologic pathways broadly related to cardiovascular risk, nitric oxide production, oxidative stress, osmotic regulation, and metabolism. One metabolite, serine, was independently (positively) associated with previously reported improvements in the primary vascular outcome of brachial artery flow-mediated dilation.Conclusions This proof-of-concept study provides the first evidence that DSR is a stimulus that induces significant changes in urinary metabolomic profiles. Moreover, serine was independently associated with corresponding changes in vascular endothelial function after DSR. Larger follow-up studies will be required to confirm and further elucidate the metabolic pathways that are altered in response to DSR.

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“…barbata has been most extensively studied for breast cancer treatment, with extensive testing done on five different types of breast cancer cells showing S. barbata extracts had more than 50% inhibition in three out of the five cell lines (Campbell et al, 2002). BZL101 was repeatedly documented to exhibit cytotoxic effects on both ER+ and ER-breast cancer cell lines (Fong et al, 2008;Klawitter et al, 2011;Marconett et al, 2010). Due to strong preclinical data, BZL101…”

Section: Figurementioning

confidence: 99%

Current therapeutic role and medicinal potential of Scutellaria barbata in Traditional Chinese Medicine and Western research

Tao

Balunas

2016

Journal of Ethnopharmacology

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Ethnopharmacological relevance: Scutellaria barbata is a common herb in Traditional ChineseMedicine (TCM) most often used to treat cancer. S. barbata has been found to exhibit efficacy both in vitro and in vivo on a variety of cancer types. Similarly encouraging results have been shown in patients with metastatic breast cancer from Phase Ia and Ib clinical trials. This study aims to elucidate the current use of S. barbata by TCM practitioners and in current Western research. Materials and Methods:Semi-structured interviews were conducted with fifteen TCM practitioners in Beijing and Nanjing, China to understand their clinical use of S. barbata.Practitioners were also asked to comment on the future development of TCM using Western research methods and the potential for integration of the two types of medicine in clinical therapy. Statistical analyses were conducted to compare use of S. barbata by disease and in conjunction with other herbs.Results: Current Western research related to S. barbata is focused on cancer treatment, which corresponds to the most common use of S. barbata by TCM practitioners. Other common uses that practitioners reported included infection and inflammation, for which Beijing practitioners reported use of S. barbata more often than Nanjing practitioners (p < 0.05). Hedyotis diffusa was found to be the most commonly cited herb to pair with S. barbata for cancer treatment (p < 0.05).When compared to Western clinical trials of BZL101, an S. barbata extract, TCM practitioners reported using smaller doses of S. barbata in shorter durations, in combination with numerous other herbs with the goal to potentiate therapeutic efficacy and mitigate side effects. In addition, TCM practitioners repeatedly emphasized symptom differentiating as the key to achieving maximum therapeutic potential of S. barbata, a factor typically overlooked in Western research.

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Bezielle (BZL101)‐induced oxidative stress damage followed by redistribution of metabolic fluxes in breast cancer cells: A combined proteomic and metabolomic study

Cited by 24 publications

References 50 publications

Bezielle Selectively Targets Mitochondria of Cancer Cells to Inhibit Glycolysis and OXPHOS

Bezielle Selectively Targets Mitochondria of Cancer Cells to Inhibit Glycolysis and OXPHOS

Effect of Dietary Sodium Restriction on Human Urinary Metabolomic Profiles

Current therapeutic role and medicinal potential of Scutellaria barbata in Traditional Chinese Medicine and Western research

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