title: Bezielle (BZL101)-induced oxidative stress damage followed by redistribution of metabolic fluxes in breast cancer cells: a combined proteomic and metabolomic study.
abstract: Bezielle is an orally administered aqueous extract of Scutellaria barbata for treatment of advanced and metastatic breast cancer. Phase I trials showed promising tolerability and efficacy. In our study, we used a combined proteomic-metabolomic approach to investigate the molecular pathways affected by Bezielle in ER-positive BT474 and ER-negative SKBR3 cell lines. In both, Bezielle inhibited cell proliferation, induced cell death and G2 cycle arrest by regulating the mediator proteins Jab1, p27(Kip1)  and p21(Cip1) . In addition, it stimulated reactive oxygen species production, hyperactivation of PARP and inhibition of glycolysis. Bezielle's ability to induce oxidative stress was associated with the changes in expression of redox potential maintaining enzymes: glutathione- and thioredoxin-related proteins and peroxiredoxins. In regards to cell metabolism, decreased expression of α-enolase was associated with a reduction of de novo (13) C-lactate formation. Reduced Krebs cycle activity as evidenced by the reduced expression of α-ketoglutarate dehydrogenase and succinyl-CoA synthetase led to decreased intracellular succinate concentrations. By inhibiting glucose metabolism, cells reacted by lowering the expression of glucose transporters and resulting in decreased intracellular glucose concentration. Decreased expression of fatty acid synthase and reduced concentration of phosphocholine indicated considerable changes in phospholipid metabolism. Ultimately, by inhibiting the major energy-producing pathways, Bezielle caused depletion of ATP and NAD(H). Both cell lines were responsive, thus suggesting that Bezielle has the potential to be effective against ER-negative breast cancers. In conclusion, Bezielle's cytotoxicity toward cancer cells is primarily based on inhibition of metabolic pathways that are preferentially activated in tumor cells thus explaining its specificity for cancer cells.
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, CO, USA. jelena.klawitter@ucdenver.edu
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.forename: Jost
authors.initials: J
authors.lastname: Klawitter
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gurshtein
authors.forename: Kyler
authors.initials: K
authors.lastname: Corby
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fong
authors.forename: Mary
authors.initials: M
authors.lastname: Tagliaferri
authors.forename: Linda
authors.initials: L
authors.lastname: Quattrochi
authors.forename: Isaac
authors.initials: I
authors.lastname: Cohen
authors.forename: Emma
authors.initials: E
authors.lastname: Shtivelman
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D055432:Metabolomics / Q000379:methods*; D018384:Oxidative Stress; D010936:Plant Extracts / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods*; D031363:Scutellaria; D031364:Scutellaria baicalensis; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010936:Plant Extracts; C524947:Scutellaria barbata extract