Novel Pathways Associated with Quinone-Induced Stress in Breast Cancer Cells

Abstract

Hormone-dependent breast cancers that overexpress the ligand-binding nuclear transcription factor, estrogen receptor (ER), represent the most common form of breast epithelial malignancy. Exposure of breast epithelial cells to a redox-cycling and arylating quinone induces mitogen-activated protein kinase phosphorylation of the cytoskeletal filament protein, cytokeratin-8, along with thiol arylation of H3 nuclear histones. Exogenous or endogenous quinones can also induce ligand-independent nuclear translocation and phosphorylation of ER; with excess exposure, these quinones can arylate ER zinc fingers, impairing ER DNA-binding and altering ER-inducible gene expression. Immunoaffinity enrichment for low abundance proteins such as ER, coupled with modern mass spectrometry techniques, promises to improve understanding of the protein-modifications produced by endogenous and exogenous quinone exposure and their role in the development or progression of epithelial malignancies such as breast cancer.

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

“…Promising results were also reported for cyclodextrin conjugates [79]. Such prodrugs include nitroarenes [94], quinones [95], amidoximes [96], platinum(IV) complexes [38] [97] [98], and Noxides exemplified here with tirapazamine (5.63) [99 -102]. One such target is the human intestinal peptide transporter (hPEPT1) [80], which showed good affinity and good transport capacity toward amino acid ester prodrugs of antiviral agents [81].…”

Oxidative stress and antioxidants in the pathophysiology of malignant melanoma

“…vitamin C has antioxidant activity when it reduces oxidizing substances such as H 2 O 2 , however, at high doses it can also reduce metal ions leading to the generation of free radicals through the fenton reaction) (Uetaki et al, 2015); some anticancer drugs (i.e. adriamycin and other anthracyclines, bleomycin, and cisplatin which bind to DNA and generate ROS) (Kovacic and Wakelin, 2001); or quinones (highly redox active molecules which can redox cycle with their semiquinone radicals, leading to formation of ROS) (Benz et al, 2006). The chemical reactivity of the many different reactive species may vary by up to 11 orders of magnitude when assayed against a given target [with comparable rate constants of 7 × 10 9 l × mol −1 × s −1 for hydroxyl radicals (HO˙) versus 2 × 10 −2 l × mol −1 × s −1 for H 2 O 2 ] (Sies et al, 2017).…”

The TERE1 protein interacts with mitochondrial TBL2: Regulation of trans‐membrane potential, ROS/RNS and SXR target genes

“…Since the electron transport chain is an abundant source of mitochondrial superoxide radicals [Castello et al, 2006;Poyton et al, 2009;Cardoso et al, 2012], and menaquinone is known to undergo redox-cycling and generate reactive oxygen species [ Benz et al, 2006;Klaus et al, 2010], we conducted studies that demonstrate that ectopic TERE1 and TBL2 expression can affect the cellular levels of oxidative stress as evidenced by oxidation of the CellROX fluorogenic probe. We also found that ectopic TERE1 can increase caspase 3/7 activity two-fold.…”