Charles R. Myers, PhD
Professor; Assistant Director, Center for Disease Prevention Research
- Pharmacology and Toxicology
MS, Microbiology/Biology, University of Wisconsin, Oshkosh, 1985
BS, Carrol College, Waukesha, Wisconsin, 1978
- Chromium Compounds
- Cytochromes c
- Manganese Compounds
- Metals, Heavy
- Mitochondrial Membrane Transport Proteins
- Oxidative Stress
- Reactive Oxygen Species
- Thioredoxin Reductase 1
Methodologies and Techniques
- Blotting, Western
- Cell Culture Techniques
- Electron Transport
- Endoplasmic Reticulum, Smooth
- Membrane Potential, Mitochondrial
- Membrane Proteins
- Molecular Biology
- Oxidative Stress
- Anti-Bacterial Agents
- Antibiotics, Antitubercular
- Antifungal Agents
- Antineoplastic Agents
- Antiparasitic Agents
- Antiviral Agents
- Cytochrome P-450 Enzyme System
- Drug Interactions
- Drug Resistance, Microbial
The focus of my research has been on redox-active agents, with special emphasis on metals and metal complexes, including factors which affect their redox state and bioavailability, the mechanisms by which they are enzymatically reduced by microbial and human electron transport systems and other enzymes, their toxic and potentially therapeutic effects, their ability to promote reactive species formation, to compromise antioxidant defense mechanisms, and to damage electron transport complexes.
For the past several years, I have studied the ability of metals, metal complexes, electrophiles, and anti-cancer agents to disrupt cellular thiol redox balance, specifically through differential effects on thioredoxin reductase (TrxR), thioredoxins (Trx), peroxiredoxins (Prx), and mitochondrial electron transport. These systems have central roles in protein thiol redox control, oxidant defense, and redox signaling, and are critical to cell survival. I have used these systems as endogenous indicators of redox stress, noting very tight correlation between disruption of their function and loss of clonogenic survival. The thioredoxin-peroxiredoxin system is therefore highly useful as an endogenous indicator of redox stress, and to validate other redox stress indicators. Since there are cytosolic and mitochondrial isoforms, this approach also provides key insights into the subcellular location of redox stress. For example, we determined that chromium(VI), antitumor thiosemicarbazones, and Mito-honokiol preferentially cause early disruption of mitochondrial peroxiredoxin-3 and/or mitochondrial thioredoxin-2, with important implications for cytotoxicity and loss of thiol redox control. In contrast, the electrophile acrolein initially targets cytosolic TrxR1 and Trx1, with higher doses also promoting mitochondrial effects. Inhibitors of TrxR activity such as auranofin and cisplatin can markedly enhance the mitochondrial pro-oxidant effects of thiosemicarbazones. Complementary approaches have included the use of EPR to demonstrate damage to mitochondrial electron transport proteins (e.g. iron-sulfur centers in complex I) and aconitase by some pro-oxidants. Recent collaborative efforts have focused on various agents that cause oxidative stress as a primary mechanism for their antitumor effects including thiosemicarbazones, Mito-honokiol and other mitochondrial-targeted novel compounds, and Magnolia Extract.
Collaborations with Professor Elias Arnér (Karolinska Institute, Stockholm) have generated multiple insights into the diverse redox chemistry of the selenoprotein thioredoxin reductase 1 (TrxR1). While TrxR1 has multiple roles in antioxidant defense, we characterized several pro-oxidant properties including the generation of superoxide by its N-terminal C59/C64 dithiol, and the peroxidase activity of its C497/U498 selenocystine motif. TrxR1 (specifically its flavin/C59 motif) was also shown to have robust activity to reduce antitumor iron(III)-thiosemicarbazones, which promotes their redox-cycling and reactive species generation that are important for their antitumor effects. TrxR1 also reduces Fe(III)-bleomycin and this activity is dependent on its selenocysteine. The marked elevation of TrxR1 in many tumors could contribute to the selective tumor toxicity of these drugs by enhancing their redox activation. We also contributed to studies demonstrating that the conserved Trp114 of TrxR1 is highly susceptible to oxidation. Oxidation of Trp114 promotes oligomerization of TxrR1, and such oligomers are promoted in tumor cells by the anticancer compound RITA, resulting in cell death that cannot be prevented by antioxidants. Together, these studies revealed multiple new insights into the complex redox chemistry of TrxR1 and ways in which it may be exploited for cancer treatment.
(Antholine WE, Myers CR.) Int J Mol Sci. 2019 Jun 22;20(12).
(Cheng G, Zhang Q, Pan J, Lee Y, Ouari O, Hardy M, Zielonka M, Myers CR, Zielonka J, Weh K, Chang AC, Chen G, Kresty L, Kalyanaraman B, You M.) Nat Commun. 2019 05 17;10(1):2205.
(Antholine WE, Vasquez-Vivar J, Quirk BJ, Whelan HT, Wu PK, Park JI, Myers CR.) Int J Mol Sci. 2019 Mar 06;20(5).
(Cheng G, Zielonka M, Dranka B, Kumar SN, Myers CR, Bennett B, Garces AM, Dias Duarte Machado LG, Thiebaut D, Ouari O, Hardy M, Zielonka J, Kalyanaraman B.) J Biol Chem. 2018 06 29;293(26):10363-10380.
(Pan J, Lee Y, Cheng G, Zielonka J, Zhang Q, Bajzikova M, Xiong D, Tsaih SW, Hardy M, Flister M, Olsen CM, Wang Y, Vang O, Neuzil J, Myers CR, Kalyanaraman B, You M.) iScience. 2018 May 25;3:192-207.
(Yin N, Lepp A, Ji Y, Mortensen M, Hou S, Qi XM, Myers CR, Chen G.) J Biol Chem. 2017 09 08;292(36):15070-15079.
(Yin N, Qi X, Tsai S, Lu Y, Basir Z, Oshima K, Thomas JP, Myers CR, Stoner G, Chen G.) Oncogene. 2016 Feb 25;35(8):1039-48.
(Myers CR.) Free Radic Biol Med. 2016 Feb;91:81-92.
(Xu J, Eriksson SE, Cebula M, Sandalova T, Hedström E, Pader I, Cheng Q, Myers CR, Antholine WE, Nagy P, Hellman U, Selivanova G, Lindqvist Y, Arnér ES.) Cell Death Dis. 2015 Jan 22;6:e1616.
(Myers JM, Cheng Q, Antholine WE, Kalyanaraman B, Filipovska A, Arnér ES, Myers CR.) Free Radic Biol Med. 2013 Jul;60:183-94.
(Myers CR.) Free Radic Biol Med. 2012 May 15;52(10):2091-107.
p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription.
(Qi X, Zhi H, Lepp A, Wang P, Huang J, Basir Z, Chitambar CR, Myers CR, Chen G.) J Biol Chem. 2012 Apr 27;287(18):14681-91.