Albena T. Dinkova-Kostova obtained her PhD in Biochemistry from Washington State University. Her doctoral work was on the purification and characterization of enzymes of the phenylpropanoid pathway. During that time she became intrigued by the fact that phenylpropanoids, some of which (podophyllotoxin and the semi-synthetic etoposide and tenoposide) are used in cancer chemotherapy; others (nordihydroguaiaretic acid) are potent antioxidants, are also inducers of anticarcinogenic enzymes. She joined the laboratory of Paul Talalay (Johns Hopkins University) where she became interested in chemoprevention by chemical and dietary induction of cytoprotective proteins.
In 2007 Albena joined the Medical Research Institute, University of Dundee, Scotland as a Lecturer and Research Councils UK Academic Fellow. Her work is focused on the mechanism of induction of cytoprotective proteins through the Keap1/Nrf2 pathway, and the chemistry of inducers. Her publications have been highlighted in commentaries and attracted more than 10000 citations. She is the recipient of the 2011 Arthur C. Neish Young Investigator Award of the Phytochemical Society of North America.
The steady increase in the number of new cancer cases diagnosed each year and the modest success in cancer treatment highlight the urgent need for the development of strategies for prevention. It is important to understand that the disease cancer is the process of carcinogenesis itself that begins many years, often decades, before any clinical symptoms become apparent. Protection against cancer in animal models can be accomplished by induction of the Keap1/Nrf2 pathway, which controls the gene expression of numerous enzymes (e.g., glutathione S-transferases, epoxide hydrolase, quinone reductase 1, heme oxygenase 1) that catalyze versatile reactions collectively leading to detoxification of electrophiles and oxidants. However, the Keap1/Nrf2 pathway is often upregulated in established tumors, where it contributes to cancer cell survival, metabolic adaptation, chemo- and radioresistance.
The expression of Nrf2-dependent genes can be elevated by a wide variety of pharmacological agents termed “inducers”, some of which are present in the human diet. Inducers react with specific cysteine residues of the sensor protein Keap1, thereby allowing transcription factor Nrf2 to translocate to the nucleus and activate transcription. The discrete events in the regulation of the Keap1/Nrf2 pathway and the mechanism of action of Nrf2 inducers are a major objective of our research. We are also investigating the regulation of the heat shock response, another cellular cytoprotective pathway, and the ability of small molecules, which can inhibit Hsp90 to interfere with cancer cell proliferation.
In addition to biochemical studies in various in vitro and cellular systems, we also employ in vivo models with a focus on models of UV radiation-induced cutaneous squamous cell carcinoma and colorectal cancer. The knowledge obtained from these models will allow the design of clinical trials to determine the effectiveness of Nrf2 modulators for cancer prevention and treatment in high-risk populations.
'Phenethyl isothiocyanate, a dual activator of transcription factors NRF2 and HSF1' Molecular Nutrition & Food Research, vol. 62, no. 18, 1700908.
'C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape' Scientific Reports, vol. 8, 8037, pp. 1-12.
'Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1' Nature, vol. 556, no. 7699, pp. 113-117.
'Author Correction: Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates' Scientific Reports, vol. 8, 4064, pp. 1-2.
'Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)' CMGH: Cellular and Molecular Gastroenterology and Hepatology, vol. 5, no. 3, pp. 367-398.
'The role of Nrf2 signaling in counteracting neurodegenerative diseases' FEBS Journal.
'Targeting the Co REST complex with dual histone deacetylase and demethylase inhibitors' Nature Communications, vol. 9, no. 1, 53, pp. 1-13.
'Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses' Oncogene, vol. 36, no. 44, pp. 6204-6212.
'KEAP1 and done? Targeting the NRF2 pathway with sulforaphane: Targeting the NRF2 Pathway with Sulforaphane' Trends in Food Science and Technology, vol. 69, no. B, pp. 257-269.
'Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival' Cancer Cell, vol. 32, no. 5, pp. 539-541.
'Epigenetic Control of NRF2-Directed Cellular Antioxidant Status in Dictating Life-Death Decisions' Molecular Cell, vol. 68, no. 1, pp. 5-7.
'Oxidative stress and chronic inflammation in osteoarthritis: can Nrf2 counteract these partners in crime?' Annals of the New York Academy of Sciences, vol. 1401, pp. 114-135.
'Transcription factors NRF2 and HSF1 have opposing functions in autophagy' Scientific Reports, vol. 7, 11023, pp. 1-12.
'Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy-Mitochondria, Calcium Dynamics and Reactive Oxygen Species' International Journal of Molecular Sciences, vol. 18, no. 9, 1935, pp. 1-19.
'Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity' Molecular Therapy, vol. 25, no. 8, pp. 1900-1916.
'Oxidative stress management in the hair follicle: Could targeting NRF2 counter age-related hair disorders and beyond? ' Bio Essays, vol. 39, no. 8, 1700029, pp. 1-9.
'KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients' Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 23, pp. e4676-e4685.
'Regulation of the mammalian heat shock factor 1' FEBS Journal, vol. 284, no. 11, pp. 1606-1627.
'Flavonolignan 2,3-dehydrosilydianin activates Nrf2 and upregulates NAD(P)H: quinone oxidoreductase 1 in Hepa1c1c7 cells' Fitoterapia, vol. 119, pp. 115-120.
'Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates' Scientific Reports, vol. 7, 1666, pp. 1-14.
'Activation of Nrf2 signaling as a common treatment of neurodegenerative diseases' Neurodegenerative Disease Management, vol. 7, no. 2, pp. 97-100.
'Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants' Archives of Biochemistry and Biophysics, vol. 617, pp. 84-93.
'NRF2 as an emerging therapeutic target' Oxidative Medicine and Cellular Longevity, vol. 2017, 8165458.
'Whole-exome sequencing validates a preclinical mouse model for the prevention and treatment of cutaneous squamous cell carcinoma' Cancer Prevention Research, vol. 10, no. 1, pp. 67-75.
'Semisynthetic flavonoid 7-O-galloylquercetin activates Nrf2 and induces Nrf2-dependent gene expression in RAW264.7 and Hepa1c1c7 cells' Chemico-Biological Interactions, vol. 260, pp. 58-66.
'The multifaceted role of Nrf2 in mitochondrial function' Current Opinion in Toxicology, vol. 1, pp. 80-91.
'Regulation of the CNC-b ZIP transcription factor Nrf2 by Keap1 and the axis between GSK-3 and β-Tr CP' Current Opinion in Toxicology, vol. 1, pp. 92-103.
'Nrf2-mediated neuroprotection response to recurrent hypoglycemia is insufficient to prevent cognitive impairment in a rodent model of type 1 diabetes' Diabetes, vol. 65, no. 10, pp. 3151-3160.
'Heat Shock Factor 1 is a Substrate for p38 Mitogen-Activated Protein Kinases' Molecular and Cellular Biology, vol. 36, no. 18, pp. 2403-2417.
'Electron affinity of tricyclic, bicyclic, and monocyclic compounds containing cyanoenones correlates with their potency as inducers of a cytoprotective enzyme' Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 17, pp. 4345-4349.
'NAD(P)H: quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives' Drug Design, Development and Therapy, vol. 10, pp. 2515-2524.
'Rhodiola rosea L. from golden root to green cell factories' Phytochemistry Reviews, vol. 15, no. 4, pp. 515-536.
'SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models' Cell Chemical Biology, vol. 23, no. 7, pp. 849-861.
'Potency of extracts from selected Egyptian plants as inducers of the Nrf2-dependent chemopreventive enzyme NQO1' Journal of Natural Medicines, vol. 70, no. 3, pp. 683-688.
'Loss of Nrf2 abrogates the protective effect of Keap1 down regulation in a preclinical model of cutaneous squamous cell carcinoma' Scientific Reports, vol. 6, 25804.
'Nrf2 activation in the treatment of neurodegenerative diseases: A focus on its role in mitochondrial bioenergetics and function' Biological Chemistry, vol. 397, no. 5, pp. 383-400.
'Filaggrin genotype does not determine the skin's threshold to UV-induced erythema' Journal of Allergy and Clinical Immunology, vol. 137, no. 4, pp. 1280-1282.e3.
'Chemical constituents and NAD(P)H:Quinone oxidoreductase 1 (NQO1) inducer activity of Teucrium oliverianum Ging. ex Benth' Indian Journal of Traditional Knowledge, vol. 15, no. 2, pp. 232-236.
'Synthesis, molecular modeling and NAD(P)H: quinone oxidoreductase 1 inducer activity of novel 2-phenylquinazolin-4-amine derivatives' Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 31, no. 6, pp. 1612-1618.
'Bioactive polymethoxylated flavonoids from Chiliadenus montanus' Journal of Chemical and Pharmaceutical Research, vol. 8, no. 3, pp. 788-793.
The multifaceted role of sulforaphane in protection against uv radiation-mediated skin damage. in Broccoli: Cultivation, Nutritional Properties and Effects on Health. Nova Science Publishers, pp. 185-208.
'NAD(P)H: Quinone oxidoreductase 1 inducer activity of novel 4-aminoquinazoline derivatives' Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 31, no. 6, pp. 1369-1374.
'Synthesis and biological evaluation of novel 2-phenylquinazoline-4-amine derivatives: identification of 6-phenyl-8H-benzo[g]quinazolino[4,3-b]quinazolin-8-one as a highly potent inducer of NAD(P)H quinone oxidoreductase 1' Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 31, no. Suppl. 1, pp. 34-49.
'Synthesis and NAD(P)H: Quinone oxidoreductase 1 inducer activity of acetamide and pyridine-3-carbonitrile derivatives' Biomedical Research, vol. 27, no. 4, pp. 1045-1048.
Glucosinolates from the Brassica Vegetables and Their Health Effects. in B Caballero, PM Finglas & F Toldrá (eds), Encyclopedia of Food and Health. Reference Module in Food Science, Elsevier Inc., pp. 248-255.
'The emerging role of Nrf2 in mitochondrial function' Free Radical Biology and Medicine, vol. 88, no. Part B, pp. 179-188.
'Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease' Free Radical Biology and Medicine, vol. 88, no. Part B, pp. 108-146.
'Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action' Biochemical and Biophysical Research Communications, vol. 465, no. 3, pp. 402-407.
'Design, synthesis, and evaluation of triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction' Journal of Medicinal Chemistry, vol. 58, no. 18, pp. 7186-7194.
'The spatiotemporal regulation of the Keap1-Nrf2 pathway and its importance in cellular bioenergetics' Biochemical Society Transactions, vol. 43, no. 4, pp. 602-610.
'Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of β-Tr CP and GSK-3' Biochemical Society Transactions, vol. 43, no. 4, pp. 611-620.
'New monocyclic, bicyclic, and tricyclic ethynylcyanodienones as activators of the Keap1/Nrf2/ARE pathway and inhibitors of inducible nitric oxide synthase' Journal of Medicinal Chemistry, vol. 58, no. 11, pp. 4738-4748.
'Nrf2 activation protects against solar-simulated ultraviolet radiation in mice and humans' Cancer Prevention Research, vol. 8, no. 6, pp. 475-486.
'Nrf2 regulates ROS production by mitochondria and NADPH oxidase' Biochimica et Biophysica Acta: General Subjects, vol. 1850, no. 4, pp. 794-801.
'Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection' Trends in Pharmacological Sciences, vol. 36, no. 1, pp. 6-14.
'NAD(P)H: Quinone oxidoreductase 1 inducer activity of some enaminone derivatives' Biomedical Research, vol. 26, no. 1, pp. 7-12.
'Novel Thioureido Derivatives Carrying Thione and Sulfonamide Moieties Induce the Cytoprotective Enzyme NAD(P)H:Quione Oxidoreductase 1: Quinone oxidoreductase 1' Asian Journal of Chemistry, vol. 26, no. 24, pp. 8501-8504.
'Synthesis, molecular modeling and NAD(P)H:quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides: quinone oxidoreductase 1 inducer activity of novel cyanoenone and enone benzenesulfonamides' Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 29, no. 6, pp. 840-845.
'Monitoring Keap1-Nrf2 interactions in single live cells' Biotechnology Advances, vol. 32, no. 6, pp. 1133-1144.
'Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes, but not with insulin resistance' Molecular and Cellular Biology, vol. 34, no. 17, pp. 3305-3320.
'Chemical tuning enhances both potency toward Nrf2 and in vitro therapeutic index of triterpenoids' Toxicological Sciences, vol. 140, no. 2, pp. 462-469.
'Synthesis of 13C215N2-labeled anti-inflammatory and cytoprotective tricyclic bis(cyanoenone) ([13C215N2]-TBE-31) as an internal standard for quantification by stable isotope dilution LC-MS method' Journal of Labelled Compounds & Radiopharmaceuticals, vol. 57, no. 10, pp. 606-610.
'The Nrf2 regulatory network provides an interface between redox and intermediary metabolism' Trends in Biochemical Sciences, vol. 39, no. 4, pp. 199-218.
'Nrf2 affects the efficiency of mitochondrial fatty acid oxidation' Biochemical Journal, vol. 457, no. 3, pp. 415-424.
'Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation' British Journal of Cancer, vol. 110, no. 1, pp. 71-82.
'Synthesis and biological evaluation of biotin conjugates of (±)-(4b S,8a R,10a S)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydro-phenanthrene-2,6-dicarbonitrile, an activator of the Keap1/Nrf2/ARE pathway, for the isolation of its protein targets' Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 20, pp. 5540-5543.
'Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex' Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 38, pp. 15259-15264.
'Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration' Open Biology, vol. 2, no. 8, pp. 761-770.
'NAD(P)H: Quinone oxidoreductase 1 inducer activity of some Saudi Arabian medicinal plants' Planta Medica, vol. 79, no. 6, pp. 459-464.
'Diffusion dynamics of the Keap1-Cullin3 interaction in single live cells' Biochemical and Biophysical Research Communications, vol. 433, no. 1, pp. 58-65.
Chemoprotection Against Cancer by Isothiocyanates: A Focus on the Animal Models and the Protective Mechanisms. in JM Pezzuto & N Suh (eds), Natural Products in Cancer Prevention and Therapy. Topics in Current Chemistry, vol. 329, Springer , Berlin, pp. 179-201.
'The indirect antioxidant sulforaphane protects against thiopurine-mediated photooxidative stress' Carcinogenesis, vol. 33, no. 12, pp. 2457-2466.
'Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and cytoprotective agents' Journal of Medicinal Chemistry, vol. 55, no. 10, pp. 4837-4846.
'Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity' Biochimica et Biophysica Acta. Molecular Basis of Disease, vol. 1822, no. 5, pp. 753-783.
'Arthur Neish Young Investigator Award Lecture a Novel Role for Sulfhydryl-Reactive Activators of Transcription Factor NRF2: HSF1-Dependent Upregulation of Hsp70' Pharmaceutical Biology, vol. 50, no. 5, pp. 625-625.
'Glutathione S-transferase genotype is associated with sensitivity to psoralen-ultraviolet A photochemotherapy' British Journal of Dermatology, vol. 166, no. 2, pp. 380-388.
'Glucosinolates and isothiocyanates in health and disease' Trends in Molecular Medicine, vol. 18, no. 6, pp. 337-347.
'Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): Implications for protection against UV radiation during thiopurine therapy' Cancer Prevention Research, vol. 5, no. 7, pp. 973-981.
'Neuroprotective effects of sulforaphane after contusive spinal cord injury' Journal of Neurotrauma, vol. 29, no. 16, pp. 2576-2586.
'HSF1-Dependent Upregulation of Hsp70 by Sulfhydryl-Reactive Inducers of the KEAP1/NRF2/ARE Pathway' Chemistry & Biology, vol. 18, no. 11, pp. 1355-1361.
'Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway' Cancer Prevention Research, vol. 4, no. 10, pp. 1665-1674.
'Induction of the Keapl/Nrf2/ARE pathway by oxidizable diphenols' Chemico-Biological Interactions, vol. 192, no. 1-2, pp. 101-106.
'Synthesis and biological evaluation of 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4-ethynylimidazole. A novel and highly potent anti-inflammatory and cytoprotective agent' Bioorganic & Medicinal Chemistry Letters, vol. 21, no. 8, pp. 2188-2191.
'The cytoprotective role of the Keap1-Nrf2 pathway' Archives of Toxicology, vol. 85, no. 4, pp. 241-272.
'Effects of chemoprotective agent HBB-2 on cell survival in SH-SY5Y neuroblastoma cells' FEBS Journal, vol. 278, no. S1, P14.37, pp. 268 .
'Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders' Antioxidants & Redox Signaling, vol. 13, no. 11, pp. 1763-1811.
'An Exceptionally Potent Inducer of Cytoprotective Enzymes elucidation of the structural features that determine inducer potency and reactivity with Keap1' Journal of Biological Chemistry, vol. 285, no. 44, pp. 33747-33755.
'NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector' Archives of Biochemistry and Biophysics, vol. 501, no. 1, pp. 116-123.
'Potency ranking of triterpenoids as inducers of a cytoprotective enzyme and as inhibitors of a cellular inflammatory response via their electron affinity and their electrophilicity index' Chemico-Biological Interactions, vol. 186, no. 2, pp. 118-126.
The effectiveness of the isothiocyanate sulforaphane in chemoprotection. in M Hansen (ed.), Proceedings of the Vth international symposium on brassicas, and XVIth crucifer genetics workshop . vol. 867, Acta Horticulturae, vol. 867, International Society for Horticultural Science , Lillehammer, Norway, pp. 27-36, Proceedings of the Fifth International Symposium on Brassicas and the Sixteenth International Crucifer Genetics Workshop, , Lillehammer, Norway, 8/09/08.
'Electrophilic tuning of the chemoprotective natural product sulforaphane' Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 21, pp. 9590-9595.
'Glutathione S-transferase M1 (GSTM1) genotype is associated with serum 8-MOP concentration and PUVA sensitivity' British Journal of Dermatology, vol. 162, no. 4, pp. 941-941.
'Activation of the NRF2 Signaling Pathway by Copper-Mediated Redox Cycling of Para- and Ortho-Hydroquinones' Chemistry & Biology, vol. 17, no. 1, pp. 75-85.
'Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway' Antioxidants & Redox Signaling, vol. 13, no. 11, pp. 1713-1748.
'Dietary glucoraphanin-rich broccoli sprout extracts protect against UV radiation-induced skin carcinogenesis in SKH-1 hairless mice' Photochemical & Photobiological Sciences, vol. 9, no. 4, pp. 597-600.
'Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis' Free Radical Biology and Medicine, vol. 48, no. 2, pp. 357-371.
Phenolics in Aging and Neurodegenerative Disorders. in CG Fraga (ed.), Plant Phenolics and Human Health: Biochemistry, Nutrition, and Pharmacology. pp. 427-451.
'Nitric Oxide in Cell Survival: A Janus Molecule' Antioxidants & Redox Signaling, vol. 11, no. 11, pp. 2717-2739.
'Cross-talk between Transcription Factors Ah R and Nrf2: Lessons for Cancer Chemoprevention from Dioxin' Toxicological Sciences, vol. 111, no. 2, pp. 199-201.
'Precise determination of the erythema response of human skin to ultraviolet radiation and quantification of effects of protectors' Photodermatology, photoimmunology & photomedicine, vol. 25, no. 1, pp. 45-50.