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Stephen Safe

Stephen Safe

Distinguished Professor & Sid Kyle Endowed Chair in Veterinary Toxicology Department of Veterinary Physiology & Pharmacology
Contact
VTPP Faculty Information
ssafe@cvm.tamu.edu
9798455988
TAMU Mailstop: 4466

Research and Scholarly Interests

The development of novel mechanism-based anticancer drugs which target the nuclear orphan receptors (NR4A1, NR4A2 and NR4A3), the aryl hydrocarbon receptor, and specificity protein (Sp) transcription factors

Education

  • B.S., Queen's University, Canada, 1962
  • M.S., Queen's University, Canada, 1963
  • D.Phil., Oxford University, Great Britain, 1965

Molecular & Cellular Oncology Laboratory (Safe Lab)

  • Environmental Health
  • Oncology
  • Pharmacology
  • Toxicology

Stephen Safe is accepting trainees of these groups:

  • Graduate Students
  • Non-Thesis Masters
  • Postdoctoral Fellow
  • Undergraduate Scholars

Current lab members:

  • Evan Farkas - Graduate Assistant - Research
  • Amanuel E. Hailemariam - Graduate Assistant - Research 
  • Mi-Ok Lee - Program Aide
  • Amber N. Meyer - Administrative Assistant IV
  • Arafat Rahman Oany - Graduate Assistant - Research 
  • Gargi Siaram - Student Research Assistant 
  • Wai Ning Tiffany Tsui - Graduate Assistant - Research 
  • Srijana Upadhyay - Senior Research Associate

 

Google Scholar

PubMed

  • Upadhyay S, Lee M, Zhang L, Oany AR, Mikheeva SA, Mikheev AM, Rostomily RC, Safe S. Dual nuclear receptor 4A1 (NR4A1/NR4A2) ligands inhibit glioblastoma growth and target TWIST1. Molecular Pharmacology. 2025;107(2):100009. Doi: 10.1016/j.molpha.2024.100009.
  • Madison CA, Debler RA, Gallegos PL, Hillbrick L, Chapkin RS, Safe S, Eitan S. 1,4-dihydroxy-2-naphthoic acid prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced motor function deficits. Behav Pharmacol. 2025 Feb 1;36(1):40-46. doi: 10.1097/FBP.0000000000000806. Epub 2024 Dec 12. PMID: 39660867; PMCID: PMC11781791.
  • Safe S, Farkas E, Hailemariam AE, Oany AR, Sivaram G, Tsui WNT. Activation of Genes by Nuclear Receptor/Specificity Protein (Sp) Interactions in Cancer. Cancers (Basel). 2025 Jan 17;17(2):284. doi: 10.3390/cancers17020284. PMID: 39858066; PMCID: PMC11763981.
  • Garcia-Villatoro EL, Bomstein ZS, Allred KF, Callaway ES, Safe S, Chapkin RS, Jayaraman A, Allred CD. Involvement of Intestinal Epithelium Aryl Hydrocarbon Receptor Expression and 3, 3'-Diindolylmethane in Colonic Tertiary Lymphoid Tissue Formation. Int J Mol Sci. 2024 Sep 21;25(18):10153. doi: 10.3390/ijms251810153. PMID: 39337636; PMCID: PMC11432480.
  • Garcia-Villatoro EL, Ufondu A, Callaway ES, Allred KF, Safe SH, Chapkin RS, Jayaraman A, Allred CD. Aryl hydrocarbon receptor activity in intestinal epithelial cells in the formation of colonic tertiary lymphoid tissues. Am J Physiol Gastrointest Liver Physiol. 2024 Aug 1;327(2):G154-G174. doi: 10.1152/ajpgi.00274.2023. Epub 2024 Apr 2. PMID: 38563893.
  • Debler RA, Gallegos PL, Ojeda AC, Perttula AM, Lucio A, Chapkin RS, Safe S, Eitan S. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces depression-like phenotype. Neurotoxicology. 2024 Jun 3:S0161-813X(24)00055-X. doi: 10.1016/j.neuro.2024.05.010. Epub ahead of print. PMID: 38838945.
  • Safe S. Natural products and synthetic analogs as selective orphan nuclear receptor 4A (NR4A) modulators. Histol Histopathol. 2024 May;39(5):543-556. doi: 10.14670/HH-18-689. Epub 2023 Dec 13. PMID: 38116863.
  • Rocha SM, Gustafson DL, Safe S, Tjalkens RB. Comparative safety, pharmacokinetics, and off-target assessment of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane in mouse and dog: implications for therapeutic development. Toxicol Res (Camb). 2024 Apr 21;13(2):tfae059. doi: 10.1093/toxres/tfae059. PMID: 38655145; PMCID: PMC11033559.
  • DelGiorno KE, Safe S, Bailey-Lundberg JM. Editorial: Emerging anti-cancer compounds and immunomodulators for pancreatic cancer treatment. Front Oncol. 2024 Apr 19;14:1411836. doi: 10.3389/fonc.2024.1411836. PMID: 38737907; PMCID: PMC11082743.
  • Upadhyay S, Hailemariam AE, Mariyam F, Hafiz Z, Martin G, Kothari J, Farkas E, Sivaram G, Bell L, Tjalkens R, Safe S. Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands. Biomolecules. 2024 Feb 27;14(3):284. doi: 10.3390/biom14030284. PMID: 38540704; PMCID: PMC10967861.
  • DeVito M, Bokkers B, van Duursen MBM, van Ede K, Feeley M, Antunes Fernandes Gáspár E, Haws L, Kennedy S, Peterson RE, Hoogenboom R, Nohara K, Petersen K, Rider C, Rose M, Safe S, Schrenk D, Wheeler MW, Wikoff DS, Zhao B, van den Berg M. The 2022 world health organization reevaluation of human and mammalian toxic equivalency factors for polychlorinated dioxins, dibenzofurans and biphenyls. Regul Toxicol Pharmacol. 2024 Jan;146:105525. doi: 10.1016/j.yrtph.2023.105525. Epub 2023 Nov 14. PMID: 37972849; PMCID: PMC10870838.
  • Mohankumar K, Wright G, Kumaravel S, Shrestha R, Zhang L, Abdelrahim M, Chapkin RS, Safe S. Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion. Cancer Immunol Immunother. 2023 Dec;72(12):3985-3999. doi: 10.1007/s00262-023-03530-3. Epub 2023 Oct 17. PMID: 37847301; PMCID: PMC10700478.
  • Zhang L, Martin G, Mohankumar K, Wright GA, Mariyam F, Safe S. Piperlongumine is a ligand for the orphan nuclear receptor 4A1 (NR4A1). Front Pharmacol. 2023 Sep 21;14:1223153. doi: 10.3389/fphar.2023.1223153. PMID: 37808182; PMCID: PMC10551445.
  • Pan Q, Ai W, Chen Y, Kim DM, Shen Z, Yang W, Jiang W, Sun Y, Safe S, Guo S. Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure. Diabetes. 2023 Sep 1;72(9):1193-1206. doi: 10.2337/db23-0180. PMID: 37343276; PMCID: PMC10450826.
  • Zhang L, Mohankumar K, Martin G, Mariyam F, Park Y, Han SJ, Safe S. Flavonoids Quercetin and Kaempferol Are NR4A1 Antagonists and Suppress Endometriosis in Female Mice. Endocrinology. 2023 Aug 28;164(10):bqad133. doi: 10.1210/endocr/bqad133. PMID: 37652054; PMCID: PMC10502789.
  • Debler RA, Madison CA, Hillbrick L, Gallegos P, Safe S, Chapkin RS, Eitan S. Selective aryl hydrocarbon receptor modulators can act as antidepressants in obese female mice. J Affect Disord. 2023 Jul 15;333:409-419. doi: 10.1016/j.jad.2023.04.044. Epub 2023 Apr 19. PMID: 37084978.
  • Lee M, Upadhyay S, Mariyam F, Martin G, Hailemariam A, Lee K, Jayaraman A, Chapkin RS, Lee SO, Safe S. Flavone and Hydroxyflavones Are Ligands That Bind the Orphan Nuclear Receptor 4A1 (NR4A1). Int J Mol Sci. 2023 May 2;24(9):8152. doi: 10.3390/ijms24098152. PMID: 37175855; PMCID: PMC10179475.
  • Safe S. Specificity Proteins (Sp) and Cancer. Int J Mol Sci. 2023 Mar 8;24(6):5164. doi: 10.3390/ijms24065164. PMID: 36982239; PMCID: PMC10048989.
  • Madison CA, Hillbrick L, Kuempel J, Albrecht GL, Landrock KK, Safe S, Chapkin RS, Eitan S. Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms. Behav Brain Res. 2023 Feb 25;440:114256. doi: 10.1016/j.bbr.2022.114256. Epub 2022 Dec 14. PMID: 36528169; PMCID: PMC9839636.
  • Safe S, Kothari J, Hailemariam A, Upadhyay S, Davidson LA, Chapkin RS. Health Benefits of Coffee Consumption for Cancer and Other Diseases and Mechanisms of Action. Int J Mol Sci. 2023 Jan 31;24(3):2706. doi: 10.3390/ijms24032706. PMID: 36769029; PMCID: PMC9916720.
  • Madison CA, Debler RA, Vardeleon NI, Hillbrick L, Jayaraman A, Safe S, Chapkin RS, Eitan S. Sex-dependent differences in the stress mitigating and antidepressant effects of selective aryl hydrocarbon receptor modulators. J Affect Disord. 2022 Dec 15;319:213-220. doi: 10.1016/j.jad.2022.09.155. Epub 2022 Oct 4. PMID: 36206882.
  • Madison CA, Hillbrick L, Kuempel J, Albrecht GL, Landrock KK, Safe S, Chapkin RS, Eitan S. Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms. Behav Brain Res. 2022 Dec 14;440:114256. doi: 10.1016/j.bbr.2022.114256. Epub ahead of print. PMID: 36528169.
  • Safe S, Zhang L. The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer. Cancers (Basel). 2022 Nov 14;14(22):5574. doi: 10.3390/cancers14225574. PMID: 36428667; PMCID: PMC9688153.
  • Park H, Jin UH, Martin G, Chapkin RS, Davidson LA, Lee K, Jayaraman A, Safe S. Structure-activity relationships among mono- and dihydroxy flavones as aryl hydrocarbon receptor (AhR) agonists or antagonists in CACO2 cells. Chem Biol Interact. 2022 Sep 25;365:110067. doi: 10.1016/j.cbi.2022.110067. Epub 2022 Jul 31. PMID: 35917944; PMCID: PMC9667734.
  • Schoeller A, Karki K, Jayaraman A, Chapkin RS, Safe S. Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer. Am J Cancer Res. 2022 Jul 15;12(7):3422-3436. PMID: 35968335; PMCID: PMC9360213.
  • Madison CA, Kuempel J, Albrecht GL, Hillbrick L, Jayaraman A, Safe S, Chapkin RS, Eitan S. 3,3'-Diindolylmethane and 1,4-dihydroxy-2-naphthoic acid prevent chronic mild stress induced depressive-like behaviors in female mice. J Affect Disord. 2022 Jul 15;309:201-210. doi: 10.1016/j.jad.2022.04.106. Epub 2022 Apr 21. PMID: 35461819.
  • Zhang L, Martin G, Mohankumar K, Hampton JT, Liu WR, Safe S. RESVERATROL BINDS NUCLEAR RECEPTOR 4A1 (NR4A1) AND ACTS AS AN NR4A1 ANTAGONIST IN LUNG CANCER CELLS. Mol Pharmacol. 2022 Jun 9;102(2):80–91. doi: 10.1124/molpharm.121.000481. Epub ahead of print. PMID: 35680166; PMCID: PMC9341251.
  • Lee HS, Kim DH, Lee IS, Park JH, Martin G, Safe S, Kim KJ, Kim JH, Jang BI, Lee SO. Plant Alkaloid Tetrandrine Is a Nuclear Receptor 4A1 Antagonist and Inhibits Panc-1 Cell Growth In Vitro and In Vivo. Int J Mol Sci. 2022 May 9;23(9):5280. doi: 10.3390/ijms23095280. PMID: 35563670; PMCID: PMC9104798.
  • Yang Y, Osorio D, Davidson LA, Han H, Mullens DA, Jayaraman A, Safe S, Ivanov I, Cai JJ, Chapkin RS. Single-cell RNA Sequencing Reveals How the Aryl Hydrocarbon Receptor Shapes Cellular Differentiation Potency in the Mouse Colon. Cancer Prev Res (Phila). 2022 Jan;15(1):17-28. doi: 10.1158/1940-6207.CAPR-21-0378. Epub 2021 Nov 22. PMID: 34815312; PMCID: PMC8741728.
  • Han H, Davidson LA, Fan YY, Landrock KK, Jayaraman A, Safe SH, Chapkin RS. Loss of aryl hydrocarbon receptor suppresses the response of colonic epithelial cells to IL22 signaling by upregulating SOCS3. Am J Physiol Gastrointest Liver Physiol. 2022 Jan 1;322(1):G93-G106. doi: 10.1152/ajpgi.00074.2021. Epub 2021 Nov 10. PMID: 34755534; PMCID: PMC8714253.

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