Cancer Institute

  • Dale George Nagle

    Professor, Department of Pharmacognosy
    Research Professor, Research Institute of Pharmaceutical Sciences (RIPS)
    Molecular Cancer Therapeutics Program
    PhD, Pharmacy (Marine Natural Products), 1995, Oregon State University, Corvallis, OR
    Postdoc, 1995-96, University of Guam Marine Laboratory, Mangilao, Guam
    Research Instructor, 1996-97, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX

    Contact information 
    School of Pharmacy
    Department of Pharmacognosy
    University of Mississippi
    Faser Hall, Room 405A
    University, MS 39677
    Phone: (662) 915-7026
    E-mail: dnagle@olemiss.edu

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    Research interests

    • Discovery of molecular-targeted antitumor agents that target HIF-1
    • Role of mitochondria in the regulation of hypoxic signaling
    • Idiosyncratic mitochondria-mediated natural product toxicity

    Research synopsis

    My research focuses on the discovery of drug leads for the treatment of cancer through the use of molecular mechanism-targeted bioassay techniques. This research integrates newly developed molecular-based bioassays to investigate natural products for their potential to synergistically enhance the antitumor effects of other chemotherapeutic agents by acting as promoters of tumor differentiation and cell death. The past two decades have seen dramatic progress in the identification of genes involved in tumor formation, the molecular mechanisms that control this process, and the biochemical/physiological conditions required for tumor growth and metastatic spread. As tumors grow, they rapidly outstrip the ability of surrounding blood vessels to supply oxygen, creating hypoxic regions within the growing solid tumor. The primary goal of our National Cancer Institute-funded research program "Anticancer Drug Discovery That Targets Tumor Hypoxia" (2R01 CA098787) is to discover non-cytotoxic molecular-targeted antitumor agents that inhibit the ability of tumor hypoxia to activate the transcription factor hypoxia-inducible factor-1 (HIF-1). As the crucial mediator of the transcriptional response to cellular hypoxia, HIF-1 controls the expression of over 100 genes involved in promoting tumor cells to adapt and survive under hypoxic stress. The activation of HIF-1 is associated with advanced stage cancer and treatment resistance. One consequence of this research is the discovery and characterization of dozens of new marine and plant-derived mitochondrial disruptors. This work has led to a new recognition of the widespread nature of potentially toxic mitochondrial inhibitors in many plant species, including a considerable number of those used as botanical dietary supplement (BDS) products.

    Selected publications

    • Datta, S.; Zhou, Y.-D.; Nagle, D.G. “Comparative Study of Chromatographic Medium-Associated Mass and Potential Antitumor Activity Loss with Bioactive Extracts” ” J. Nat. Prod. 2013, 76, xxx. np-2012-00858c, In Press.
    • Li,J.; Mahdi,F.; Du, L.; Jekabsons,M.B.; Zhou, Y.-D.; Nagle, D.G. “Semisynthetic studies identify mitochondria poisons from botanical dietary supplements – geranyloxycoumarins from Aegle marmelosBioorg. Med. Chem. 2013, 21, 1795-1803, NIHMS442459. (http://www.sciencedirect.com/science/article/pii/S0968089613000874
    • Datta, S.; Li,J.; Mahdi,F.; Jekabsons,M.B.; Nagle, D.G.; Zhou, Y.-D. “Glycolysis inhibitor screening identifies the bis-geranylacylphloroglucinol protonophore moronone from Moronobea coccinea” J. Nat. Prod. 2012, 75, 2216-2222. PMCID: PMC3532528. (http://pubs.acs.org/doi/abs/10.1021/np300711e)
    • Du,L.; Mahdi,F.; Jekabsons,M.B.; Nagle, D.G.; Zhou, Y.-D. “Structures and mechanisms of antitumor agents - Xestoquinones uncouple cellular respiration and disrupt HIF signaling in human breast tumor cells” J. Nat. Prod. 2012, 75, 1553-1559. PMCID: PMC3482980. (http://dx.doi.org/10.1021/np3002892).
    • Nagle, D.G.; Zhou, Y.-D.  “Mechanism-based screening for cancer therapeutics with examples from the discovery of marine natural product-based HIF-1 inhibitors” Chapter 5.7 in Handbook of Marine Natural Products. Fattorusso, E., Gerwick, W.H., Taglialatela-Scafati, O., eds., Springer, New York, ISBN 978-90-481-3833-3, 2012, 1111-1144. 
    •  Li,J.; Mahdi,F.; Du,L.; Datta,S.; Nagle, D.G.; Zhou, Y.-D. “Mitochondrial respiration inhibitors suppress protein translation and hypoxic signaling via the hyperphosphorylation and inactivation of translation initiation factor eIF2a and elongation factor eEF2.”  J. Nat. Prod. 2011, 74, 1894-1901. PMCID: PMC3179826. (http://dx.doi.org/10.1021/np200370z).
    •  Mahdi, F.; Falkenberg, M.; Ioannou, E.; Roussis, V.; Zhou, Y.-D.; Nagle, D.G. “Thyrsiferol inhibits mitochondrial respiration and HIF-1 activation” Phytochem. Lett. 2011, 4, 75-78. PMCID: PMC3139250. (http://dx.doi.org/10.1016/j.phytol.2010.09.003)
    • Du,L.; Mahdi,F.; Jekabsons,M.B.; Nagle, D.G.; Zhou, Y.-D. “Natural and semisynthetic Mammea-type isoprenylated dihydroxycoumarins uncouple cellular respiration” J. Nat. Prod. 2011, 74, 240-248. PMCID: PMC3045645. (http://dx.doi.org/10.1021/np100762s)
    • Nagle, D.G.; Zhou, Y.-D.  “Natural products as inhibitors of hypoxia-inducible factor-1 (HIF-1)” Chapter 7 in Bioactive Compounds from Natural Sources, Second Edition: Natural Products as Lead Compounds in Drug Discovery. Tringali, C., ed., Taylor & Francis, New York, ISBN 978-1-4398-2229-6, 2011, 187-263.
    • Nagle, D.G.; Zhou, Y.-D. “Natural Products as Probes of Selected Targets in Tumor Cell Biology and Hypoxic Signaling” Chapter 2.23 in Comprehensive Natural Products Chemistry II, Mander, L.N. ed. in chief; Vol. 2: Structural Diversity II – Secondary Metabolite Sources, Evolution, and Selected Molecular Structures, Moore, B.S., Crews, P., Vol. eds., Elsevier, Oxford, 2010, pp. 651-683.