Skip to main content
SpringerLink
Log in

Deguelin and Its Role in Chronic Diseases

  • Chapter
  • First Online:
Book cover Drug Discovery from Mother Nature

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 929))

Abstract

Deguelin is one of four major naturally occurring rotenoids isolated from root extracts and is best recognized as a NADH: ubiquinone oxidoreductase (complex I) inhibitor, resulting in significant alterations in mitochondrial function. Deguelin has also been implicated as a regulator of apoptosis through signaling pathways, such as the (PI3K)/Akt pathway, as well as an initiator of cell cycle arrest. Consequently, this compound has accrued great interest as a potential chemopreventive and chemotherapeutic. Additionally, deguelin exposure has been linked to Parkinson’s disease (PD). PD is a neurodegenerative disorder, characterized by a substantial loss of dopaminergic neurons in the substantia nigra, as well the manifestation of symptoms such as bradykinesia, rigidity, and rest tremor. While exploring the genetic impact of PD is imperative, environmental factors, such as exposure to pesticides, herbicides, and insecticides, have also been connected to the development of PD. The etiology and pathogenesis of PD are yet to be fully understood and elucidated, but mitochondrial dysfunction is gaining recognition as a molecular hallmark of PD. In fact, deguelin has been reported to elicit PD-like symptoms (degeneration of the dopaminergic pathway) in rats administered with deguelin (6 mg/kg/day for 6 days), possibly through the inhibition of mitochondrial complex I. Further research investigating the mechanisms by which deguelin inhibits central cellular processes is essential in order to advance any prospective research addressing potential applications and risks of deguelin.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Baba Y, Fujii M, Maeda T, Suzuki A, Yuzawa S, Kato Y (2015) Deguelin induces apoptosis by targeting both EGFR-Akt and IGF1R-Akt pathways in head and neck squamous cell cancer cell lines. Biomed Res Int 2015:657179

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bekris LM, Mata IF, Zabetian CP (2010) The genetics of Parkinson disease. J Geriatr Psychiatry Neurol 23:228–242

    Article  PubMed  PubMed Central  Google Scholar 

  3. Boreddy SR, Srivastava SK (2013) Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model. Oncogene 32:3980–3991

    Article  CAS  PubMed  Google Scholar 

  4. Bortul R, Tazzari PL, Billi AM, Tabellini G, Mantovani I, Cappellini A, Grafone T, Martinelli G, Conte R, Martelli AM (2005) Deguelin, A PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway. Br J Haematol 129:677–686

    Article  CAS  PubMed  Google Scholar 

  5. Boyd J, Saksena A, Patrone JB, Williams HN, Boggs N, Le H, Theodore M (2011) Exploring the boundaries of additivity: mixtures of NADH: quinone oxidoreductase inhibitors. Chem Res Toxicol 24:1242–1250

    Article  CAS  PubMed  Google Scholar 

  6. Caboni P, Sherer TB, Zhang N, Taylor G, Na HM, Greenamyre JT, Casida JE (2004) Rotenone, deguelin, their metabolites, and the rat model of Parkinson’s disease. Chem Res Toxicol 17:1540–1548

    Article  CAS  PubMed  Google Scholar 

  7. Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2003) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031

    Article  CAS  PubMed  Google Scholar 

  8. Chu ZH, Liang XH, Zhou XL, Huang RF, Zhan Q, Jiang JW (2011) Effects of deguelin on proliferation and apoptosis of MCF-7 breast cancer cells by phosphatidylinositol 3-kinase/Akt signaling pathway. Zhong Xi Yi Jie He Xue Bao 9:533–538

    Article  CAS  PubMed  Google Scholar 

  9. Chun KH, Kosmeder JW, Sun S, Pezzuto JM, Lotan R, Hong WK, Lee HY (2003) Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J Natl Cancer Inst 95:291–302

    Article  CAS  PubMed  Google Scholar 

  10. Clark EP (1931) Deguelin. I. The preparation, purification and properties of deguelin, a constituent of certain tropical fish-poisoning plants. J Am Chem Soc 53:313–317

    Article  CAS  Google Scholar 

  11. Corrigan FM, Wienburg CL, Shore RF, Daniel SE, Mann D (2000) Organochlorine insecticides in substantia nigra in Parkinson’s disease. J Toxicol Environ Health A 59:229–234

    Article  CAS  PubMed  Google Scholar 

  12. Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909

    Article  CAS  PubMed  Google Scholar 

  13. Davidson WM (1930) The relative value as contact insecticides of some constituents of Derris. J Econ Entomol 23:877–879

    Article  CAS  Google Scholar 

  14. Davie CA (2008) A review of Parkinson’s disease. Br Med Bull 86:109–127

    Article  CAS  PubMed  Google Scholar 

  15. Deguelin; MSDS [Online]; Sigma-Aldrich 06/27/2014. Accessed 16 Nov 2015

    Google Scholar 

  16. Fang N, Casida JE (1999) Cubé resin insecticide: identification and biological activity of 29 rotenoid constituents. J Agric Food Chem 47:2130–2136

    Article  CAS  PubMed  Google Scholar 

  17. Fato R, Bergamini C, Bortolus M, Maniero AL, Leoni S, Ohnishi T, Lenaz G (2009) Differential effects of mitochondrial complex I inhibitors on production of reactive oxygen species. Biochim Biophys Acta 1787:384–392

    Article  CAS  PubMed  Google Scholar 

  18. Gerhäuser C, Lee SK, Kosmeder JW, Moriarty RM, Hamel E, Mehta RG, Moon RC, Pezzuto JM (1997) Regulation of ornithine decarboxylase induction by deguelin, a natural product cancer chemopreventive agent. Cancer Res 57:3429–3435

    CAS  PubMed  Google Scholar 

  19. Gersdorff WA (1931) A study of the toxicity of toxicarol, deguelin and tephrosin using the goldfish as the test animal. J Am Chem Soc 53:1897–1901

    Article  CAS  Google Scholar 

  20. Hers I, Vincent EE, Tavare JM (2011) Akt signalling in health and disease. Cell Signal 23:1515–1527

    Article  CAS  PubMed  Google Scholar 

  21. Holland EA (1938) Suicide by ingestion of derris root sp. in New Ireland. Trans Roy Soc Trop Med Hyg 32:293–294

    Article  CAS  Google Scholar 

  22. Hsu YC, Chiang JH, Yu CS, Hsia TC, Wu RS, Lien JC, Lai KC, Yu FS, Chung JG (2015) Antitumor effects of deguelin on H460 human lung cancer cells in vitro and in vivo: roles of apoptotic cell death and H460 tumor xenografts model. Environ Toxicol

    Google Scholar 

  23. Hu J, Ye H, Fu A, Chen X, Wang Y, Ye X, Xiao W, Duan X, Wei Y, Chen L (2010) Deguelin–an inhibitor to tumor lymphangiogenesis and lymphatic metastasis by downregulation of vascular endothelial cell growth factor-D in lung tumor model. Int J Cancer 127:2455–2466

    Article  CAS  PubMed  Google Scholar 

  24. Jin Q, Feng L, Behrens C, Bekele BN, Wistuba II, Hong WK, Lee HY (2007) Implication of AMP-activated protein kinase and Akt-regulated survivin in lung cancer chemopreventive activities of deguelin. Cancer Res 67:11630–11639

    Article  CAS  PubMed  Google Scholar 

  25. Kang HW, Kim JM, Cha MY, Jung HC, Song IS, Kim JS (2012) Deguelin, an Akt inhibitor, down-regulates NF-kappaB signaling and induces apoptosis in colon cancer cells and inhibits tumor growth in mice. Dig Dis Sci 57:2873–2882

    Article  CAS  PubMed  Google Scholar 

  26. Kim WY, Chang DJ, Hennessy B, Kang HJ, Yoo J, Han SH, Kim YS, Park HJ, Seo SY, Mills G, Kim KW, Hong WK, Suh YG, Lee HY (2008) A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy. Cancer Prev Res (Phila) 1:577–587

    Article  CAS  Google Scholar 

  27. Kussmaul L, Hirst J (2006) The mechanism of superoxide production by NADH: ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci U S A 103:7607–7612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980

    Article  CAS  PubMed  Google Scholar 

  29. Lee H, Lee JH, Jung KH, Hong SS (2010) Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer. Oncol Rep 24:957–963

    CAS  PubMed  Google Scholar 

  30. Li A, Dubey S, Varney ML, Dave BJ, Singh RK (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170:3369–3376

    Article  CAS  PubMed  Google Scholar 

  31. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278:8516–8525

    Article  CAS  PubMed  Google Scholar 

  32. Li Z, Wu J, Wu C, Jiang J, Zheng X, Xu B, Li M (2012) Deguelin, a natural rotenoid, inhibits mouse myeloma cell growth in vitro via induction of apoptosis. Oncol Lett 4:677–681

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lopiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11:32–50

    Article  CAS  PubMed  Google Scholar 

  34. Mehta RR, Katta H, Kalra A, Patel R, Gupta A, Alimirah F, Murillo G, Peng X, Unni A, Muzzio M, Mehta RG (2013) Efficacy and mechanism of action of deguelin in suppressing metastasis of 4T1 cells. Clin Exp Metastasis 30:855–866

    Article  CAS  PubMed  Google Scholar 

  35. Mittler R, Vanderauwera S, Suzuki N, Miller G, Tognetti VB, Vandepoele K, Gollery M, Shulaev V, van Breusegem F (2011) ROS signaling: the new wave? Trends Plant Sci 16:300–309

    Article  CAS  PubMed  Google Scholar 

  36. Murillo G, Peng X, Torres KE, Mehta RG (2009) Deguelin inhibits growth of breast cancer cells by modulating the expression of key members of the Wnt signaling pathway. Cancer Prev Res (Phila) 2:942–950

    Article  CAS  Google Scholar 

  37. Murillo G, Salti GI, Kosmeder JW, Pezzuto JM, Mehta RG (2002) Deguelin inhibits the growth of colon cancer cells through the induction of apoptosis and cell cycle arrest. Eur J Cancer 38:2446–2454

    Article  CAS  PubMed  Google Scholar 

  38. Nagatsu T, Sawada M (2006) Cellular and molecular mechanisms of Parkinson’s disease: neurotoxins, causative genes, and inflammatory cytokines. Cell Mol Neurobiol 26:781–802

    Article  CAS  PubMed  Google Scholar 

  39. Nair AS, Shishodia S, Ahn KS, Kunnumakkara AB, Sethi G, Aggarwal BB (2006) Deguelin, an Akt inhibitor, suppresses IkappaBalpha kinase activation leading to suppression of NF-kappaB-regulated gene expression, potentiation of apoptosis, and inhibition of cellular invasion. J Immunol 177:5612–5622

    Article  CAS  PubMed  Google Scholar 

  40. Negherbon WO (1959) Handbook of toxicology, vol III. Insecticides

    Google Scholar 

  41. Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36:2503–2508

    Article  CAS  PubMed  Google Scholar 

  42. Oh SH, Woo JK, Yazici YD, Myers JN, Kim WY, Jin Q, Hong SS, Park HJ, Suh YG, Kim KW, Hong WK, Lee HY (2007) Structural basis for depletion of heat shock protein 90 client proteins by deguelin. J Natl Cancer Inst 99:949–961

    Article  CAS  PubMed  Google Scholar 

  43. Okun JG, Lummen P, Brandt U (1999) Three classes of inhibitors share a common binding domain in mitochondrial complex I (NADH: ubiquinone oxidoreductase). J Biol Chem 274:2625–2630

    Article  CAS  PubMed  Google Scholar 

  44. Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS (2001) Environmental risk factors and Parkinson’s disease: a metaanalysis. Environ Res 86:122–127

    Article  CAS  PubMed  Google Scholar 

  45. Richardson JR, Shalat SL, Buckley B, Winnik B, O’Suilleabhain P, Diaz-Arrastia R, Reisch J, German DC (2009) Elevated serum pesticide levels and risk of Parkinson disease. Arch Neurol 66:870–875

    Article  PubMed  PubMed Central  Google Scholar 

  46. Thamilselvan V, Menon M, Thamilselvan S (2011) Anticancer efficacy of deguelin in human prostate cancer cells targeting glycogen synthase kinase-3 beta/beta-catenin pathway. Int J Cancer 129:2916–2927

    Article  CAS  PubMed  Google Scholar 

  47. Tomlin CDS (1997) The pesticide manual, 11 edn. xliii+1606p–xliii+1606p

    Google Scholar 

  48. Udeani GO, Zhao GM, Shin YG, Kosmeder JW, Beecher CW, Kinghorn AD, Moriarty RM, Moon RC, Pezzuto JM (2001) Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats. Cancer Chemother Pharmacol 47:263–268

    Article  CAS  PubMed  Google Scholar 

  49. van der Mark M, Brouwer M, Kromhout H, Nijssen P, Huss A, Vermeulen R (2012) Is pesticide use related to Parkinson disease? Some clues to heterogeneity in study results. Environ Health Perspect 120:340–347

    Article  PubMed  Google Scholar 

  50. Vrana JA, Boggs N, Currie HN, Boyd J (2013) Amelioration of an undesired action of deguelin. Toxicon 74:83–91

    Article  CAS  PubMed  Google Scholar 

  51. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  CAS  PubMed  Google Scholar 

  52. Xiong JR, Liu HL (2013) Regulatory effects of deguelin on proliferation and cell cycle of Raji cells. J Huazhong Univ Sci Technol Med Sci 33:491–495

    Article  CAS  PubMed  Google Scholar 

  53. Yan Y, Wang Y, Tan Q, Lubet RA, You M (2005) Efficacy of Deguelin and Silibinin on Benzo(a)pyrene-Induced Lung Tumorigenesis in A/J Mice1. Neoplasia 7:1053–1057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia, USA

    Jonathan Boyd & Alice Han

Authors
  1. Jonathan Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alice Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan Boyd .

Editor information

Editors and Affiliations

  1. Banaras Hindu University, Varanasi, Uttar Pradesh, India

    Subash Chandra Gupta

  2. MD Anderson Cancer Center, University of Texas, Houston, Texas, USA

    Sahdeo Prasad

  3. Inflammation Research Institute, San Diego, California, USA

    Bharat B. Aggarwal

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Boyd, J., Han, A. (2016). Deguelin and Its Role in Chronic Diseases. In: Gupta, S., Prasad, S., Aggarwal, B. (eds) Drug Discovery from Mother Nature. Advances in Experimental Medicine and Biology, vol 929. Springer, Cham. https://doi.org/10.1007/978-3-319-41342-6_16

Download citation

Publish with us

Policies and ethics

Search

Navigation