Tumor Biology

, Volume 37, Issue 2, pp 2083–2093 | Cite as

Gedunin abrogates aldose reductase, PI3K/Akt/mToR, and NF-κB signaling pathways to inhibit angiogenesis in a hamster model of oral carcinogenesis

  • Kranthi Kiran Kishore T
  • Raghu Ganugula
  • Deepak Reddy Gade
  • Geereddy Bhanuprakash Reddy
  • Siddavaram Nagini
Original Article

Abstract

Aberrant activation of oncogenic signaling pathways plays a central role in tumor development and progression. The aim of this present study was to investigate the chemopreventive effects of the neem limonoid gedunin in the hamster model of oral cancer based on its ability to modulate aldose reductase (AR), phosphatidyl inositol-3-kinase (PI3K)/Akt, and nuclear factor kappa B (NF-κB) pathways to block angiogenesis. Administration of gedunin suppressed the development of HBP carcinomas by inhibiting PI3K/Akt and NF-κB pathways through the inactivation of Akt and inhibitory kappa B kinase (IKK), respectively. Immunoblot and molecular docking interactions revealed that inhibition of these signaling pathways may be mediated via inactivation of AR by gedunin. Gedunin blocked angiogenesis by downregulating the expression of miR-21 and the pro-angiogenic factors vascular endothelial growth factor and hypoxia inducible factor-1 alpha (HIF-1α). In conclusion, the results of the present study provide compelling evidence that gedunin prevents progression of hamster buccal pouch (HBP) carcinomas via inhibition of the kinases Akt, IKK, and AR, and the oncogenic transcription factors NF-κB and HIF-1α to block angiogenesis.

Keywords

Gedunin Angiogenesis Aldose reductase Phosphatidyl inositol-3-kinase Akt Nuclear factor kappa B 

Notes

Acknowledgments

Financial support from the Indian Council of Medical Research, New Delhi, India, in the form of a Senior Research Fellowship to Mr. Kranthi Kiran Kishore T. is gratefully acknowledged.

Conflicts of interest

None

Authors’ contributions

SN, GBR, and TKK designed the experiments. TKK, GR, and GDR performed the experiments and analyzed the data. SN, TKK, and GBR were involved in the preparation of the manuscript.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Kranthi Kiran Kishore T
    • 1
  • Raghu Ganugula
    • 2
  • Deepak Reddy Gade
    • 3
  • Geereddy Bhanuprakash Reddy
    • 2
  • Siddavaram Nagini
    • 1
  1. 1.Department of Biochemistry and Biotechnology, Faculty of ScienceAnnamalai UniversityAnnamalainagarIndia
  2. 2.Biochemistry DivisionNational Institute of NutritionHyderabadIndia
  3. 3.Medicinal Chemistry Research DivisionVishnu Institute of Pharmaceutical Education and ResearchNarsapurIndia

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