Gedunin abrogates aldose reductase, PI3K/Akt/mToR, and NF-κB signaling pathways to inhibit angiogenesis in a hamster model of oral carcinogenesis.
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.
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India.
Kranthi Kiran
KK
Kishore T
Biochemistry Division, National Institute of Nutrition, Hyderabad, 500 007, India.
Raghu
R
Ganugula
Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India.
Deepak Reddy
DR
Gade
Biochemistry Division, National Institute of Nutrition, Hyderabad, 500 007, India.
Geereddy Bhanuprakash
GB
Reddy
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India. s_nagini@yahoo.com.
Siddavaram
S
Nagini
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D036701:Limonins / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D062105:Molecular Docking Simulation; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D036701:Limonins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C106014:gedunin
Akt; Aldose reductase; Angiogenesis; Gedunin; Nuclear factor kappa B; Phosphatidyl inositol-3-kinase