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

Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kranthi Kiran Kishore TS Nagini

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.

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Citations

Jan 26, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Teresa M BragaAgostinho Cruz
Jul 8, 2020·Journal of Cellular and Molecular Medicine·Reza KhayamiMohammad Amin Kerachian
May 10, 2020·International Journal of Molecular Sciences·Choudhary HarshaAjaikumar B Kunnumakkara
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Dec 16, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Angeline Julius, Waheeta Hopper
Jun 9, 2021·Nutrition and Cancer·Andrés Cardona-MendozaSandra J Perdomo
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Luiselva Torrescano-De LabraAntonio Ruperto Jiménez-Aparicio
Dec 9, 2020·Journal of Medicinal Chemistry·Yulin Ren, A Douglas Kinghorn

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