Background and Objectives: Aldose Reductase (AR), a polyol pathway enzyme that mediates
diabetic complications is implicated in tumour development and progression. This study was undertaken to
determine whether gedunin, a neem limonoid prevents the hallmarks of cancer by inhibiting AR and the associated
downstream PI3K/Akt/mTOR/ERK/NF-κB signalling axis in the SCC131 oral cancer cell line.
Methods: The expression of AR and key molecules involved in cell proliferation, apoptosis, autophagy, invasion
and angiogenesis was analysed by qRT-PCR, and immunoblotting. ROS generation and cell cycle were
analysed by FACS. Alamar blue assay and scratch assay were used to evaluate cell proliferation and migration
in the endothelial cell line Eahy926.
Results: Gedunin and the AR inhibitor epalrestat inhibited AR expression and ROS generation. Cell cycle arrest
at G1/S was associated with cell death by autophagy with subsequent switch over to apoptosis. Furthermore,
hypoxia-induced cell migration was inhibited in Eahy926 cells with downregulation of pro-invasive and proangiogenic
proteins in SCC131 as well as Eahy926 cells. Co-inactivation of Akt and ERK was coupled with
abrogation of IKK/NF-κB signaling. However, the combination of gedunin and epalrestat was more effective
than single agents.
Conclusion: Inhibition of AR-mediated ROS signalling may be a key mechanism by which gedunin and epalrestat
exert their anticancer effects. Our results provide compelling evidence that the combination of gedunin
and epalrestat modulates expression of key oncogenic signalling kinases and transcription factors primarily by
influencing phosphorylation and subcellular localisation. AR inhibitors such as gedunin and epalrestat are novel
candidate agents for cancer prevention and therapy.