Gedunin, A Neem Limonoid in Combination with Epalrestat Inhibits Cancer Hallmarks by Attenuating Aldose Reductase-Driven Oncogenic Signaling in SCC131 Oral Cancer Cells

Abstract

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.

Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

“…This results in the AKT/mTOR-mediated regulation of angiogenesis, EMT, migration and invasion at the same time, subsequently causing metastasis. In a particular study, a neem limonoid, gedunin, in association with epalrestat, an aldose reductase inhibitor used for the treatment of diabetic neuropathy, was found to inhibit cell migration by inhibiting AKT/mTOR signaling in squamous cell carcinoma (SCC)-131 cells [122]. In another study, C-reactive protein (CRP) increased the invasion and migration of OSCC cells plausibly via the activation of the AKT/mTOR axis [123].…”

Aldose reductase inhibitor form Cassia glauca: A comparative study of cytotoxic activity with Ag nanoparticles (NPs) and molecular docking evaluation

“…The overexpression and the increased activity of aldose reductase enzymes in different human cancers were also reported [66]. Aldose reductase enzymes were found to be involved in the tumorigenesis process via the production of growth factors that promote cell proliferation and inflammatory cytokines [17,18,67], thus aldose reductase activity inhibition could be evidence for cytotoxic effects. Aldose reductase inhibitors were found to be doxorubicin sensitivity enhancers as reported in the case of colon cancer cells and this can explain the synergistic effect on the cytotoxic activity with doxorubicin.…”

“…The role of inhibition of aldose reductase in cancer management was investigated and proven through inhibition of aldose reductase-mediated ROS signaling and preventing activation of various oncogenic kinases and transcription factors that are responsible for the production of several carcinogenic mediators [ 17 , 18 ]. The use of doxorubicin, a potent chemotherapeutic drug against cancers, became limited due to its cardiotoxic effects [ 19 – 21 ].…”

Biological Activities of Gedunin—A Limonoid from the Meliaceae Family

“…Gedunin's effect on oral cancer has been recently studied in vitro [35] and in vivo [34]. The in vivo approach investigated the effects of gedunin on the phosphoinositide 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) and nuclear factor kappa B (NF-κB) signaling pathways, as well as hypoxia-inducible factor 1α (HIF1α)-mediated vascular endothelial growth factor (VEGF) signaling in a hamster buccal pouch (HBP) carcinogenesis model.…”

“…The in vitro approach used the SCC131 oral cancer cell line to investigate how gedunin, alone or combined with epalrestat, prevented the hallmarks of cancer by inhibiting ARase and the associated downstream PI3K/Akt/mTOR/ERK/NF-κB signaling axis. Tanagala et al [35] concluded that gedunin, alone and combined, blocked cell proliferation, invasion, and angiogenesis, and induced cell death by blocking ARase-driven oncogenic signalling networks. Furthermore, gedunin combined with epalrestat was more effective than each single agent, suppressing the growth of SCC131 cells at half the concentrations used individually (0 to 180 µM for gedunin and 0 to 1.6 µM for epalrestat) [35].…”