Antitumor effects of deguelin on H460 human lung cancer cells in vitro and in vivo: Roles of apoptotic cell death and H460 tumor xenografts model

Abstract

Deguelin, a naturally occurring rotenoid of the flavonoid family, is known to be an Akt inhibitor, to have chemopreventive activities and anti-tumor effect on several cancers. In this study, investigation to elucidate the effect of deguelin on apoptotic pathways in human lung cancer cells and on the anti-tumor effect in lung cancer xenograft nu/nu mice was performed. In vitro studies, found that deguelin induced cell morphological changes, and decreased the percentage of viability through the induction of apoptosis in H460 lung cancer cells. Deguelin triggered apoptosis in H460 cells was also confirmed by DAPI staining, DNA gel electrophoresis, and Annexin V-FITC staining and these effects are dose-dependent manners. It was also found that deguelin promoted the Ca production and activation of caspase-3 but decreased the level of ΔΨ in H460 cells. Western blots indicated that the protein levels of cytochrome c, AIF, and pro-apoptotic Bax and Bak protein were increased, but the anti-apoptotic Bcl-2 and Bcl-x were decreased that may have led to apoptosis in H460 cells after exposure to deguelin. It was also confirmed by confocal laser microscope examination that deguelin promoted the release of AIF from mitochondria to cytosol. In vivo studies, found that in immunodeficient nu/nu mice bearing H460 tumor xenografts showed that the deguelin significantly suppressed tumor growth. Deguelin might be a potential therapeutic agent for the treatment of lung cancer in the future. This finding might fully support a critical event for deguelin via induction of apoptotic cell death and H460 tumor xenografts model against human lung cancer. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 84-98, 2017.

Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib‐resistant BRAFV600E mutation bearing metastatic melanoma cells

“…Additional validation by immunoblotting further confirmed the initial results from our phospho‐array where we observed either an increase in Akt‐phosphorylation at the residue S473 or no difference at residue T308. The contradictory results observed could be due to the early time points that were the focus of the present study as time kinetics for deguelin's inhibition have been previously done in the context of H460 lung cancer cells and only show a decrease after 24 hours of treatment at both phosphorylation sites . Those data suggest that the PI3K‐Akt axis of deguelin's activity may be only indirectly tied to its inhibition of OXPHOS requiring some time for the necessary signaling to occur.…”

“…It follows that if PI3K‐Akt signaling occurs at later time points then deguelin's characteristic induction of apoptosis does as well . Indeed, in the present study we observed no evidence for induction of apoptosis at early time points. However, we did observe a significant decrease in viability as soon as 24 hours after treatment, which is around the time survival signaling that has been shown to be inhibited in other contexts.…”

Fisetin Induces Apoptosis of HSC3 Human Oral Cancer Cells Through Endoplasmic Reticulum Stress and Dysfunction of Mitochondria-mediated Signaling Pathways

“…We used several methods, including DAPI and comet staining, to show that fisetin induced apoptosis of HSC3 cells. DAPI staining in cancer cells has been used as a method to measure apoptotic cell death (39,40). We found that fisetin increased the productions of ROS and Ca 2+ in HSC3 cells ( Figure 4A and B).…”

An Intramolecular CAr–H•••O=C Hydrogen Bond and the Configuration of Rotenoids

“…In our previous work, (−)-rotenone and its analogues and (−)-tephrosin were found to exhibit cytotoxicity toward a small panel of human cancer cell lines [16–19], with similar effects observed for deguelin and 13-homo-13-oxa-2,3-dehydrodeguelin by other groups [20, 21]. Interestingly, deguelin was found to show in vivo cancer chemopreventive and antitumor effects [22, 23]. Tumor growth was inhibited, when thirty six-week-old male athymic BALB/c nu/nu mice bearing H460 human lung tumor xenografts were treated with deguelin (1 or 4 mg/kg, once every three days for 30 days) [23].…”

“…Interestingly, deguelin was found to show in vivo cancer chemopreventive and antitumor effects [22, 23]. Tumor growth was inhibited, when thirty six-week-old male athymic BALB/c nu/nu mice bearing H460 human lung tumor xenografts were treated with deguelin (1 or 4 mg/kg, once every three days for 30 days) [23]. …”