Combined effects of 17-DMAG and TNF on cells through a mechanism related to the NF-kappaB pathway

Abstract

ObjectiveThe tumor necrosis factor (TNF) and the cellular NF-κB pathway protein IKKβ play important roles in various cellular processes such as cell proliferation, survival, differentiation, and apoptosis. A heat shock protein 90 inhibitor, 17-DMAG, can induce apoptosis of some tumor cells. This study is to determine the combined effects of 17-DMAG and TNF on malignant cells and the related mechanisms.MethodsWe have determined effects of 17-DMAG, an Hsp90 inhibitor, and TNF treatments on the small cell lung cancer cell line (MS-1), the adenocarcinoma cell line (A549), the squamous-cell carcinoma cell line (LK-2), and the normal human bronchial epithelium cell line (NuLi-1) by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrozolium bromide assay. To determine if 17-DMAG inhibit the expression of IKKβ in the normal human NuLi-1 cells, and the malignant MS-1, A549, and LK-2 cells, immunoblotting assays and luciferase assays were performed.ResultsIt was found that the combined treatments resulted in synergistic killing of malignant cells, which was confirmed by the apoptosis determination using a fluorescence microscopic assay following staining of the drug-treated cells with Hoescht 33258. The immunoblotting results indicated that the synergistic killing due to 17-DMAG and TNF treatments may be related to the decreases in IKKβ levels in the presence of 17-DMAG.ConclusionsThe results suggest that combination of 17-DMAG and TNF treatments might be useful for treating malignancies upon further study in the further.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2041198513886824

Astragalin-induced cell death is caspase-dependent and enhances the susceptibility of lung cancer cells to tumor necrosis factor by inhibiting the NF-κB pathway

“…Our study demonstrated that AG attenuated NF-κB activity and induced a synergistic increase in apoptosis in A549 cells treated with TNFα. In accord with past reports, the inhibition of NF-κB activation led to increased TNFα-induced apoptosis [ 57 ]. Moreover, AG reduced TNFα-stimulated IκBα degradation, which suppressed the nuclear translocation of NF-κB.…”

Comparison of Inhibitory Effect of 17-DMAG Nanoparticles and Free 17-DMAG in HSP90 Gene Expression in Lung Cancer

“…Studies have showed that encapsulating drugs to PLGA-PEG reduces dosage of drug and causes low adverse side effects of the drug (Mirakabad et al, 2013). 17DMAG is a hydrophilic gaeldamaycin derivative that can good bioavailability and better activity in vitro and in vivo and has significant anticancer activity (Sharp and Workman, 2006;Qu et al, 2013;Sun et al, 2013).…”

“…PLGA-PEG (poly (DL-lactic-co-glycolic acid)-polyethyleneglycol)-17DMAG is a kind of nanoparticle that may be to inhibit the expression of HSP90 gene in lung cancer cell line (Pearl and Toft, 2008;Banerji, 2009;Qu et al, 2013;Sun et al, 2013). In this study, we investigated whether nanocapsulating 17DMAG improve the anti cancer effect of free 17DMAG in the A549 lung cancer cell line.…”

Molecular mechanism and targeted therapy of Hsp90 involved in lung cancer: New discoveries and developments (Review)

“…As a potent proteasome inhibitor, PS-341 inhibits various types of cancer, interestingly, Hsp90 inhibitor 17-AAG enhances PS-341-induced lung cancer cell death by degrading upstream regulators of IκB, IRAK-1, and IκB kinases (IKKs) (83). In addition, combination of 17-DMAG and TnF brings about synergistic killing of lung cancer cells via downregulation of IKKβ (84). Hsp90 inhibitor ganetespib induces loss of EMl4-AlK expression and depletion of multiple oncogenic signaling proteins in AlK-driven nSClC cells (85).…”