Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs

Abstract

BackgroundCancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs.MethodsThe anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of δ-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-α using total RNAs derived from plasmas of hepatitis C patients was investigated.ResultsOur data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% - 87%) with doses of 2.5–20 μM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, δ-tocotrienol, and quercetin were 70% - 92%. However, thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, and quinine sulphate were effective in pancreatic, prostate, breast, lungs, melanoma, Β-lymphocytes, and T-cells (Jurkat: 40% to 95%) compared to respective controls. In lung cancer cells, these compounds were effective between 5 and 40 μM. The IC50 values of anti-proliferation properties of thiostrepton in most of these cell lines were between doses of 2.5–5 μM, dexamethasone 2.5–20 μM, 2-methoxyestradiol 2.5–10 μM, δ-tocotrienol 2.5–20 μM, quercetin 10–40 μM, and (−) Corey lactone 40–80 μM. In hepatitis C patients, δ-tocotrienol treatment resulted in significant decrease in the expression of pro-inflammatory cytokines.ConclusionsThese data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, Β-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

“…Since the ubiquitination of IκB by the SCF-B-TrCP ubiquitin ligase complex and the subsequent degradation by the 26S proteasome is a crucial step in the NF-κB activation pathways, preventing the degradation of IκBα is a potential method of treatment to prevent NF-κB activation [ 13 , 14 , 141 , 155 , 156 ].…”

δ-Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple-signaling pathways in chronic hepatitis C patients

“…Collectively, the effects of δ-tocotrienol on “canonical pathways” observed in IPA of total mRNA sample of hepatitis C patients resulted in modulation of over 360 pathways, which are associated with multiple signaling pathways. It is conceivable that some or most of these pathways may be controlled by the proteasome, since the protein ubiquitination pathway was down-regulated by δ-tocotrienol treatment as described previously [ 1 ].…”

“…The details of study design, inclusion/exclusion criteria, experimental design, and physical characteristics of hepatitis C patients were same as reported [ 1 ]. In short, the total mRNA was extracted from plasma of EDTA treated fresh whole blood of each hepatitis C patients ( n = 14) fed δ-tocotrienol (500 mg/d) for 6 weeks by total RNA purification kit (NORGEN Bioteck Corporation, Thorold, ON, Canada).…”

“…The results of most important cytokines and other biomarkers associated with the present investigation were estimated by real-time RT-PCR by using plasma total RNAs purified from pre-dose versus post-dose samples after feeding δ-tocotrienol for 6-weeks to chronic hepatitis C patients has been published recently [ 1 ], therefore present manuscript lacks in vitro estimations of RT-PCR data. The same plasma total RNAs were used in the present study.…”

“…We have recently reported that δ-tocotrienol is a potent anti-cancer agent (liver, pancreas, prostrate, breast cancer cell lines, Hela, melanoma, B lymphocytes and T-cells), and also a modulator of proteasome function, as compared to other outstanding proteasome inhibitors (thiostrepton, 2-methoxyestradiol, and quercetin) [ 1 ]. Moreover, plasma total mRNAs obtained from δ-tocotrienol treated hepatitis C patients showed significant inhibition in the expression of pro-inflammatory cytokines (TNF-α and VCAM-1), and induction in expression of ICAM-1, IFN-γ, whereas proteasome subunits X, Y, Z, LMP7, LMP2, LMP10 (22–44%) were significantly inhibited compared to pre-dose values, and this down-regulation of proteasome subunits leads to autophagy and apoptosis of cells [ 1 ]. The present study is an extension of these findings to study the effect of δ-tocotrienol (Fig.…”