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Purity Optimization of D-Gamma-Tocotrienol from Palm Oil. A Promising Radiation Protective Agent for Treatment of Acute Radiation SyndromeFobi, Kwabena 01 May 2020 (has links)
D-γ-tocotrienol (G-T3) chiefly present in palm oil has stolen the spotlight as a promising radiation protective agent for the treatment of acute radiation syndrome (ARS). Although G-T3 is a promising counteracting agent discovered, the separation and purification from its matrix are painstaking. These have limited its characterization, derivatization, and biomedical application. In this study, we developed chromatographic and distillation methods to enhance the purity and synthesis of G-T3 derivatives. Exactly 8% ethyl acetate (EA) in hexanes used in TLC resulted in right spots separation. Two gradient column chromatographic methods were examined using solvent mixtures of EA/hexanes and EA/petroleum ether (PE), respectively. We verified that a gradient elution with EA in PE led to the maximum purity (≥95%) based on the NMR and GC-MS outcomes. Also, G-T3 was stable in an emulsion to some extent, and some soluble G-T3 derivatives were synthesized, and their structure was confirmed
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Upregulation of pERK and c-JUN by γ-Tocotrienol and Not α-Tocopherol Are Essential to the Differential Effect on Apoptosis in Prostate Cancer CellsMoore, Christine, Palau, Victoria E., Mahboob, Rashid, Lightner, Janet, Stone, William, Krishnan, Koyamangalath 15 May 2020 (has links)
BACKGROUND: α-tocopherol (AT) and γ-tocotrienol (GT3) are vitamin E isoforms considered to have potential chemopreventive properties. AT has been widely studied in vitro and in clinical trials with mixed results. The latest clinical study (SELECT trial) tested AT in prostate cancer patients, determined that AT provided no benefit, and could promote cancer. Conversely, GT3 has shown antineoplastic properties in several in vitro studies, with no clinical studies published to date. GT3 causes apoptosis via upregulation of the JNK pathway; however, inhibition results in a partial block of cell death. We compared side by side the mechanistic differences in these cells in response to AT and GT3. METHODS: The effects of GT3 and AT were studied on androgen sensitive LNCaP and androgen independent PC-3 prostate cancer cells. Their cytotoxic effects were analyzed via MTT and confirmed by metabolic assays measuring ATP. Cellular pathways were studied by immunoblot. Quantitative analysis and the determination of relationships between cell signaling events were analyzed for both agents tested. Non-cancerous prostate RWPE-1 cells were also included as a control. RESULTS: The RAF/RAS/ERK pathway was significantly activated by GT3 in LNCaP and PC-3 cells but not by AT. This activation is essential for the apoptotic affect by GT3 as demonstrated the complete inhibition of apoptosis by MEK1 inhibitor U0126. Phospho-c-JUN was upregulated by GT3 but not AT. No changes were observed on AKT for either agent, and no release of cytochrome c into the cytoplasm was detected. Caspases 9 and 3 were efficiently activated by GT3 on both cell lines irrespective of androgen sensitivity, but not in cells dosed with AT. Cell viability of non-cancerous RWPE-1 cells was affected neither by GT3 nor AT. CONCLUSIONS: c-JUN is a recognized master regulator of apoptosis as shown previously in prostate cancer. However, the mechanism of action of GT3 in these cells also include a significant activation of ERK which is essential for the apoptotic effect of GT3. The activation of both, ERK and c-JUN, is required for apoptosis and may suggest a relevant step in ensuring circumvention of mechanisms of resistance related to the constitutive activation of MEK1.
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γ-Tocotrienol Induces Apoptosis in Pancreatic Cancer Cells by Upregulation of Ceramide Synthesis and Modulation of Sphingolipid TransportPalau, Victoria E., Chakraborty, Kanishka, Wann, Daniel, Lightner, Janet, Hilton, Keely, Brannon, Marianne, Stone, William, Krishnan, Koyamangalath 16 May 2018 (has links)
Background: Ceramide synthesis and metabolism is a promising target in cancer drug development. γ-tocotrienol (GT3), a member of the vitamin E family, orchestrates multiple effects that ensure the induction of apoptosis in both, wild-type and RAS-mutated pancreatic cancer cells. Here, we investigated whether these effects involve changes in ceramide synthesis and transport. Methods: The effects of GT3 on the synthesis of ceramide via the de novo pathway, and the hydrolysis of sphingomyelin were analyzed by the expression levels of the enzymes serine palmitoyl transferase, ceramide synthase-6, and dihydroceramide desaturase, and acid sphingomyelinase in wild-type RAS BxPC3, and RAS-mutated MIA PaCa-2 and Panc 1 pancreatic cancer cells. Quantitative changes in ceramides, dihydroceramides, and sphingomyelin at the cell membrane were detected by LCMS. Modulation of ceramide transport by GT3 was studied by immunochemistry of CERT and ARV-1, and the subsequent effects at the cell membrane was analyzed via immunofluorescence of ceramide, caveolin, and DR5. Results: GT3 favors the upregulation of ceramide by stimulating synthesis at the ER and the plasma membrane. Additionally, the conversion of newly synthesized ceramide to sphingomyelin and glucosylceramide at the Golgi is prevented by the inhibition of CERT. Modulation ARV1 and previously observed inhibition of the HMG-CoA pathway, contribute to changes in membrane structure and signaling functions, allows the clustering of DR5, effectively initiating apoptosis. Conclusions: Our results suggest that GT3 targets ceramide synthesis and transport, and that the upregulation of ceramide and modulation of transporters CERT and ARV1 are important contributors to the apoptotic properties demonstrated by GT3 in pancreatic cancer cells.
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