Delving into the Latest Updates on Gamma-Tocotrienol with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target-

Action

stimulants, inhibitors

Mechanism

Apoptosis stimulants, Gene expression inhibitors

Therapeutic Areas

Endocrinology and Metabolic DiseaseNeoplasms

Active Indication-

Inactive Indication

HypercholesterolemiaSolid tumor

Originator Organization

Davos Life Science Pte Ltd.

Active Organization-

Inactive Organization

Davos Life Science Pte Ltd.

License Organization-

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC28H42O2

InChIKeyOTXNTMVVOOBZCV-NTZRDTQNSA-N

CAS Registry16772-32-0

Introduction:Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) is involved in the progression of hepatocellular carcinoma (HCC).Aims:This study aimed to investigate the inhibitory effect of gamma-tocotrienol (γ-T3) on the proliferation and growth of HSD17B4-overexpressing HepG2 cells.Methods:HepG2 cells were transfected with empty or HSD17B4-overexpressing plasmids, followed by vitamin E (VE) or γ-T3 treatment. MTS assay, Western blotting, qRT-PCR, and flow cytometry were employed to assess cell proliferation, protein expression, mRNA levels, and apoptosis. HSD17B4 interaction with γ-T3 was assessed by quantifying γ-T3 in the collected precipitate of HSD17B4 using anti-flag magnetic beads. Tumor xenografts were established in NSG mice, and tumor growth was monitored.Results:HSD17B4 overexpression significantly promoted HepG2 cell proliferation, which was effectively counteracted by VE or γ-T3 treatment in a dose-dependent manner. VE and γ-T3 did not exert their effects through direct regulation of HSD17B4 expression. Instead, γ-T3 was found to interact with HSD17B4, inhibiting its activity in catalyzing the conversion of estradiol (E2) into estrone. Moreover, γ-T3 treatment led to a reduction in cyclin D1 expression and suppressed key proliferation signaling pathways, such as ERK, MEK, AKT, and STAT3. Additionally, γ-T3 promoted apoptosis in HSD17B4-overexpressing HepG2 cells. In an in vivo model, γ-T3 effectively reduced the growth of HepG2 xenograft tumors.Conclusion:In conclusion, our study demonstrates that γ-T3 exhibits potent anti-proliferative and anti-tumor effects against HepG2 cells overexpressing HSD17B4. These findings highlight the therapeutic potential of γ-T3 in HCC treatment and suggest its role in targeting HSD17B4-associated pathways to inhibit tumor growth and enhance apoptosis.

08 May 2024·Radiation Research

Validating a Four-gene Set for H-ARS Severity Prediction in Peripheral Blood Samples of Irradiated Rhesus Macaques

Article

Author: Abend, M ; Fatanmi, O O ; Ostheim, P ; Wiegel, T ; Schüle, S ; Stewart, S ; Wise, S Y ; Hackenbroch, C ; Port, M ; Schwanke, D ; Singh, V K

Increased radiological and nuclear threats require preparedness. Our earlier work identified a set of four genes (DDB2, FDXR, POU2AF1 and WNT3), which predicts severity of the hematological acute radiation syndrome (H-ARS) within the first three days postirradiation In this study of 41 Rhesus macaques (Macaca mulatta, 27 males, 14 females) irradiated with 5.8-7.2 Gy (LD29-50/60), including some treated with gamma-tocotrienol (GT3, a radiation countermeasure) we independently validated these genes as predictors in both sexes and examined them after three days. At the Armed Forces Radiobiology Research Institute/Uniformed Services University of the Health Sciences, peripheral whole blood (1 ml) of Rhesus macaques was collected into PAXgene® Blood RNA tubes pre-irradiation after 1, 2, 3, 35 and 60 days postirradiation, stored at -80°C for internal experimental analyses. Leftover tubes from these already ongoing studies were kindly provided to Bundeswehr Institute of Radiobiology. RNA was isolated (QIAsymphony), converted into cDNA, and for further gene expression (GE) studies quantitative RT-PCR was performed. Differential gene expression (DGE) was measured relative to the pre-irradiation Rhesus macaques samples. Within the first three days postirradiation, we found similar results to human data: 1. FDXR and DDB2 were up-regulated, FDXR up to 3.5-fold, and DDB2 up to 13.5-fold in the median; 2. POU2AF1 appeared down regulated around tenfold in nearly all Rhesus macaques; 3. Contrary to human data, DDB2 was more up-regulated than FDXR, and the difference of the fold change (FC) ranged between 2.4 and 10, while the median fold changes of WNT3, except days 1 and 35, were close to 1. Nevertheless, 46% of the Rhesus macaques showed down-regulated WNT3 on day one postirradiation, which decreased to 12.2% on day 3 postirradiation. Considering the extended phase, there was a trend towards decreased fold changes at day 35, with median-fold changes ranging from 0.7 for DDB2 to 0.1 for POU2AF1, and on day 60 postirradiation, DGE in surviving animals was close to pre-exposure values for all four genes. In conclusion, the diagnostic significance for radiation-induced H-ARS severity prediction of FDXR, DDB2, and POU2AF1 was confirmed in this Rhesus macaques model. However, DDB2 showed higher GE values than FDXR. As shown in previous studies, the diagnostic significance of WNT3 could not be reproduced in Rhesus macaques; this could be due to the choice of animal model and methodological challenges.

08 May 2024·Radiation Research

Validating Radiosensitivity with Pre-Exposure Differential Gene Expression in Peripheral Blood Predicting Survival and Non-Survival in a Second Irradiated Rhesus Macaque Cohort

Article

Author: Fatanmi, O O ; Schüle, S ; Stewart, S ; Kaletka, G ; Abend, M ; Wiegel, T ; Port, M ; Wise, S Y ; Ostheim, P ; Schwanke, D ; Singh, V K

Radiosensitivity differs in humans and possibly in closely related nonhuman primates. The reasons for variation in radiosensitivity are not well known. In an earlier study, we examined gene expression (GE) pre-radiation in peripheral blood among male (n = 62) and female (n = 60) rhesus macaques (n = 122), which did or did not survive (up to 60 days) after whole-body exposure of 7.0 Gy (LD66/60). Eight genes (CHD5, CHI3L1, DYSF, EPX, IGF2BP1, LCN2, MBOAT4, SLC22A4) revealed significant associations with survival. Access to a second rhesus macaque cohort (males = 40, females = 23, total n = 63) irradiated with 5.8-7.2 Gy (LD29-50/60) and some treated with gamma-tocotrienol (GT3, a radiation countermeasure) allowed us to validate these gene expression changes independently. Total RNA was isolated from whole blood samples and examined by quantitative RT-PCR on a 96-well format. cycle threshold (Ct)-values normalized to 18S rRNA were analyzed for their association with survival. Regardless of the species-specific TaqMan assay, similar results were obtained. Two genes (CHD5 and CHI3L1) out of eight revealed a significant association with survival in the second cohort, while only CHD5 (involved in DNA damage response and proliferation control) showed mean gene expression changes in the same direction for both cohorts. No expected association of CHD5 GE with dose, treatment, or sex could be established. Instead, we observed significant associations for those comparisons comprising pre-exposure samples with CHD5 Ct values ≤ 11 (total n = 17). CHD5 Ct values ≤ 11 in these comparisons were mainly associated with increased frequencies (61-100%) of non-survivors, a trend which depending on the sample numbers, reached significance (P = 0.03) in males and, accordingly, in females. This was also reflected by a logistic regression model including all available samples from both cohorts comprising CHD5 measurements (n = 104, odds ratio 1.38, 95% CI 1.07-1.79, P = 0.01). However, this association was driven by males (odds ratio 1.62, 95% CI 1.10-2.38, P = 0.01) and CHD5 Ct values ≤ 11 since removing low CHD5 Ct values from this model, converted to insignificance (P = 0.19). A second male subcohort comprising high CHD5 Ct values ≥ 14.4 in both cohorts (n = 5) appeared associated with survival. Removing these high CHD5 Ct values converted the model borderline significant (P = 0.051). Based on the probability function of the receiver operating characteristics (ROC) curves, 8 (12.3%) and 5 (7.7%) from 65 pre-exposure RNA measurements in males, death and survival could be predicted with a negative and positive predictive value ranging between 85-100%. An associated odds ratio reflected a 62% elevated risk for dying or surviving per unit change (Ct-value) in gene expression, considering the before-mentioned CHD5 thresholds in RNA copy numbers. In conclusion, we identified two subsets of male animals characterized by increased (Ct values ≤ 11) and decreased (Ct values ≥ 14.4) CHD5 GE copy numbers before radiation exposure, which independently of the cohort, radiation exposure or treatment appeared to predict the death or survival in males.

100 Deals associated with Gamma-Tocotrienol

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypercholesterolemia	Phase 1	Japan	Davos Life Science Pte Ltd.	-
Solid tumor	Phase 1	Australia	Davos Life Science Pte Ltd.	-
Solid tumor	Phase 1	Hong Kong	Davos Life Science Pte Ltd.	-
Solid tumor	Phase 1	Singapore	Davos Life Science Pte Ltd.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASN2011	Not Applicable	Fanconi Syndrome	-	Gamma-Tocotrienol (Tert-butyl hydroperoxide (TBHP))	txipmwihzi(auxmaaqznc) = vfyxmmraoj tljixavjog (sartaxwvbx ) View more	Positive	08 Nov 2011
				Gamma-tocotrienol (GT3)	ccfbwcakdb(esofcbfoau) = hlpghiecql wirnozdgvv (obamurdqri )
AACR2011	Phase 1	Pancreatic Cancer	12	Δ-tocotrienol	(dvgbwyjatz) = bqrjtdyccy vteqhmhwrc (bgxqfcfjhh ) View more	-	15 Apr 2011
Pubmed	Not Applicable	-	-	gamma-tocotrienol	oiskqirjki(bzqyngchrj) = otryybpiiy urbgkfvfla (aaczobzxrh ) View more	-	01 Sep 2003
				Treatment with 15 mg gamma-tocotrienol/kg diet	oiskqirjki(bzqyngchrj) = wzrwljvkdu urbgkfvfla (aaczobzxrh ) View more