Table 1.
Summary of information and findings of the included studies.
| Authors | Treatment | Models | Major Findings | OHAT Tier |
|---|---|---|---|---|
| Wali et al. [43] | γ-tocotrienol (0–40 μM, 24 h treatment) | Mammary tumor +SA cells | γ-tocotrienol induced concentration- and time-dependent cell death with the upregulation of ERS response signaling proteins (phosphor-PERK, phosphor-eIF2α, ATF4, ATF6α), cleaved caspase-12 and ERS-related cell death proteins (CHOP & TRB3, but not Grp78). Tocotrienol-mediated ERS was independent of Grp78 and the mevalonate pathway. |
1 |
| Park et al. [44] | α-, δ- & γ-tocotrienols (0–40 μM, 24 h treatment) | Murine mammary tumour 66cl-4-GFP cells, human mammary tumour MCF-7, MDA-MB-231 and MDA-MB-468 cells | δ- & γ-tocotrienols exerted potent anti-cancer activities as compared to α-tocotrienol. γ-tocotrienol induced mammary tumor cell apoptosis in JNK- & p38-mediated CHOP and DR5-dependent manner. ERS was involved in the upstream mechanism of tocotrienol-induced apoptosis as evidenced by the upregulation of ATF4, CHOP, and Grp78 levels; and Xbp-1 mRNA splicing. ERS inhibitor (salubrinal) protected the cells from γ-tocotrienol-induced MAPK activation and apoptosis. |
1 |
| Gopalan et al. [45] | γ-tocotrienol (0–10 μM, 24–72 h treatment) | Human mammary tumor MCF-7 and MDA-MB-435 cells | γ-tocotrienol was more potent than γ-tocopherol. γ-tocotrienol induced mammary tumor cell apoptosis with caspases activation, PARP cleavage, JNK activation, and upregulation of DR5 and CHOP levels. γ-tocotrienol increased the intracellular ceramide and dihydroceramide levels. De novo ceramide synthesis inhibitor protected the cells from tocotrienol-mediated apoptosis, JNK activation, DR5 and CHOP upregulation, and caspases activation. |
1 |
| Patacsil et al. [46] | α- & γ-tocotrienols (0–80 μM, 24–72 h treatment) | Human mammary tumor MCF-7 and MDA-MB-231 cells, and non-cancerous human mammary MCF-10A cells | γ-tocotrienol was more potent than α-tocotrienol. γ-tocotrienol induced mammary tumor cell G1 arrest and apoptosis. Transcriptomic analysis revealed the involvement of ERS response and UPR pathways. γ-tocotrienol upregulated the Grp78, ATF3 and CHOP levels with ERS markers (ATF4, phosphor-PERK, phosphor-IRE1α & eIF2α but not ATF6). |
1 |
| Xiong et al. [47] | γ-tocotrienol (0–20 μM, 24 h treatment) | Human mammary tumor MDA-MB-231 and SUM159 cells | γ-tocotrienol induced mammary tumor cell apoptosis with the upregulation of Grp78, CHOP & DR5 levels. | 1 |
| Tuerdi et al. [48] | γ-tocotrienol (20 μM, 24–48 h treatment) | Human malignant mesothelioma H2052, H28, H242 and MSTO-211H cells | γ-tocotrienol induced malignant mesothelioma cell death with the increase in CHOP, Grp78, and caspase-4 mRNA levels. | 1 |
| Tiwari et al. [49] | γ-tocotrienol (40 μM, 6–24 h treatment) | Human mammary tumour MCF-7 and MDA-MB-231 cells, and non-cancerous human mammary MCF-10A cells | γ-tocotrienol induced mammary tumor cell apoptosis and autophagy with JNK & p38 (but not ERK) activation and early upregulation of Grp78, TRB3, CHOP and ERS markers (IRE1α, phosphor-PERK, phosphor-eIF2α ATF4). | 1 |
| Comitato et al. [50] | TRF, α-, δ- & γ-tocotrienols (5–20 μg/mL, 24–48 h treatment) * 12.6–50.4 μM (δ-tocotrienol) and 12.2–48.7 μM (γ-tocotrienol) |
Human cervical tumour HeLa cells and human mammary tumour MCF-7 cells without oestrogen receptor | α-, δ- & γ-tocotrienols (but not TRF) induced the release of endoplasmic reticulum calcium ions into the cytosol. δ- & γ-tocotrienols upregulated the Xbp-1 and CHOP mRNA levels, upregulated Grp78 protein level, and ERβ-independent Xbp-1 alternative splicing and caspase-12 activation. Tocotrienols (especially δ-tocotrienol) induced IRE1α phosphorylation but not ATF6 and PERK phosphorylation. |
1 |
| Marelli et al. [51] | δ-tocotrienol (5–20 μg/mL, 24–48 h treatment) * 12.6–50.4 μM |
Human melanoma BLM and A375 cells, and human primary melanocytes Melanoma-xenograft nude mice model was used but no contribution to the mechanistic findings |
δ-tocotrienol induced cytotoxicity and apoptosis on melanoma cells but not on non-cancerous melanocytes. δ-tocotrienol activated the caspase 4 and upregulated the ERS markers (Grp78, PERK, phosphor- eIF2α & IRE1α) and ERS-related apoptosis markers (ATF4, CHOP & ERO1α). δ-tocotrienol induced nuclear translocation of CHOP and ATF4 and upregulated the CHOP and IRE1α mRNA. Salubrinal protected the melanoma cells from δ-tocotrienol-induced ERS-mediated apoptosis. |
1 |
| Fontana et al. [52] | δ-tocotrienol (0–20 μg/mL, 24–72 h treatment) * 0–50.4 μM |
Human prostate tumour DU145 and PC3 cells, and non-cancerous human prostate epithelial RWPE-1 cells | δ-tocotrienol induced cytotoxicity, apoptosis and autophagy on prostate cancer cells but not on non-cancerous melanocytes. δ-tocotrienol upregulated ERS markers (Grp78, phosphor-eIF2α & IRE1α) and ERS-related apoptosis markers (ATF4 & CHOP). Salubrinal and 4-phenylbutyrate protected the prostate tumour cells from δ-tocotrienol-induced ERS-mediated apoptosis and autophagy. |
1 |
| Ambra et al. [53] | δ- & γ-tocotrienols (5–20 μg/mL, 24 h treatment) * 12.6–50.4 μM (δ-tocotrienol) and 12.2–48.7 μM (γ-tocotrienol) |
Human cervical tumour HeLa cells | γ-tocotrienol significantly upregulated 3 miRNAs including miR-190b, miR-215 and miR-148a. δ- & γ-tocotrienols induced Xbp1 alternative splicing via miR-190b. Anti-miR-190b suppressed while miR-190b overexpression promoted tocotrienol-induced apoptosis. |
1 |
* Tocotrienol concentration was converted based on the molecular weight of 410.6 g/mol (γ-tocotrienol) and 396.6 g/mol (δ-tocotrienol). Abbreviations: ATF3, activating transcription factor 3; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; CHOP, CAAT/enhancer-binding protein homologous protein; eIF2α, eukaryotic initiation factor 2 α subunit; ERK, extracellular signal-regulated kinase; ERO1α, ER oxidoreductin 1α; ERS, endoplasmic reticulum stress; Grp78, 78kDa glucose-regulated kinase; IRE1 α, inositol requiring element 1 α subunit; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; OHAT, Office of Health Assessment and Translation; PERK, protein kinase-like endoplasmic reticulum kinase; TRB3, tribbles 3; TRF, tocotrienol-rich fraction; Xbp1, X-box binding protein 1.