Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells

Lim, Su-Wen; Loh, Hwei‐San; Ting, Kang Nee; Bradshaw, Tracey D.; Allaudin, Zeenathul Nazariah

doi:10.1186/1472-6882-14-469

Cited by 48 publications

(47 citation statements)

References 43 publications

(62 reference statements)

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“…The observation that δ-TT is associated with a significant proapoptotic effect in melanoma cells is in agreement with the reported antitumor activity of TTs (mainly δ-TT and γ-TT) in different types of tumors19333544.…”

Section: Discussionsupporting

confidence: 91%

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Marelli

Marzagalli

Moretti

et al. 2016

Sci Rep

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Malignant melanoma is the leading cause of death from skin cancer. Drug toxicity and resistance represent a serious challange for melanoma treatments. Evidence demonstrates that natural compounds may play a crucial role in cancer prevention, growth and progression. Vitamin E tocotrienols (TT) were shown to possess antitumor activity. Here, we analyzed the effects of δ-TT on melanoma cell growth and the involvement of the endoplasmic reticulum (ER) stress in this activity. The experiments were performed on human melanoma cell lines, BLM and A375. δ-TT exerted a significant proapoptotic effect on both cell lines, involving the intrinsic apoptosis pathway; importantly, this compound did not affect the viability of normal human melanocytes. In melanoma cells, δ-TT exerted its antitumor effect through activation of the PERK/p-eIF2α/ATF4/CHOP, IRE1α and caspase-4 ER stress-related branches. Salubrinal, an inhibitor of the ER stress, counteracted the cytotoxic activity of δ-TT. In vivo experiments performed in nude mice bearing A375 xenografts evidenced that δ-TT reduces tumor volume and tumor mass; importantly, tumor progression was significantly delayed by δ-TT treatment. In conclusion, δ-TT exerts a proapoptotic activity on melanoma cells, through activation of the ER stress-related pathways. δ-TT might represent an effective option for novel chemopreventive/therapeutic strategies for melanoma.

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Section: Discussionsupporting

confidence: 91%

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Marelli

Marzagalli

Moretti

et al. 2016

Sci Rep

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“…Recent studies suggest that T3s, which are the unsaturated forms of Vitamin E, are a promising class of anti-cancer compounds that inhibit the growth and survival of many cancer cells—including breast, ovarian, prostate, pancreas, liver, and different skin cancers—without impacting normal cells [7,8,9]. Vitamin E (VE), including T3 analogues, has been shown to be a highly useful compound to encapsulate and enhance the delivery of poorly water-soluble drugs, such as genistein (Gen), quercetin, and other active polyphenols in green tea [10,11].…”

Section: Introductionmentioning

confidence: 99%

Tocotrienol Nanoemulsion Platform of Curcumin Elicit Elevated Apoptosis and Augmentation of Anticancer Efficacy against Breast and Ovarian Carcinomas

Steuber

Wadhwa

et al. 2016

IJMS

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Vitamin E (VE) tocotrienols (T3), recognized for their cancer-specific anti-proliferative and pro-apoptotic activities, have been previously fabricated into bio-active nanoemulsion (NE) formulations. Here, our viscosity-adapted δ-T3 NE platform was developed to additionally incorporate curcumin (CUR), which is known for its potent suppression of signaling pathways involved in malignant cell growth, survival and metastasis. Thanks to efficient 70:30 wt % surfactant mix of Lutrol F-127:VE-TPGS, in conjunction with optimal CUR loading, a prototype CUR in δ-T3 NE was successfully prepared. Model CUR/δ-T3 NE demonstrated excellent nano-scale aspects (mean particle size = 261 nm, PDI = 0.27, and ζ-potential = −35 mV), pharmaceutical stability, and controlled release properties. Suitability for systemic administration was also verified via standardized in vitro biocompatibility and hemocompatibility assays. In two human cancer cells (MCF-7 and OVCAR-8), our CUR/δ-T3 NE prominently suppressed constitutive NF-κB activation, and significantly induced apoptosis. Finally, the combined CUR/δ-T3 NE produced superior cytotoxicity profiles, in concentration- and time-dependent manners (p ≤ 0.05), at least three to four folds lower IC50 than in closest CUR control. The strong synergism, estimated in both cultured carcinomas, revealed the augmented therapeutic efficacy of our CUR/δ-T3 NE combined platform, supporting its strong potential towards pharmaceutical development for cancer therapy.

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“…49 Numerous results from recent studies on tocotrienols also indicated that γ-and δ-tocotrienols exhibited greater anticancer activity than α-or β-tocotrienols, whereas δ-tocotrienol shows a higher efficacy and effectiveness in the induction of apoptosis in both A549 and U87MG cancer cells compared with α-and γ-tocotrienols. 50 Therefore, induction of apoptosis in A549 and H520 cells with be either the result of individual γ-and δ-tocotrienol isomers or their cumulative effects.…”

mentioning

confidence: 99%

“…In lung cancer, the deregulation of the Notch is primarily associated with activating missense mutations mostly in ligand-binding domain (EGF repeats 11 and 12) or the ankyrin domains that lead to a ligand-independent activation. 50 In addition, as a key component of the Notch-mediated transcription complex, Notch can regulate the expression of a number of microRNAs; at the same time, Notch ligands, Notch receptors, or Notch effectors are also subject to regulation by microRNAs. For instance, miR-34a decreased the expression of Notch-1 and its downstream targets, including Hes-1, cyclin D1, Survivin, and Bcl-2, impairing Notch signaling, cell proliferation, and invasion and inducing apoptosis in NSCLC cells.…”

mentioning

confidence: 99%

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells

Rajasinghe¹,

Gupta²

2017

NDS

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Abstract:Lung cancer is one of the leading causes of cancer deaths. Non-small cell lung cancer (NSCLC), with a 5-year survival rate of 5% at stage IIIB, accounts for 80%-85% of all lung cancers. Aberrant Notch-1 expressions have been reported in lung cancer patients and could potentially be a beneficial molecular/therapeutic target against NSCLC. Tocotrienols, isomers of vitamin E, have been shown to exhibit antitumor activity via inhibition of different signaling pathways in tumor cells. Previously, we reported that delta-tocotrienol downregulates Notch-1 via NF-κB. However, the pure isomers are presently not available in quantities required for animal or clinical studies. Therefore, the objective of this study was to investigate the interactions and effects of commercially available tocotrienols (a mixture of isomers) on the Notch-1 pathway in NSCLC, adenocarcinoma (A549) and squamous cell lung cancer (H520) cell lines. A dose-dependent decrease in all growth, cell migration, and tumor invasiveness was observed in both cancer cell lines with the addition of tocotrienols. A significant induction of apoptosis was also observed using Annexin V stain in flow cytometry analysis. Since tocotrienols significantly affected proliferation, apoptosis, migration, and invasiveness, reverse transcription polymerase chain reaction and Western blot analysis were used to explore the molecular mechanisms responsible for the regulations by testing the expression of Notch-1 and its downstream genes. A dose-dependent decrease in expression of proteins was observed in Notch-1, Hes-1, Survivin, and Bcl-XL. In addition, we found a mechanism linking the NF-κB pathway and Notch-1 down-regulation from NF-κB DNA-binding activities. Thus, our data suggest that commercially available tocotrienols inhibits cell growth, migration, and tumor cell invasiveness via downregulation of Notch 1 and NF-κB while inducing apoptosis. Hence, these commercially available tocotrienol-rich mixture could potentially be an effective supplementation for lung cancer prevention.

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Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells

Cited by 48 publications

References 43 publications

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Tocotrienol Nanoemulsion Platform of Curcumin Elicit Elevated Apoptosis and Augmentation of Anticancer Efficacy against Breast and Ovarian Carcinomas

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells

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Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells

Cited by 48 publications

References 43 publications

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Vitamin E δ-tocotrienol triggers endoplasmic reticulum stress-mediated apoptosis in human melanoma cells

Tocotrienol Nanoemulsion Platform of Curcumin Elicit Elevated Apoptosis and Augmentation of Anticancer Efficacy against Breast and Ovarian Carcinomas

Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-&kappa;B pathways in NSCLC cells

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Tocotrienol-rich mixture inhibits cell proliferation and induces apoptosis via down-regulation of the Notch-1/NF-κB pathways in NSCLC cells