Targeting melanoma stem cells with the Vitamin E derivative δ-tocotrienol

Marzagalli, Monica; Moretti, Roberta M.; Messi, Elio; Marelli, Marina Montagnani; Fontana, Fabrizio; Anastasia, Alessia; Bani, Maria Rosa; Beretta, Giangiacomo; Limonta, Patrizia

doi:10.1038/s41598-017-19057-4

Cited by 46 publications

(38 citation statements)

References 69 publications

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“…The stemness of cancer cells has also been reported to be inhibited by tocotrienols. δ‐T3 was shown to inhibit the formation of tumorspheres of human melanoma cells 147 . δ‐T3 was also reported to inhibit the expression of stem cell transcription factors, including NANOG, OCT4, and SOX2, in pancreatic cancer cells and surface stemness marker CD44 in xenograft tumors of pancreatic cancer cells 148 .…”

Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 98%

“…δ-T3 was shown to inhibit the formation of tumorspheres of human melanoma cells. 147 Other properties of cancer cells such as cell migration, cell invasion, and epithelial-mesenchymal transition have also been reported to be inhibited by tocotrienols in lung cancer cells, gastric cancer cells, and breast cancer cells in vitro, in cell migration assay, wound healing assay, and cell invasive assay. 119,123,153 In γ-T3-treated breast cancer MDA-MB-231 cells, cell migration machinery regulators such as RAC1 and WAVE2 signaling were reduced.…”

Section: Suppression Of Stemness and Inhibition Of Cell Migration/imentioning

confidence: 99%

“…δ‐T3 and γ‐T3 have been demonstrated to inhibit tumor growth in xenograft models of pancreatic cancer cells, 136,148 gastric cancer cells, 150 mouse mammary cancer cells, 151 liver cancer cells, 128 and melanoma cells, 147 as well as the transgenic pancreatic cancer mouse models (LSL‐KrasG12D; LSL‐Trp53R127H; and Pdx‐1‐Cre [KPC mice]) 152 …”

Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 99%

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Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Yang

Luo

Zeng

et al. 2020

Molecular Carcinogenesis

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α‐Tocopherol (α‐T) is the major form of vitamin E (VE) in animals and has the highest activity in carrying out the essential antioxidant functions of VE. Because of the involvement of oxidative stress in carcinogenesis, the cancer prevention activity of α‐T has been studied extensively. Lower VE intake or nutritional status has been shown to be associated with increased cancer risk, and supplementation of α‐T to populations with VE insufficiency has shown beneficial effects in lowering the cancer risk in some intervention studies. However, several large intervention studies with α‐T conducted in North America have not demonstrated a cancer prevention effect. More recent studies have centered on the γ‐ and δ‐forms of tocopherols and tocotrienols (T3). In comparison with α‐T, these forms have much lower systemic bioavailability but have shown stronger cancer‐preventive activities in many studies in animal models and cell lines. γ‐T3 and δ‐T3 generally have even higher activities than γ‐T and δ‐T. In this article, we review recent results from human and laboratory studies on the cancer‐preventive activities of different forms of tocopherols and tocotrienols, at nutritional and pharmacological levels. We aim to elucidate the possible mechanisms of the preventive actions and discuss the possible application of the available information for human cancer prevention by different VE forms.

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Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 98%

Section: Suppression Of Stemness and Inhibition Of Cell Migration/imentioning

confidence: 99%

Section: Laboratory Studies On Ve and Cancer Preventionmentioning

confidence: 99%

See 1 more Smart Citation

Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Yang

Luo

Zeng

et al. 2020

Molecular Carcinogenesis

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“…The anti-neoplastic effects of T3 have been extensively studied using tumor cells of mammary gland [351][352][353][354][355][356], lung [357][358][359][360][361][362], liver [363][364][365][366][367] pancreas [368], prostate [362,[369][370][371][372], cervix [373,374], skin [362,[375][376][377], brain [357][358][359]378], stomach [379], and colon [378,380]. Besides that, T3 tends to accumulate in the liver and pancreatic tissues as well as tumor tissues with an unknown mechanism [367,381].…”

Section: Effects Of Tocotrienol On Cancersmentioning

confidence: 99%

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence

et al. 2020

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Tocotrienol (T3) is a subfamily of vitamin E known for its wide array of medicinal properties. This review aimed to summarize the health benefits of T3, particularly in prevention or treatment of non-communicable diseases (NCDs), including cardiovascular, musculoskeletal, metabolic, gastric, and skin disorders, as well as cancers. Studies showed that T3 could prevent various NCDs, by suppressing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the mevalonate pathway, inflammatory response, oxidative stress, and alternating hormones. The efficacy of T3 in preventing/treating these NCDs is similar or greater compared to tocopherol (TF). TF may lower the efficacy of T3 because the efficacy of the combination of TF and T3 was lower than T3 alone in some studies. Data investigating the effects of T3 on osteoporosis, arthritis, and peptic ulcers in human are limited. The positive outcomes of T3 treatment obtained from the preclinical studies warrant further validation from clinical trials.Nutrients 2020, 12, 259 2 of 84 Nutrients 2020, 12, 259 4 of 84 the order δ > γ > β > α [45]. Using HepG2 cells, γT3 was shown to stimulate apolipoprotein B (Apo-B) degradation by decreasing its translocation into the endoplasmic reticulum (ER) lumen. This action eventually caused a reduction in the number of Apo-B in lipoprotein particles [46]. Other reports showed that γT3 and δT3 had the potential to reduce the hepatic TG synthesis and very-low-density lipoprotein (VLDL) secretion by suppressing expression of genes involved in lipid homeostasis, particularly the TG, cholesterol, and VLDL biosynthesis. Moreover, δT3 also promoted the efflux of LDL through LDL receptor expression [47]. A summary of the literature on effect of T3 supplementation on lipid profile of hypercholesterolemic model in vitro is shown in Table 1.Animal models of dyslipidemia have been used to investigate the effects of T3 on lipid profile. Several animals have been tested, including chicken, swine and rodents (rats, hamsters, guinea pigs). In chickens fed with a varying level of αTF and γT3, Qureshi et al. (1996) showed that αTF enhanced the inhibition of HMGCR by γT3. They further stipulated that the vitamin E mixture should contain 15-20% of αTF and approximately 60% of γT3 or δT3 for optimal anti-cholesterol effects [48]. In the subsequent study, demonstrated that combination of 50 ppm T3-rich fraction (TRF) and 50 ppm lovastatin was more effective in suppressing HMGCR activity compared to lovastatin alone in chickens. The combination also reduced serum TC and LDL-C, TG, Apo-B, thromboxane B 2 , and platelet factor 4 in contrast to individual treatment [49]. Using chicken supplemented with 50 ppm of δT3, Qureshi et al. (2011) further revealed that δT3 reduced TC and LDL-C besides suppressing the lipid elevating effects of dexamethasone and potentiated the TG-lowering effect of riboflavin [50]. Using genetically hypercholesterolemic swine, Qureshi et al. (1991) demonstrated the significant effect of TRF in lowering serum TC, LDL-C, Apo-B, thrombo...

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“…More recently, we reported that a subpopulation of autofluorescent cells expressing the ABCG2 stem cell marker is present in human melanospheres; δ‐TT specifically target this CSCs subpopulation (Marzagalli et al, ).…”

Section: Anticancer Properties Of Tts: In Vitro and In Vivo Studiesmentioning

confidence: 99%

Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets

Marelli

Marzagalli

Fontana

et al. 2018

Journal Cellular Physiology

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Vitamin E is composed of two groups of compounds: α-, β-, γ-, and δ-tocopherols (TPs), and the corresponding unsaturated tocotrienols (TTs). TTs are found in natural sources such as red palm oil, annatto seeds, and rice bran. In the last decades, TTs (specifically, γ-TT and δ-TT) have gained interest due to their health benefits in chronic diseases, based on their antioxidant, neuroprotective, cholesterol-lowering, anti-inflammatory activities. Several in vitro and in vivo studies pointed out that TTs also exert a significant antitumor activity in a wide range of cancer cells. Specifically, TTs were shown to exert antiproliferative/proapoptotic effects and to reduce the metastatic or angiogenic properties of different cancer cells; moreover, these compounds were reported to specifically target the subpopulation of cancer stem cells, known to be deeply involved in the development of resistance to standard therapies. Interestingly, recent studies pointed out that TTs exert a synergistic antitumor effect on cancer cells when given in combination with either standard antitumor agents (i.e., chemotherapeutics, statins, "targeted" therapies) or natural compounds with anticancer activity (i.e., sesamin, epigallocatechin gallate (EGCG), resveratrol, ferulic acid). Based on these observations, different TT synthetic derivatives and formulations were recently developed and demonstrated to improve TT water solubility and to reduce TT metabolism in cancer cells, thus increasing their biological activity. These promising results, together with the safety of TT administration in healthy subjects, suggest that these compounds might represent a new chemopreventive or anticancer treatment (i.e., in combination with standard therapies) strategy. Clinical trials aimed at confirming this antitumor activity of TTs are needed.

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Targeting melanoma stem cells with the Vitamin E derivative δ-tocotrienol

Cited by 46 publications

References 69 publications

Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Vitamin E and cancer prevention: Studies with different forms of tocopherols and tocotrienols

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence

Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets

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