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

Abstract

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.

Beta-Tocotrienol Exhibits More Cytotoxic Effects than Gamma-Tocotrienol on Breast Cancer Cells by Promoting Apoptosis via a P53-Independent PI3-Kinase Dependent Pathway

“…Although many studies in the literature have reported the anti-tumor effect of T3 in vitro and in vivo [29,59], very few studies have focused on the potency of beta-tocotrienol in this respect. Beta-T3 is known for its low abundance in nature, which makes its extraction difficult; however, it is found to be the predominant vitamin E form in all 6 tested varieties of whole wheat with amounts ranging from 0.9 to 1.9 mg /100 mg of wheat [9].…”

“…In the last decades, literature is focusing on the importance of tocotrienols especially with several data showing superiority of tocotrienols as antioxidants compared to tocopherols [19,20], in addition to their role as anti-inflammatory [21,22], hypoglycemic [23], immuno-stimulatory [1], cardio- [24,25], hepato- [26], neuro- [27] and nephro-protective agents [28]. Moreover, many anti-cancer effects of tocotrienols have been documented in vitro and in vivo involving proliferation, metastasis, apoptosis and angiogenesis pathways [29,30].…”

“…Although many studies in the literature have reported the anti-tumor effect of T3 in vitro and 346 in vivo [29,59], very few studies have focused on the potency of beta-tocotrienol in this respect. Beta-347…”

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

“…Some recent studies (published in 2011‐2019) are summarized in Table 4. Earlier work has been covered by some excellent recent reviews 7–9,12 and a book 115 . Some of the proposed molecular targets or pathways are highlighted in Figure 3.…”

“…In 2010, we reviewed the cancer‐preventive activities of tocopherols and tocotrienols 2 . Since then, this topic has been studied by a large number of investigators and reviewed by different authors 7–12 …”