Synergistic Anticancer Effect of Tocotrienol Combined with Chemotherapeutic Agents or Dietary Components: A Review

Abstract

Tocotrienol (T3), unsaturated vitamin E, is gaining a lot of attention owing to its potent anticancer effect, since its efficacy is much greater than that of tocopherol (Toc). Various factors are known to be involved in such antitumor action, including cell cycle arrest, apoptosis induction, antiangiogenesis, anti-metastasis, nuclear factor-κB suppression, and telomerase inhibition. Owing to a difference in the affinity of T3 and Toc for the α-tocopherol transfer protein, the bioavailability of orally ingested T3 is lower than that of Toc. Furthermore, cellular uptake of T3 is interrupted by coadministration of α-Toc in vitro and in vivo. Based on this, several studies are in progress to screen for molecules that can synergize with T3 in order to augment its potency. Combinations of T3 with chemotherapeutic drugs (e.g., statins, celecoxib, and gefitinib) or dietary components (e.g., polyphenols, sesamin, and ferulic acid) exhibit synergistic actions on cancer cell growth and signaling pathways. In this review, we summarize the current status of synergistic effects of T3 and an array of agents on cancer cells, and discuss their molecular mechanisms of action. These combination strategies would encourage further investigation and application in cancer prevention and therapy.

Keywords: cancer; synergy; tocotrienol; vitamin E.

Figure 1

Chemical structure of vitamin E.

Figure 2

Mevalonate pathway and intermediates necessary for the posttranslational modification of Ras, Rho, and insulin-like growth factor I (IGF-I) receptor. T3, tocotrienol; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A. Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.

Figure 3

Epidermal growth factor receptor (EGFR) and its downstream signaling proteins. EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; JAK, Janus kinase; STAT, signal transducer and activator of transcription; PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinase; Akt, protein kinase B; P, phosphorylation. Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.

Figure 4

Crosstalk between EGFR and nuclear factor-κB (NF-κB) signaling pathway. PGE₂, prostaglandin E₂; IκB, inhibitors of κB; IKK, IκB kinase; COX-2, cyclooxygenase-2; mTOR, mammalian target of rapamycin; Ub, ubiquitylation; PLA₂, phosphorlipase A₂; P, phosphorylation. Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.

Figure 5

Metabolic pathway of γ-T3. The second and fourth cycles of β-oxidation are needed for 2,4-dienoyl-CoA reductase (A) and 3,2-enoyl-CoA isomerase (B). Arrows and perpendicular lines indicate activation/induction and inhibition/suppression, respectively.