Delta-tocotrienol induces apoptotic cell death via depletion of intracellular squalene in ED40515 cells

Abstract

Here, we examined the effect of tocotrienols (T3) on the growth of adult T-cell leukemia (ATL) cells. All three forms (β-, γ-, and δ-T3) inhibited cell proliferation in a dose-dependent manner; δ-T3 showed the strongest growth-inhibitory effect. δ-T3 increased the G1, G2/M, and subG1 populations and induced internucleosomal DNA fragmentation. δ-T3 treatment also increased the levels of cleaved caspase-3, -6, -7, -9, and poly-ADP ribose polymerase (PARP), and this was accompanied by downregulation of Bcl-2, Bcl-xL, and XIAP. Moreover, δ-T3 decreased nuclear p65 NF-κB levels, indicating downregulation of NF-κB activity. This cytotoxic effect of δ-T3 was abrogated by squalene (SQL) but not mevalonate (MVL), farnesyl diphosphate (FPP), geranylgeranyl diphosphate (GGPP), or cholesterol (CL). δ-T3 decreased intracellular SQL levels, and inhibition of de novo cholesterol synthesis did not affect the action of SQL. Furthermore, δ-T3 significantly decreased farnesyl-diphosphate farnesyltransferase 1 (FDFT1) expression. Taken together, it is evident that δ-T3, due to its ability to potently induce apoptosis via the depletion of intracellular SQL, shows the potential to be considered a therapeutic agent in patients with ATL.

Current Insights into the Biological Action of Squalene

“…In adult T cell leukemia cells, incubation with 6.4 mM squalene suppressed the delta‐tocotrienol‐induced decreases in nuclear p65 NF‐kappa B levels and intracellular squalene levels that result in apoptosis. Inhibition of de novo cholesterol synthesis did not affect the action of squalene . In contrast, squalene did not inhibit statin‐induced apoptosis in C6 glioma cells, thus suggesting that statins induce apoptosis when geranylgeranyl pyrophosphate biosynthesis is inhibited .…”

Roles of Farnesyl-Diphosphate Farnesyltransferase 1 in Tumour and Tumour Microenvironments

“…FDFT1 regulates cell cycle progression. For example, inhibition of FDFT1 expression significantly attenuated cell proliferation, remarkably increased the sub G1, G1, and G2/M-phase populations, and decreased the S-phase population [14,117,125]. Conversely, supplementation with exogenous cholesterol, increased raft-associated cholesterol and abrogated the suppressive effects on proliferation [124].…”

The Role of Tocotrienol in Preventing Male Osteoporosis—A Review of Current Evidence

“…This was echoed by studies using cancer cells, demonstrating down-regulation of HMGR expression by T3, which partially explains its anticancer activities [144,145,146]. As a result, of HMGR suppression, metabolites along the mevalonate pathway, such as farnesyl-diphosphate, squalene and cholesterol were reduced [147].…”