BackgroundTocotrienols, especially the gamma isomer was discovered to possess cytotoxic effects associated with the induction of apoptosis in numerous cancers. Individual tocotrienol isomers are believed to induce dissimilar apoptotic mechanisms in different cancer types. This study was aimed to compare the cytotoxic potency of alpha-, gamma- and delta-tocotrienols, and to explore their resultant apoptotic mechanisms in human lung adenocarcinoma A549 and glioblastoma U87MG cells which are scarcely researched.MethodsThe cytotoxic effects of alpha-, gamma- and delta-tocotrienols in both A549 and U87MG cancer cells were first determined at the cell viability and morphological aspects. DNA damage types were then identified by comet assay and flow cytometric study was carried out to support the incidence of apoptosis. The involvements of caspase-8, Bid, Bax and mitochondrial membrane permeability (MMP) in the execution of apoptosis were further expounded.ResultsAll tocotrienols inhibited the growth of A549 and U87MG cancer cells in a concentration- and time-dependent manner. These treated cancer cells demonstrated some hallmarks of apoptotic morphologies, apoptosis was further confirmed by cell accumulation at the pre-G1 stage. All tocotrienols induced only double strand DNA breaks (DSBs) and no single strand DNA breaks (SSBs) in both treated cancer cells. Activation of caspase-8 leading to increased levels of Bid and Bax as well as cytochrome c release attributed by the disruption of mitochondrial membrane permeability in both A549 and U87MG cells were evident.ConclusionsThis study has shown that delta-tocotrienol, in all experimental approaches, possessed a higher efficacy (shorter induction period) and effectiveness (higher induction rate) in the execution of apoptosis in both A549 and U87MG cancer cells as compared to alpha- and gamma-tocotrienols. Tocotrienols in particular the delta isomer can be an alternative chemotherapeutic agent for treating lung and brain cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/1472-6882-14-469) contains supplementary material, which is available to authorized users.

The pure vitamin isomer, β-tocotrienol has the least abundance among the other vitamin E isomers that are present in numerous plants. Hence, it is very scarcely studied for its bioactivity. In this study, the antiproliferative effects and primary apoptotic mechanisms of β-tocotrienol on human lung adenocarcinoma A549 and glioblastoma U87MG cells were investigated. It was evidenced that β-tocotrienol had inhibited the growth of both A549 (GI50=1.38±0.334μM) and U87MG (GI50=2.53±0.604μM) cells at rather low concentrations. Cancer cells incubated with β-tocotrienol were also found to exhibit hallmarks of apoptotic morphologies including membrane blebbing, chromatin condensation and formation of apoptotic bodies. The apoptotic properties of β-tocotrienol in both A549 and U87MG cells were the results of its capability to induce significant (P<0.05) double-strand DNA breaks (DSBs) without involving single-strand DNA breaks (SSBs). β-Tocotrienol is said to induce activation of caspase-8 in both A549 and U87MG cells guided by no activation when caspase-8 inhibitor, z-IETD-fmk was added. Besides, disruption on the mitochondrial membrane permeability of the cells in a concentration- and time-dependent manner had occurred. The induction of apoptosis by β-tocotrienol in A549 and U87MG cells was confirmed to involve both the death-receptor mediated and mitochondria-dependent apoptotic pathways. These findings could potentiate the palm oil derived β-tocotrienol to serve as a new anticancer agent for treating human lung and brain cancers.

The extracts (especially ethyl acetate and hexane) of Acalypha wilkesiana possess valuable cytotoxic effects that trigger apoptosis in U87MG and A549 cancer cells through induction of DNA SSBs and DSBs.

Recent studies suggested that combined treatment approaches can be used to improve anticancer potency and circumvent the limitations of high-dose tocotrienols administration. Acalypha wilkesiana is a medicinal plant that has been used as an adjunct treatment for cancers in traditional medicine. Herein, the effects of single and combined treatments of β-, γ- and δ-tocotrienols and ethyl acetate extract (9EA) of Acalypha wilkesiana on lung (A549) and brain (U87MG) cancer cells were investigated. γ- and δ-tocotrienols exhibited higher potent antiproliferative effects against A549 (12.1 μg/ml and 13.6 μg/ml) and U87MG cells (3.3 μg/ml and 5.2 μg/ml) compared to β-tocotrienols (9.4 μg/ml and 92.4 μg/ml), respectively. Whereas, 9EA induced potent antiproliferative effects against U87MG cells only (2.0 μg/ml). Combined treatments of tocotrienols and 9EA induced a synergistic growth inhibition with up to 8.4-fold reduction in potent doses of β-, γ- and δ-tocotrienols on A549 cells. Apoptotic features were also evidenced on A549 cells receiving single and combined treatments. The synergism may greatly improve the therapeutic outcome for lung cancer.