Improved antitumor activity and reduced cardiotoxicity of epirubicin using hepatocyte-targeted nanoparticles combined with tocotrienols against hepatocellular carcinoma in mice.

Nasr M, Nafee N, Saad H, Kazem A.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Epirubicin (EPI), an anthracycline derivative, is one of the main line treatments for HCC. However, serious side effects including cardiomyopathy and congestive heart failure limit its long term administration. Our main goal is to develop a delivery strategy that ensures improved efficacy of the chemotherapeutic agent together with reduced cardiotoxicity. In this context, EPI was loaded in chitosan-PLGA nanoparticles linked with asialofetuin (EPI-NPs) selectively targeting hepatocytes. In an attempt to reduce cardiotoxicity, targeted EPI-NPs were coadministered with tocotrienols. EPI-NPs significantly enhanced the antiproliferative effect compared to free EPI as studied on Hep G2 cell line. Nanoencapsulated EPI injected in HCC mouse model revealed higher p53-mediated apoptosis and reduced angiogenesis in the tumor. Combined therapy of EPI-NPs with tocotrienols further enhanced apoptosis and reduced VEGF level in a dose dependent manner. Assessment of cardiotoxicity indicated that EPI-NPs diminished the high level of proinflammatory cytokine tumor necrosis factor-α (TNF-α) as well as oxidative stress-induced cardiotoxicity as manifested by reduced level of lipid peroxidation products (TBARS) and nitric oxide (NO). EPI-NPs additionally restored the diminished level of superoxide dismutase (SOD) and reduced glutathione (GSH) in the heart. Interestingly, tocotrienols provided both antitumor activity and higher protection against oxidative stress and inflammation induced by EPI in the heart. This hepatocyte-targeted biodegradable nanoparticle/tocotrienol combined therapy represents intriguing therapeutic strategy for EPI providing not only superior efficacy but also higher safety levels.

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Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells

Tran AT, Ramalinga M, Kedir H, Clarke R, Kumar D.

Tocomin® represents commercially available mixture of naturally occurring tocotrienols (T3s) and tocopherols extracted from palm oil/palm fruits that possess powerful antioxidant, anticancer, neuro/cardioprotective and cholesterol-lowering properties. Cellular autophagy represents a defense mechanism against oxidative stress and several anticancer compounds. Recently, we reported that T3s induce apoptosis and endoplasmic reticulum stress in breast cancer cells.


We studied the effects of Tocomin® on MCF-7 and MDA-MB 231 breast cancer cells and non-tumor MCF-10A cells.


Tocomin® inhibited cell proliferation and induced apoptosis in both MCF-7 and MDA-MB 231 breast cancer cell lines without affecting the viability of MCF-10A cells. We also showed that Tocomin® negatively modulates phosphoinositide 3-kinase and mTOR pathways and induces cytoprotective autophagic response in triple negative MDA-MB 231 cells. Lastly, we demonstrate that autophagy inhibitor 3-methyladenine (3-MA) potentiated the apoptosis induced by Tocomin® in MDA-MB 231 cells.


Together, our data indicate anticancer effects of Tocomin® in breast cancer cells, which is potentiated by the autophagy inhibitor 3-MA.

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The estrogen receptor β-PI3K/Akt pathway mediates the cytoprotective effects of tocotrienol in a cellular Parkinson’s disease model.

Nakaso K, Tajima N, Horikoshi Y, Nakasone M, Hanaki T, Kamizaki K, Matsura T.

Tocotrienols (T3s) are members of the vitamin E family, have antioxidant properties, and are promising candidates for neuroprotection in the pathogenesis of neurodegenerative disorders such as Parkinson’s disease (PD). However, whether their antioxidant capacities are required for their cytoprotective activity remains unclear. In this regard, the antioxidant-independent cytoprotective activity of T3s has received considerable attention. Here, we investigated the signaling pathways that are induced during T3-dependent cytoprotection of human neuroblastoma SH-SY5Y cells, as these cells are used to model certain elements of PD. T3s were cytoprotective against 1-methyl-4-phenylpyridinium ion (MPP+) and other PD-related toxicities. γT3 and δT3 treatments led to marked activation of the PI3K/Akt signaling pathway. Furthermore, we identified estrogen receptor (ER) β as an upstream mediator of PI3K/Akt signaling following γT3/δT3 stimulation. Highly purified γT3/δT3 bound to ERβ directly in vitro, and knockdown of ERβ in SH-SY5Y cells abrogated both γT3/δT3-dependent cytoprotection and Akt phosphorylation. Since membrane-bound ERβ was important for the signal-related cytoprotective effects of γT3/δT3, we investigated receptor-mediated caveola formation as a candidate for the early events of signal transduction. Knockdown of caveolin-1 and/or caveolin-2 prevented the cytoprotective effects of γT3/δT3, but did not affect Akt phosphorylation. This finding suggests that T3s and, in particular, γT3/δT3, exhibit not only antioxidant effects but also a receptor signal-mediated protective action following ERβ/PI3K/Akt signaling. Furthermore, receptor-mediated caveola formation is an important event during the early steps following T3 treatment.

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A Redox-Silent Analogue of Tocotrienol Inhibits Cobalt(II) Chloride-Induced VEGF Expression via Yes Signaling in Mesothelioma Cells.

Sato A, Virgona N, Ando A, Ota M, Yano T.

Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis and represents an attractive anticancer target. We have previously demonstrated that a redox-silent analogue of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) exhibits potent anti-carcinogenic property in human malignant mesothelioma (MM) cells. However, inhibition of tumor growth by targeting VEGF pathway remains undetermined. In this study, we explored the inhibitory effect of T3E on the paracrine secretion of VEGF in MM cells under mimicked hypoxia by cobalt chloride (CoCl2). In this study we examine whether T3E can suppress the secretion of VEGF in MM cells exposed to mimic hypoxia by cobalt chloride (CoCl2). We found that CoCl2-induced hypoxia treatment leads to increased up-regulated hypoxia-inducible factor-2α (HIF-2α) and subsequently induced the secretion of VEGF in MM cells. This up-regulation activation mainly depended on the activation of Yes, a member of the Src family of kinases. Treatment of hypoxic MM cells with T3E effectively inhibited the secretion of VEGF, On the other hand, T3E inhibited CoCl2-induced gene expression of VEGF due to the inactivation of Yes/HIF-2α signaling. These data suggest that Yes/HIF2-α/VEGF could be a promising therapeutic target of T3E in MM cells.

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