Synergistic Antiproliferative Effects of γ‐Tocotrienol and Statin Treatment on Mammary Tumor Cells

Wali, Vikram B.; Sylvester, Paul W.

doi:10.1007/s11745-007-3102-0

Cited by 91 publications

(97 citation statements)

References 41 publications

(53 reference statements)

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“…Therefore, c-tocotrienol in combination with lower dose of statins potentiates the inhibitory activity of statins. This had a positive outcome whereby a 2-to 11-fold of marked reduction was observed compared with individual treatment with statin in ?SA cells (highly malignant mammary tumor cells) (Wali and Sylvester 2007). In a study by Wali et al, suppression of mevalonate caused statins to display a compensatory upregulation in HMGCoA reductase levels.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Tocotrienols and breast cancer: the evidence to date

et al. 2011

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Breast cancer is the second most frequent cancer affecting women worldwide after lung cancer. The toxicity factor associated with synthetic drugs has turned the attention toward natural compounds as the primary focus of interest as anticancer agents. Vitamin E derivatives consisting of the well-established tocopherols and their analogs namely tocotrienols have been extensively studied due to their remarkable biological properties. While tocopherols have failed to offer protection, tocotrienols, in particular, a-, d-, and c-tocotrienols alone and in combination have demonstrated anticancer properties. The discovery of the antiangiogenic, antiproliferative, and apoptotic effects of tocotrienols, as well as their role as an inducer of immunological functions, not only reveals a new horizon as a potent antitumor agent but also reinforces the notion that tocotrienols are indeed more than antioxidants. On the basis of a transcriptomic platform, we have recently demonstrated a novel mechanism for tocotrienol activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate a high affinity of specific forms of tocotrienols for ERb, but not for ERa. Moreover, we have demonstrated that specific tocotrienols increase ERb translocation into the nucleus which, in turn, activates the expression of estrogenresponsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERb cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERb is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. Furthermore, a recently concluded clinical trial seems to suggest that tocotrienols in combination with tamoxifen may have the potential to extend breast cancer-specific survival.

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Section: In Vitro Studiesmentioning

confidence: 99%

Tocotrienols and breast cancer: the evidence to date

et al. 2011

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“…Statins and γ-tocotrienol both act on HMGCoA pathway. Statins are the inhibitors of HMG-CoA reductase enzyme and γ-tocotrienol causes down regulation of HMG-CoA by affecting post transcriptional modifications of enzyme [43]. Here, γ-tocotrienol showed its combination synergistic activity with simvastatin, lovastatin and mevastatin at low doses.…”

Section: Statins With γ-Tocotrienolmentioning

confidence: 90%

“…Here, γ-tocotrienol showed its combination synergistic activity with simvastatin, lovastatin and mevastatin at low doses. Combination of tocotrienol with statins induced cell cycle is arrested at G1 phase, and decreased levels of cyclins and cyclin dependent kinases [43,44]. Combination of γ-tocotrienol with statins inhibited the cyclin D1, CDK2 and further hyperphosphorylated Rb protein.…”

Section: Statins With γ-Tocotrienolmentioning

confidence: 96%

Anticancer Agents in Combination with Statins

Adnan¹,

Mohammad²,

Manik³

2017

J Bioequiv Availab

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“…Since statins and c-tocotrienol suppress HMGCoA reductase activity through independent mechanisms, it was logical to conclude that combined low-dose treatment with these agents may produce an additive or even synergistic anticancer effects, while at the same time avoiding high-dose side effects. Initial studies were conducted to examine the growth inhibitory effects of low-dose treatment with various statins alone and in combination with c-tocotrienol against the highly malignant mouse ?SA mammary tumor cells in culture maintained in serum-free defined media using EGF as a mitogen (Wali and Sylvester 2007). Studies were also conducted to determine the intracellular signaling mechanisms that were involved in mediating the inhibitory effects of combined low-dose statin and c-tocotrienol treatment on EGF-dependent proliferation and survival (Wali and Sylvester 2007).…”

Section: Combined Treatment Of Statins With C-tocotrienol Against Mammentioning

confidence: 99%

“…Combination chemotherapy optimizes the effectiveness of each drug to bring about a complimentary and synergistic therapeutic response, while at the same time, reducing toxic adverse side effects associated with high-dose monotherapy. Various investigations have shown that combined low-dose tocotrienol treatment with specific chemotherapeutic agents displays significantly enhanced anticancer effects, as compared to that observed from individual treatments alone (Bachawal et al 2010a, b;Shirode AB and Sylvester 2010;Wali and Sylvester 2007;Wali et al 2009a, b).…”

Section: Introductionmentioning

confidence: 99%

Synergistic anticancer effects of combined γ-tocotrienol with statin or receptor tyrosine kinase inhibitor treatment

Sylvester

2011

Genes Nutr

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Systemic chemotherapy is the only current method of treatment that provides some chance for longterm survival in patients with advanced or metastatic cancer. c-Tocotrienol is a natural form of vitamin E found in high concentrations in palm oil and displays potent anticancer effects, but limited absorption and transport of by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and are an example of a promising cancer chemotherapeutic agent whose clinical usefulness has been limited due to high-dose toxicity. Similarly, erlotinib and gefitinib are anticancer agents that inhibit the activation of individual HER/ErbB receptor subtypes, but have shown limited clinical success because of heterodimerization between different EGF receptor family members that can rescue cancer cells from agents directed against a single receptor subtype. Recent studies have investigated the anticancer effectiveness of low-dose treatment of various statins or EGF receptor inhibitors alone and in combination with c-tocotrienol on highly malignant ?SA mouse mammary epithelial cells in vitro. Combined treatment with subeffective doses of c-tocotrienol with these other chemotherapeutic agents resulted in a synergistic inhibition of ?SA cell growth and viability. These findings strongly suggest that combined treatment of c-tocotrienol with other anticancer agents may not only provide an enhanced therapeutic response but also provide a means to avoid the toxicity, low bioavailability, or limited therapeutic action associated with high-dose monotherapy.

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Synergistic Antiproliferative Effects of γ‐Tocotrienol and Statin Treatment on Mammary Tumor Cells

Cited by 91 publications

References 41 publications

Tocotrienols and breast cancer: the evidence to date

Tocotrienols and breast cancer: the evidence to date

Anticancer Agents in Combination with Statins

Synergistic anticancer effects of combined γ-tocotrienol with statin or receptor tyrosine kinase inhibitor treatment

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