Vitamin E amides, a new class of vitamin E analogues with enhanced proapoptotic activity

Tomic-Vatic, Adisa; Eytina, John; Chapman, James; Mahdavian, Elahe; Neužil, Jiřı́; Salvatore, Brian A.

doi:10.1002/ijc.21171

Cited by 45 publications

(45 citation statements)

References 36 publications

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“…This follows from our previous work, in which we showed that masking the free carboxylate of vitamin E analogues by methylation negated their ability to kill cancer cells (36,37). We tested whether lysosomal function was important for apoptosis induction by a-TOS-LTVSPWY due to presence of peptidases in the organelles.…”

Section: Resultsmentioning

confidence: 94%

A Peptide Conjugate of Vitamin E Succinate Targets Breast Cancer Cells with High ErbB2 Expression

Wang¹,

Birringer

Dong³

et al. 2007

Cancer Research

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Overexpression of erbB2 is associated with resistance to apoptosis. We explored whether high level of erbB2 expression by cancer cells allows their targeting using an erbB2-binding peptide (LTVSPWY) attached to the proapoptotic A-tocopheryl succinate (A-TOS). Treating erbB2-low or erbB2-high cells with A-TOS induced similar levels of apoptosis, whereas A-TOS-LTVSPWY induced greater levels of apoptosis in erbB2-high cells. A-TOS rapidly accumulated in erbB2-high cells exposed to A-TOS-LTVSPWY. The extent of apoptosis induced in erbB2-high cells by A-TOS-LTVSPWY was suppressed by erbB2 RNA interference as well as by inhibition of either endocytotic or lysosomal function. A-TOS-LTVSPWY reduced erbB2-high breast carcinomas in FVB/N c-neu transgenic mice. We conclude that a conjugate of a peptide targeting A-TOS to erbB2-overexpressing cancer cells induces rapid apoptosis and efficiently suppresses erbB2-positive breast tumors.

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Section: Resultsmentioning

confidence: 94%

A Peptide Conjugate of Vitamin E Succinate Targets Breast Cancer Cells with High ErbB2 Expression

Wang¹,

Birringer

Dong³

et al. 2007

Cancer Research

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“…When the ester bond is replaced by an amide bond, further enhancement of proapoptotic activity was observed (12, 13, 37, and 38) (Tomic-Vatic et al, 2005). Again, the unsaturated amides (13 and 38) were superior to their saturated counterparts.…”

Section: Redox-silent Tocopherol Derivatives: Modifications Of the Fumentioning

confidence: 96%

Vitamin E Analogs, a Novel Group of “Mitocans,” as Anticancer Agents: The Importance of Being Redox-Silent

Neužil¹,

Tomasetti²,

Zhao³

et al. 2007

Mol Pharmacol

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126

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The search for a selective and efficient anticancer agent for treating all neoplastic disease has yet to deliver a universally suitable compound(s). The majority of established anticancer drugs either are nonselective or lose their efficacy because of the constant mutational changes of malignant cells. Until recently, a largely neglected target for potential anticancer agents was the mitochondrion, showing a considerable promise for future clinical applications. Vitamin E (VE) analogs, epitomized by ␣-tocopheryl succinate, belong to the group of "mitocans" (mitochondrially targeted anticancer drugs). They are selective for malignant cells, cause destabilization of their mitochondria, and suppress cancer in preclinical models. This review focuses on our current understanding of VE analogs in the context of their proapoptotic/anticancer efficacy and suggests that their effect on mitochondria may be amplified by modulation of alternative pathways operating in parallel. We show here that the analogs of VE that cause apoptosis (which translates into their anticancer efficacy) generally do not possess antioxidant (redox) activity and are prototypical of the mitocan group of anticancer compounds. Therefore, by analogy to Oscar Wilde's play The Importance of Being Earnest, we use the motto in the title "the importance of being redox-silent" to emphasize an essentially novel paradigm for cancer therapy, in which redoxsilence is a prerequisite property for most of the anticancer activities described in this communication.Despite advances in molecular medicine, the third millennium has borne witness to neoplastic disease becoming a major cause for mortality in developed countries. Moreover, fast-growing economies in countries like India and China are likely to be severely affected by cancer in a decade or so as a result of heavy industrialization. Certain types of cancer, such as malignant mesothelioma (MM), seem to remain beyond the realms of treatment. In many other cases, mutations arise in the tumors, seriously compromising the outcome of the therapy. For example, in breast cancer, in which a high frequency of overexpression of the tyrosine receptor kinase erbB2 occurs, this is often associated with resistance to chemotherapy (Xia et al., 2006). We are therefore in need of treatment modalities that would overcome these problems and that are efficient, selective, and readily available to all Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.106.030122.ABBREVIATIONS: MM, malignant mesothelioma; BH, Bcl-2 homology; DHFR, dihydrofolate reductase; DR, death receptor; ERK, extracellular signal-regulated protein kinase; FLIP, Fas-associated death domain-like interleukin-1␤-converting enzyme-inhibitory protein; IAP, inhibitor of apoptosis protein; IB, inhibitory subunit of nuclear factor B; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MPTP, mitochondrial permeability transition pore; MTX, methotrexate; NFB, nuclear factor-B; O...

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“…Although experience with mitomycin C revealed an acceptable safety profile [25,26], alternative antiproliferative agents with less cytotoxic and cell degenerative effects compared to mitomycin C would still be needed. In prior studies, vitamin E isoforms have revealed an antifibrotic potential [17][18][19]21]. Based on these findings, we evaluated the effects of different tocotrienol isoforms and concentrations on human Tenon's fibroblasts regarding inhibition of proliferation, migration, and collagen synthesis, revealing a significant antifibrotic effect for all tested isoforms.…”

Section: Discussionmentioning

confidence: 93%

“…Higher (and therefore eventually more effective) concentrations have not been tested. Based on prior studies [19][20][21] γ-und δ-isoforms of tocotrienol may even have a better antiproliferative effect than α-tocotrienol. Therefore, the aim of this study was to evaluate the tocotrienol isoform with the highest antifibrotic effect compared to mitomycin C in vitro.…”

Section: Introductionmentioning

confidence: 99%

Antifibrotic effects of tocotrienols on human Tenon’s fibroblasts

Tappeiner

Meyenberg

Goldblum

et al. 2009

Graefes Arch Clin Exp Ophthalmol

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Purpose To compare the antifibrotic effect of vitamin E isoforms α-, γ-, and δ-tocotrienol on human Tenon's fibroblasts (hTf) to the antimetabolite mitomycin C. Methods Antifibrotic effects of α-(40, 60, 80, 100, and 120 μM), γ-(10, 20, 30, and 40 μM) and δ-tocotrienol (10, 20, 30, and 40 μM) on hTf cultures were evaluated by performing proliferation, migration and collagen synthesis assays. Whereas for vitamin E the exposure time was set to 7 days to mimic subconjunctival application, cultures were exposed only 5 min to mitomycin C 100 μg/ml to mimic intraoperative administration. Cell morphology (phase contrast microscopy) as an assessment for cytotoxicity and cell density by measuring DNA content in a fluorometric assay to determine proliferation inhibition was performed on day 0, 4, and 7. Migration ability and collagen synthesis of fibroblasts were measured. Results All tested tocotrienol isoforms were able to significantly inhibit hTf proliferation in a dose-dependent manner (maximal inhibitory effect without relevant morphological changes at day 4 for α-tocotrienol 80 μM with 36.7% and at day 7 for α-tocotrienol 80 μM with 42

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Vitamin E amides, a new class of vitamin E analogues with enhanced proapoptotic activity

Cited by 45 publications

References 36 publications

A Peptide Conjugate of Vitamin E Succinate Targets Breast Cancer Cells with High ErbB2 Expression

A Peptide Conjugate of Vitamin E Succinate Targets Breast Cancer Cells with High ErbB2 Expression

Vitamin E Analogs, a Novel Group of “Mitocans,” as Anticancer Agents: The Importance of Being Redox-Silent

Antifibrotic effects of tocotrienols on human Tenon’s fibroblasts

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