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Vitamin E analogues as inducers of apoptosis: structure-function relation.

Birringer M, EyTina JH, Salvatore BA, Neuzil J - Br. J. Cancer (2003)

Bottom Line: Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity.Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated.It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

View Article: PubMed Central - PubMed

Affiliation: German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.

ABSTRACT
Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of alpha-TOS with lower number of methyl substitutions on the aromatic ring were less active than alpha-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on alpha-TOS and delta-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of gamma-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

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Effect of modifications in domain III of the VE molecule on their apoptogenic activity. Jurkat (A), HBT11 (B), MCF7 (C) and MCF7-C3 cells (D) were exposed for 24 h to α-TOH, α-TOS, α-T3H, γ-T3H, γ-T3S, α-T2H, α-TroH, or α-TroS, and assessed for apoptosis using the annexin V–FITC method.
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fig6: Effect of modifications in domain III of the VE molecule on their apoptogenic activity. Jurkat (A), HBT11 (B), MCF7 (C) and MCF7-C3 cells (D) were exposed for 24 h to α-TOH, α-TOS, α-T3H, γ-T3H, γ-T3S, α-T2H, α-TroH, or α-TroS, and assessed for apoptosis using the annexin V–FITC method.

Mentions: Several modifications of the aliphatic side chain (domain III, the hydrophobic domain) are possible. Its desaturation, in the case of α-TOH, gives the naturally occurring α-T3H, which is nonapoptotic (Yu et al, 1999). γ-T3H, however, has a strong apoptogenic activity (Yu et al, 1999), which is further enhanced by its conversion to γ-T3S (Figure 6Figure 6


Vitamin E analogues as inducers of apoptosis: structure-function relation.

Birringer M, EyTina JH, Salvatore BA, Neuzil J - Br. J. Cancer (2003)

Effect of modifications in domain III of the VE molecule on their apoptogenic activity. Jurkat (A), HBT11 (B), MCF7 (C) and MCF7-C3 cells (D) were exposed for 24 h to α-TOH, α-TOS, α-T3H, γ-T3H, γ-T3S, α-T2H, α-TroH, or α-TroS, and assessed for apoptosis using the annexin V–FITC method.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2741106&req=5

fig6: Effect of modifications in domain III of the VE molecule on their apoptogenic activity. Jurkat (A), HBT11 (B), MCF7 (C) and MCF7-C3 cells (D) were exposed for 24 h to α-TOH, α-TOS, α-T3H, γ-T3H, γ-T3S, α-T2H, α-TroH, or α-TroS, and assessed for apoptosis using the annexin V–FITC method.
Mentions: Several modifications of the aliphatic side chain (domain III, the hydrophobic domain) are possible. Its desaturation, in the case of α-TOH, gives the naturally occurring α-T3H, which is nonapoptotic (Yu et al, 1999). γ-T3H, however, has a strong apoptogenic activity (Yu et al, 1999), which is further enhanced by its conversion to γ-T3S (Figure 6Figure 6

Bottom Line: Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity.Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated.It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

View Article: PubMed Central - PubMed

Affiliation: German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.

ABSTRACT
Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of alpha-TOS with lower number of methyl substitutions on the aromatic ring were less active than alpha-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on alpha-TOS and delta-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of gamma-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

Show MeSH
Related in: MedlinePlus