Alpha-tocopheryl Succinate Induces Apoptosis by Targeting Ubiquinone-binding Sites in Mitochondrial Respiratory Complex II

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2008 Apr 1

PMID 18372923

Citations 85

Authors

L-F Dong

P Low

J C Dyason

X-F Wang

L PROCHAZKA

P K Witting

R Freeman

E Swettenham

K Valis

J Liu

R Zobalova

J Turanek

D R Spitz

F E Domann

I E Scheffler

S J Ralph

J Neuzil

Affiliations

Soon will be listed here.

Abstract

Alpha-tocopheryl succinate (alpha-TOS) is a selective inducer of apoptosis in cancer cells, which involves the accumulation of reactive oxygen species (ROS). The molecular target of alpha-TOS has not been identified. Here, we show that alpha-TOS inhibits succinate dehydrogenase (SDH) activity of complex II (CII) by interacting with the proximal and distal ubiquinone (UbQ)-binding site (Q(P) and Q(D), respectively). This is based on biochemical analyses and molecular modelling, revealing similar or stronger interaction energy of alpha-TOS compared to that of UbQ for the Q(P) and Q(D) sites, respectively. CybL-mutant cells with dysfunctional CII failed to accumulate ROS and underwent apoptosis in the presence of alpha-TOS. Similar resistance was observed when CybL was knocked down with siRNA. Reconstitution of functional CII rendered CybL-mutant cells susceptible to alpha-TOS. We propose that alpha-TOS displaces UbQ in CII causing electrons generated by SDH to recombine with molecular oxygen to yield ROS. Our data highlight CII, a known tumour suppressor, as a novel target for cancer therapy.

Citing Articles

Energy metabolism in health and diseases.

Liu H, Wang S, Wang J, Guo X, Song Y, Fu K Signal Transduct Target Ther. 2025; 10(1):69.

PMID: 39966374 PMC: 11836267. DOI: 10.1038/s41392-025-02141-x.

Modification in Structures of Active Compounds in Anticancer Mitochondria-Targeted Therapy.

Pyrczak-Felczykowska A, Herman-Antosiewicz A Int J Mol Sci. 2025; 26(3).

PMID: 39941144 PMC: 11818413. DOI: 10.3390/ijms26031376.

Anticancer Potential of Tocopherols-Containing Plants and Semi-Synthetic Tocopherols.

Sianipar N, Muflikhati Z, Mangindaan D, Assidqi K Plants (Basel). 2024; 13(21).

PMID: 39519912 PMC: 11548436. DOI: 10.3390/plants13212994.

The mechanisms of action of mitochondrial targeting agents in cancer: inhibiting oxidative phosphorylation and inducing apoptosis.

Yang Y, An Y, Ren M, Wang H, Bai J, Du W Front Pharmacol. 2023; 14:1243613.

PMID: 37954849 PMC: 10635426. DOI: 10.3389/fphar.2023.1243613.

Succinate metabolism: a promising therapeutic target for inflammation, ischemia/reperfusion injury and cancer.

Zhang W, Lang R Front Cell Dev Biol. 2023; 11:1266973.

PMID: 37808079 PMC: 10556696. DOI: 10.3389/fcell.2023.1266973.

References

Neuzil J, Weber T, Gellert N, Weber C . Selective cancer cell killing by alpha-tocopheryl succinate. Br J Cancer. 2001; 84(1):87-9. PMC: 2363620. DOI: 10.1054/bjoc.2000.1559. View

Geschwind J, Ko Y, Torbenson M, Magee C, Pedersen P . Novel therapy for liver cancer: direct intraarterial injection of a potent inhibitor of ATP production. Cancer Res. 2002; 62(14):3909-13. View

Neuzil J, Massa H . Hepatic processing determines dual activity of alpha-tocopheryl succinate: a novel paradigm for a shift in biological activity due to pro-vitamin-to-vitamin conversion. Biochem Biophys Res Commun. 2005; 327(4):1024-7. DOI: 10.1016/j.bbrc.2004.12.115. View

Neuzil J, Weber T, Schroder A, Lu M, OSTERMANN G, Gellert N . Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. FASEB J. 2001; 15(2):403-15. DOI: 10.1096/fj.00-0251com. View

Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T . Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol. 2001; 3(2):173-82. DOI: 10.1038/35055085. View

Trounce I, Kim Y, Jun A, Wallace D . Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol. 1996; 264:484-509. DOI: 10.1016/s0076-6879(96)64044-0. View

Wang X, Birringer M, Dong L, Veprek P, Low P, Swettenham E . A peptide conjugate of vitamin E succinate targets breast cancer cells with high ErbB2 expression. Cancer Res. 2007; 67(7):3337-44. DOI: 10.1158/0008-5472.CAN-06-2480. View

Wallace A, Laskowski R, Thornton J . LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng. 1995; 8(2):127-34. DOI: 10.1093/protein/8.2.127. View

Hail Jr N . Mitochondria: A novel target for the chemoprevention of cancer. Apoptosis. 2005; 10(4):687-705. DOI: 10.1007/s10495-005-0792-8. View

10.

Adam-Vizi V, Chinopoulos C . Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol Sci. 2006; 27(12):639-45. DOI: 10.1016/j.tips.2006.10.005. View

11.

Word J, Lovell S, Richardson J, Richardson D . Asparagine and glutamine: using hydrogen atom contacts in the choice of side-chain amide orientation. J Mol Biol. 1999; 285(4):1735-47. DOI: 10.1006/jmbi.1998.2401. View

12.

Kogure K, Hama S, Manabe S, Tokumura A, Fukuzawa K . High cytotoxicity of alpha-tocopheryl hemisuccinate to cancer cells is due to failure of their antioxidative defense systems. Cancer Lett. 2002; 186(2):151-6. DOI: 10.1016/s0304-3835(02)00344-0. View

13.

Burnell J, John P, Whatley F . The reversibility of active sulphate transport in membrane vesicles of Paracoccus denitrificans. Biochem J. 1975; 150(3):527-36. PMC: 1165768. DOI: 10.1042/bj1500527. View

14.

Sanner M . Python: a programming language for software integration and development. J Mol Graph Model. 2000; 17(1):57-61. View

15.

Hartshorn M . AstexViewer: a visualisation aid for structure-based drug design. J Comput Aided Mol Des. 2003; 16(12):871-81. DOI: 10.1023/a:1023813504011. View

16.

Shiau C, Huang J, Wang D, Weng J, Yang C, Lin C . alpha-Tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function. J Biol Chem. 2006; 281(17):11819-25. DOI: 10.1074/jbc.M511015200. View

17.

Safford S, Oberley T, Urano M, St Clair D . Suppression of fibrosarcoma metastasis by elevated expression of manganese superoxide dismutase. Cancer Res. 1994; 54(16):4261-5. View

18.

Bonnet S, Archer S, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R . A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11(1):37-51. DOI: 10.1016/j.ccr.2006.10.020. View

19.

Maehara Y, Kusumoto T, Kusumoto H, Anai H, Sugimachi K . Sodium succinate enhances the colorimetric reaction of the in vitro chemosensitivity test: MTT assay. Oncology. 1988; 45(6):434-6. DOI: 10.1159/000226660. View

20.

Niemann S, Muller U . Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000; 26(3):268-70. DOI: 10.1038/81551. View