The disulfide compound α-lipoic acid and its derivatives: A novel class of anticancer agents targeting mitochondria

Cancer Letters

Volumn 371, Issue 1, 2016, Pages 12-19

  Dörsam, Bastian ^a   Fahrer, Jörg ^a  

^a UNIVERSITY MEDICAL CENTER MAINZ   (Germany)

Author keywords

Anticancer drugs; Apoptosis; Cancer therapy; Cell death; Mitochondria; lipoic acid

Indexed keywords

ANTINEOPLASTIC AGENT; CPI 613; DISULFIDE; PROTEIN P53; THIOCTIC ACID; UNCLASSIFIED DRUG; OCTANOIC ACID DERIVATIVE; SULFIDE;

ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; CANCER CELL; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CYTOTOXICITY; DRUG EFFECT; DRUG HALF LIFE; DRUG METABOLISM; DRUG STRUCTURE; DRUG TARGETING; ENERGY METABOLISM; GASTROINTESTINAL ABSORPTION; HUMAN; IN VIVO STUDY; MAXIMUM PLASMA CONCENTRATION; MITOCHONDRION; NONHUMAN; PRIORITY JOURNAL; SHORT SURVEY; SIGNAL TRANSDUCTION; ANALOGS AND DERIVATIVES; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; METABOLISM; NEOPLASMS; PATHOLOGY; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CAPRYLATES; DRUG DISCOVERY; ENERGY METABOLISM; HUMANS; MITOCHONDRIA; MOLECULAR STRUCTURE; NEOPLASMS; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; SULFIDES; THIOCTIC ACID;

EID: 84951748654     PISSN: 03043835     EISSN: 18727980     Source Type: Journal    
DOI: 10.1016/j.canlet.2015.11.019     Document Type: Review

References (92)

1. Reed L.J., De B.B., Gunsalus I.C., Hornberger C.S. Crystalline alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase. Science 1951, 114:93-94.
2. Jordan S.W., Cronan J.E. Biosynthesis of lipoic acid and posttranslational modification with lipoic acid in Escherichia coli. Methods Enzymol 1997, 279:176-183.
3. Wada H., Shintani D., Ohlrogge J. Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. Proc. Natl. Acad. Sci. U.S.A. 1997, 94:1591-1596.
4. Zhao X., Miller J.R., Jiang Y., Marletta M.A., Cronan J.E. Assembly of the covalent linkage between lipoic acid and its cognate enzymes. Chem. Biol 2003, 10:1293-1302.
5. Cicchillo R.M., Iwig D.F., Jones A.D., Nesbitt N.M., Baleanu-Gogonea C., Souder M.G., et al. Lipoyl synthase requires two equivalents of S-adenosyl-L-methionine to synthesize one equivalent of lipoic acid. Biochemistry 2004, 43:6378-6386.
6. Jarrett J.T. The biosynthesis of thiol- and thioether-containing cofactors and secondary metabolites catalyzed by radical S-adenosylmethionine enzymes. J. Biol. Chem 2015, 290:3972-3979.
7. Akiba S., Matsugo S., Packer L., Konishi T. Assay of protein-bound lipoic acid in tissues by a new enzymatic method. Anal. Biochem 1998, 258:299-304.
8. Satoh S., Shindoh M., Min J.Z., Toyo'oka T., Fukushima T., Inagaki S. Selective and sensitive determination of lipoyllysine (protein-bound alpha-lipoic acid) in biological specimens by high-performance liquid chromatography with fluorescence detection. Anal. Chim. Acta 2008, 618:210-217.
9. Packer L., Kraemer K., Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 2001, 17:888-895.
10. Shay K.P., Moreau R.F., Smith E.J., Smith A.R., Hagen T.M. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta 2009, 1790:1149-1160.
11. Teichert J., Kern J., Tritschler H.J., Ulrich H., Preiss R. Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers. Int. J. Clin. Pharmacol. Ther 1998, 36:625-628.
12. Carlson D.A., Smith A.R., Fischer S.J., Young K.L., Packer L. The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects. Altern. Med. Rev 2007, 12:343-351.
13. Breithaupt-Grogler K., Niebch G., Schneider E., Erb K., Hermann R., Blume H.H., et al. Dose-proportionality of oral thioctic acid - coincidence of assessments via pooled plasma and individual data. Eur. J. Pharm. Sci 1999, 8:57-65.
14. Takaishi N., Yoshida K., Satsu H., Shimizu M. Transepithelial transport of alpha-lipoic acid across human intestinal Caco-2 cell monolayers. J. Agric. Food Chem 2007, 55:5253-5259.
15. Zehnpfennig B., Wiriyasermkul P., Carlson D.A., Quick M. Interaction of alpha-Lipoic Acid with the Human Na+/Multivitamin Transporter (hSMVT). J. Biol. Chem 2015, 290:16372-16382.
16. Prasad P.D., Wang H., Kekuda R., Fujita T., Fei Y.J., Devoe L.D., et al. Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J. Biol. Chem 1998, 273:7501-7506.
17. Constantinescu A., Pick U., Handelman G.J., Haramaki N., Han D., Podda M., et al. Reduction and transport of lipoic acid by human erythrocytes. Biochem. Pharmacol 1995, 50:253-261.
18. Jones W., Li X., Qu Z.C., Perriott L., Whitesell R.R., May J.M. Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic. Biol. Med 2002, 33:83-93.
19. May J.M., Qu Z.C., Nelson D.J. Uptake and reduction of alpha-lipoic acid by human erythrocytes. Clin. Biochem 2007, 40:1135-1142.
20. Handelman G.J., Han D., Tritschler H., Packer L. Alpha-lipoic acid reduction by mammalian cells to the dithiol form, and release into the culture medium. Biochem. Pharmacol 1994, 47:1725-1730.
21. Teichert J., Hermann R., Ruus P., Preiss R. Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers. J. Clin. Pharmacol 2003, 43:1257-1267.
22. Schupke H., Hempel R., Peter G., Hermann R., Wessel K., Engel J., et al. New metabolic pathways of alpha-lipoic acid. Drug Metab. Dispos 2001, 29:855-862.
23. Ziegler D., Hanefeld M., Ruhnau K.J., Meissner H.P., Lobisch M., Schutte K., et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995, 38:1425-1433.
24. Reljanovic M., Reichel G., Rett K., Lobisch M., Schuette K., Moller W., et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha lipoic acid in diabetic neuropathy. Free Radic. Res 1999, 31:171-179.
25. Yadav V., Marracci G., Lovera J., Woodward W., Bogardus K., Marquardt W., et al. Lipoic acid in multiple sclerosis: a pilot study. Mult. Scler 2005, 11:159-165.
26. Rochette L., Ghibu S., Richard C., Zeller M., Cottin Y., Vergely C. Direct and indirect antioxidant properties of alpha-lipoic acid and therapeutic potential. Mol. Nutr. Food Res 2013, 57:114-125.
27. Haenen G.R., Bast A. Scavenging of hypochlorous acid by lipoic acid. Biochem. Pharmacol 1991, 42:2244-2246.
28. Suzuki Y.J., Tsuchiya M., Packer L. Thioctic acid and dihydrolipoic acid are novel antioxidants which interact with reactive oxygen species. Free Radic. Res. Commun 1991, 15:255-263.
29. Sigel H., Prijs B., McCormick D.B., Shih J.C. Stability and structure of binary and ternary complexes of alpha-lipoate and lipoate derivatives with Mn2+, Cu2+, and Zn2+ in solution. Arch. Biochem. Biophys 1978, 187:208-214.
30. Ou P., Tritschler H.J., Wolff S.P. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant?. Biochem. Pharmacol 1995, 50:123-126.
31. Bonomi F., Pagani S. Removal of ferritin-bound iron by DL-dihydrolipoate and DL-dihydrolipoamide. Eur. J. Biochem 1986, 155:295-300.
32. Suh J.H., Moreau R., Heath S.H., Hagen T.M. Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep 2005, 10:52-60.
33. Kagan V.E., Shvedova A., Serbinova E., Khan S., Swanson C., Powell R., et al. Dihydrolipoic acid - a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem. Pharmacol 1992, 44:1637-1649.
34. Han D., Handelman G., Marcocci L., Sen C.K., Roy S., Kobuchi H., et al. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 1997, 6:321-338.
35. Suh J.H., Wang H., Liu R.M., Liu J., Hagen T.M. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch. Biochem. Biophys 2004, 423:126-135.
36. Suh J.H., Shenvi S.V., Dixon B.M., Liu H., Jaiswal A.K., Liu R.M., et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc. Natl. Acad. Sci. U.S.A. 2004, 101:3381-3386.
37. Shay K.P., Michels A.J., Li W., Kong A.N., Hagen T.M. Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response. Biochim. Biophys. Acta 1823, 2012:1102-1109.
38. Ki S.H., Kim S.G. Phase II enzyme induction by alpha-lipoic acid through phosphatidylinositol 3-kinase-dependent C/EBPs activation. Xenobiotica 2008, 38:587-604.
39. Smith A.R., Shenvi S.V., Widlansky M., Suh J.H., Hagen T.M. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr. Med. Chem 2004, 11:1135-1146.
40. Trivedi P.P., Jena G.B. Role of alpha-lipoic acid in dextran sulfate sodium-induced ulcerative colitis in mice: studies on inflammation, oxidative stress, DNA damage and fibrosis. Food Chem. Toxicol 2013, 59:339-355.
41. Wenzel U., Nickel A., Daniel H. Alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation. Apoptosis 2005, 10:359-368.
42. Moungjaroen J., Nimmannit U., Callery P.S., Wang L., Azad N., Lipipun V., et al. Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation. J. Pharmacol. Exp. Ther 2006, 319:1062-1069.
43. Sen C.K., Sashwati R., Packer L. Fas mediated apoptosis of human Jurkat T-cells: intracellular events and potentiation by redox-active alpha-lipoic acid. Cell Death Differ 1999, 6:481-491.
44. Pack R.A., Hardy K., Madigan M.C., Hunt N.H. Differential effects of the antioxidant alpha-lipoic acid on the proliferation of mitogen-stimulated peripheral blood lymphocytes and leukaemic T cells. Mol. Immunol 2002, 38:733-745.
45. van de Mark K., Chen J.S., Steliou K., Perrine S.P., Faller D.V. Alpha-lipoic acid induces p27Kip-dependent cell cycle arrest in non-transformed cell lines and apoptosis in tumor cell lines. J. Cell. Physiol 2003, 194:325-340.
46. Dozio E., Ruscica M., Passafaro L., Dogliotti G., Steffani L., Marthyn P., et al. The natural antioxidant alpha-lipoic acid induces p27(Kip1)-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cells. Eur. J. Pharmacol 2010, 641:29-34.
47. Simbula G., Columbano A., Ledda-Columbano G.M., Sanna L., Deidda M., Diana A., et al. Increased ROS generation and p53 activation in alpha-lipoic acid-induced apoptosis of hepatoma cells. Apoptosis 2007, 12:113-123.
48. Kafara P., Icard P., Guillamin M., Schwartz L., Lincet H. Lipoic acid decreases Mcl-1, Bcl-xL and up regulates Bim on ovarian carcinoma cells leading to cell death. J. Ovarian Res 2015, 8:36.
49. Shi D.Y., Liu H.L., Stern J.S., Yu P.Z., Liu S.L. Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/Akt pathway. FEBS Lett 2008, 582:1667-1671.
50. Dörsam B., Göder A., Seiwert N., Kaina B., Fahrer J. Lipoic acid induces p53-independent cell death in colorectal cancer cells and potentiates the cytotoxicity of 5-fluorouracil. Arch. Toxicol 2015, 89:1829-1846.
51. Horn H.F., Vousden K.H. Coping with stress: multiple ways to activate p53. Oncogene 2007, 26:1306-1316.
52. Speidel D. Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol 2010, 20:14-24.
53. Yoo T.H., Lee J.H., Chun H.S., Chi S.G. alpha-Lipoic acid prevents p53 degradation in colon cancer cells by blocking NF-kappaB induction of RPS6KA4. Anticancer Drugs 2013, 24:555-565.
54. Gatei M., Shkedy D., Khanna K.K., Uziel T., Shiloh Y., Pandita T.K., et al. Ataxia-telangiectasia: chronic activation of damage-responsive functions is reduced by alpha-lipoic acid. Oncogene 2001, 20:289-294.
55. Park S., Choi S.K., Choi Y., Moon H.S. AMPK/p53 axis is essential for alpha-lipoic acid-regulated metastasis in human and mouse colon cancer cells. J. Investig. Med 2015, 63:882-885.
56. Petitjean A., Mathe E., Kato S., Ishioka C., Tavtigian S.V., Hainaut P., et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum. Mutat 2007, 28:622-629.
57. Kalo E., Kogan-Sakin I., Solomon H., Bar-Nathan E., Shay M., Shetzer Y., et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J. Cell Sci 2012, 125:5578-5586.
58. Choi S.Y., Yu J.H., Kim H. Mechanism of alpha-lipoic acid-induced apoptosis of lung cancer cells. Ann. N. Y. Acad. Sci 2009, 1171:149-155.
59. Göder A., Nagel G., Kraus A., Dörsam B., Seiwert N., Kaina B., et al. Lipoic acid inhibits the DNA repair protein O 6-methylguanine-DNA methyltransferase (MGMT) and triggers its depletion in colorectal cancer cells with concomitant autophagy induction. Carcinogenesis 2015, 36:817-831.
60. Liu Y., Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ 2015, 22:367-376.
61. Hiratsuka T., Inomata M., Kono Y., Yokoyama S., Shiraishi N., Kitano S. DHLTauZnNa, a newly synthesized alpha-lipoic acid derivative, induces autophagy in human colorectal cancer cells. Oncol. Rep 2013, 29:2140-2146.
62. Fruman D.A., Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat. Rev. Drug Discov 2014, 13:140-156.
63. Larghero P., Vene R., Minghelli S., Travaini G., Morini M., Ferrari N., et al. Biological assays and genomic analysis reveal lipoic acid modulation of endothelial cell behavior and gene expression. Carcinogenesis 2007, 28:1008-1020.
64. Shay K.P., Hagen T.M. Age-associated impairment of Akt phosphorylation in primary rat hepatocytes is remediated by alpha-lipoic acid through PI3 kinase, PTEN, and PP2A. Biogerontology 2009, 10:443-456.
65. Zhang W.J., Wei H., Hagen T., Frei B. Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc. Natl. Acad. Sci. U.S.A. 2007, 104:4077-4082.
66. Li W., Saud S.M., Young M.R., Chen G., Hua B. Targeting AMPK for cancer prevention and treatment. Oncotarget 2015, 6:7365-7378.
67. Lee W.J., Song K.H., Koh E.H., Won J.C., Kim H.S., Park H.S., et al. Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem. Biophys. Res. Commun 2005, 332:885-891.
68. Park K.G., Min A.K., Koh E.H., Kim H.S., Kim M.O., Park H.S., et al. Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. Hepatology 2008, 48:1477-1486.
69. Jeon M.J., Kim W.G., Lim S., Choi H.J., Sim S., Kim T.Y., et al. Alpha lipoic acid inhibits proliferation and epithelial mesenchymal transition of thyroid cancer cells. Mol. Cell. Endocrinol 2015, 10.1016/j.mce.2015.10.005.
70. Michikoshi H., Nakamura T., Sakai K., Suzuki Y., Adachi E., Matsugo S., et al. alpha-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells. Cancer Lett 2013, 335:472-478.
71. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
72. Lee H.S., Na M.H., Kim W.K. Alpha-lipoic acid reduces matrix metalloproteinase activity in MDA-MB-231 human breast cancer cells. Nutr. Res 2010, 30:403-409.
73. Yamasaki M., Iwase M., Kawano K., Sakakibara Y., Suiko M., Ikeda M., et al. alpha-Lipoic acid suppresses migration and invasion via downregulation of cell surface beta1-integrin expression in bladder cancer cells. J. Clin. Biochem. Nutr 2014, 54:18-25.
74. Yamasaki M., Soda S., Sakakibara Y., Suiko M., Nishiyama K. The importance of 1,2-dithiolane structure in alpha-lipoic acid for the downregulation of cell surface beta1-integrin expression of human bladder cancer cells. Biosci. Biotechnol. Biochem 2014, 78:1939-1942.
75. Fahrer J., Kaina B. O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer. Carcinogenesis 2013, 34:2435-2442.
76. Fahrer J., Frisch J., Nagel G., Kraus A., Dörsam B., Thomas A.D., et al. DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis. Carcinogenesis 2015, 36(10):1235-1244.
77. Christmann M., Verbeek B., Roos W.P., Kaina B. O(6)-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry. Biochim. Biophys. Acta 2011, 1816:179-190.
78. Olivier M., Hollstein M., Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol 2010, 2. a001008.
79. Wade M., Li Y.C., Wahl G.M. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat. Rev. Cancer 2013, 13:83-96.
80. Feuerecker B., Pirsig S., Seidl C., Aichler M., Feuchtinger A., Bruchelt G., et al. Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer Biol. Ther 2012, 13:1425-1435.
81. Abolhassani M., Guais A., Sanders E., Campion F., Fichtner I., Bonte J., et al. Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice. Invest. New Drugs 2012, 30:1331-1342.
82. Zhang S.J., Ge Q.F., Guo D.W., Hu W.X., Liu H.Z. Synthesis and anticancer evaluation of alpha-lipoic acid derivatives. Bioorg. Med. Chem. Lett 2010, 20:3078-3083.
83. Zachar Z., Marecek J., Maturo C., Gupta S., Stuart S.D., Howell K., et al. Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. J. Mol. Med. (Berl.) 2011, 89:1137-1148.
84. Stuart S.D., Schauble A., Gupta S., Kennedy A.D., Keppler B.R., Bingham P.M., et al. A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab 2014, 2:4.
85. Pardee T.S., Lee K., Luddy J., Maturo C., Rodriguez R., Isom S., et al. A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies. Clin. Cancer Res 2014, 20:5255-5264.
86. Schwartz L., Buhler L., Icard P., Lincet H., Steyaert J.M. Metabolic treatment of cancer: intermediate results of a prospective case series. Anticancer Res 2014, 34:973-980.
87. Arivazhagan P., Shila S., Kumaran S., Panneerselvam C. Effect of DL-alpha-lipoic acid on the status of lipid peroxidation and antioxidant enzymes in various brain regions of aged rats. Exp. Gerontol 2002, 37:803-811.
88. Chng H.T., New L.S., Neo A.H., Goh C.W., Browne E.R., Chan E.C. Distribution study of orally administered lipoic acid in rat brain tissues. Brain Res 2009, 1251:80-86.
89. Vander Heiden M.G., Cantley L.C., Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009, 324:1029-1033.
90. Kim J.W., Tchernyshyov I., Semenza G.L., Dang C.V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006, 3:177-185.
91. Kinnaird A., Michelakis E.D. Metabolic modulation of cancer: a new frontier with great translational potential. J. Mol. Med. (Berl.) 2015, 93:127-142.
92. Korotchkina L.G., Sidhu S., Patel M.S. R-lipoic acid inhibits mammalian pyruvate dehydrogenase kinase. Free Radic. Res 2004, 38:1083-1092.