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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death

Authors: Gang Cheng, Jacek Zielonka, Donna M McAllister, A Craig Mackinnon Jr, Joy Joseph, Michael B Dwinell, Balaraman Kalyanaraman

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Recent research has revealed that targeting mitochondrial bioenergetic metabolism is a promising chemotherapeutic strategy. Key to successful implementation of this chemotherapeutic strategy is the use of new and improved mitochondria-targeted cationic agents that selectively inhibit energy metabolism in breast cancer cells, while exerting little or no long-term cytotoxic effect in normal cells.

Methods

In this study, we investigated the cytotoxicity and alterations in bioenergetic metabolism induced by mitochondria-targeted vitamin E analog (Mito-chromanol, Mito-ChM) and its acetylated ester analog (Mito-ChMAc). Assays of cell death, colony formation, mitochondrial bioenergetic function, intracellular ATP levels, intracellular and tissue concentrations of tested compounds, and in vivo tumor growth were performed.

Results

Both Mito-ChM and Mito-ChMAc selectively depleted intracellular ATP and caused prolonged inhibition of ATP-linked oxygen consumption rate in breast cancer cells, but not in non-cancerous cells. These effects were significantly augmented by inhibition of glycolysis. Mito-ChM and Mito-ChMAc exhibited anti-proliferative effects and cytotoxicity in several breast cancer cells with different genetic background. Furthermore, Mito-ChM selectively accumulated in tumor tissue and inhibited tumor growth in a xenograft model of human breast cancer.

Conclusions

We conclude that mitochondria-targeted small molecular weight chromanols exhibit selective anti-proliferative effects and cytotoxicity in multiple breast cancer cells, and that esterification of the hydroxyl group in mito-chromanols is not a critical requirement for its anti-proliferative and cytotoxic effect.
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Literature
1.
Hsu PP, Sabatini DM: Cancer cell metabolism: Warburg and beyond. Cell. 2008, 134: 703-707. 10.1016/j.cell.2008.08.021.CrossRefPubMed
2.
Barger JF, Plas DR: Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis. Endocr Relat Cancer. 2010, 17: R287-R304. 10.1677/ERC-10-0106.CrossRefPubMed
3.
Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009, 324: 1029-1033. 10.1126/science.1160809.CrossRefPubMedPubMedCentral
4.
Cheng G, Zielonka J, Dranka BP, McAllister D, Mackinnon AC, Joseph J, Kalyanaraman B: Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death. Cancer Res. 2012, 72: 2634-2644. 10.1158/0008-5472.CAN-11-3928.CrossRefPubMedPubMedCentral
5.
Beckham TH, Lu P, Jones EE, Marrison T, Lewis CS, Cheng JC, Ramshesh VK, Beeson G, Beeson CC, Drake RR, Bielawska A, Bielawski J, Szulc ZM, Ogretmen B, Norris JS, Liu X: LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. J Pharmacol Exp Ther. 2013, 344: 167-178. 10.1124/jpet.112.199216.CrossRefPubMedPubMedCentral
6.
Wheeler HE, Maitland ML, Dolan ME, Cox NJ, Ratain MJ: Cancer pharmacogenomics: strategies and challenges. Nat Rev Genet. 2013, 14: 23-34.CrossRefPubMed
7.
Smith RA, Hartley RC, Murphy MP: Mitochondria-targeted small molecule therapeutics and probes. Antioxid Redox Signal. 2011, 15: 3021-3038. 10.1089/ars.2011.3969.CrossRefPubMed
8.
Millard M, Pathania D, Shabaik Y, Taheri L, Deng J, Neamati N: Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity. PLoS One. 2010, 5: e13131-10.1371/journal.pone.0013131.CrossRefPubMedPubMedCentral
9.
Ju J, Picinich SC, Yang Z, Zhao Y, Suh N, Kong AN, Yang CS: Cancer-preventive activities of tocopherols and tocotrienols. Carcinogenesis. 2010, 31: 533-542. 10.1093/carcin/bgp205.CrossRefPubMed
10.
Kunnumakkara AB, Sung B, Ravindran J, Diagaradjane P, Deorukhkar A, Dey S, Koca C, Yadav VR, Tong Z, Gelovani JG, Guha S, Krishnan S, Krishnan BB: {Gamma}-tocotrienol inhibits pancreatic tumors and sensitizes them to gemcitabine treatment by modulating the inflammatory microenvironment. Cancer Res. 2010, 70: 8695-8705. 10.1158/0008-5472.CAN-10-2318.CrossRefPubMedPubMedCentral
11.
Li GX, Lee MJ, Liu AB, Yang Z, Lin Y, Shih WJ, Yang CS: delta-tocopherol is more active than alpha - or gamma -tocopherol in inhibiting lung tumorigenesis in vivo. Cancer Prev Res (Phila). 2011, 4: 404-413. 10.1158/1940-6207.CAPR-10-0130.CrossRef
12.
Shah SJ, Sylvester PW: Gamma-tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor kappaB activity. Exp Biol Med (Maywood). 2005, 230: 235-241.
13.
Azzi A, Ricciarelli R, Zingg JM: Non-antioxidant molecular functions of alpha-tocopherol (vitamin E). FEBS Lett. 2002, 519: 8-10. 10.1016/S0014-5793(02)02706-0.CrossRefPubMed
14.
Neuzil J, Tomasetti M, Zhao Y, Dong LF, Birringer M, Wang XF, Low P, Wu K, Salvatore BA, Ralph SJ: Vitamin E analogs, a novel group of “mitocans,” as anticancer agents: the importance of being redox-silent. Mol Pharmacol. 2007, 71: 1185-1199. 10.1124/mol.106.030122.CrossRefPubMed
15.
Dong LF, Freeman R, Liu J, Zobalova R, Marin-Hernandez A, Stantic M, Rohlena J, Valis K, Rodriguez-Enriquez S, Butcher B, Goodwin J, Brunk UT, Witting PK, Moreno-Sanchez R, Scheffler IE, Ralph SJ, Neuzil J: Suppression of tumor growth in vivo by the mitocan alpha-tocopheryl succinate requires respiratory complex II. Clin Cancer Res. 2009, 15: 1593-1600. 10.1158/1078-0432.CCR-08-2439.CrossRefPubMed
16.
Dong LF, Jameson VJ, Tilly D, Cerny J, Mahdavian E, Marin-Hernandez A, Hernandez-Esquivel L, Rodriguez-Enriquez S, Stursa J, Witting PK, Stantic B, Rohlena J, Truksa J, Kluckova K, Dyason JC, Ledvina M, Salvatore BA, Moreno-Sánchez R, Coster MJ, Ralph SJ, Smith RA, Neuzil J: Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II. J Biol Chem. 2011, 286: 3717-3728. 10.1074/jbc.M110.186643.CrossRefPubMed
17.
Wang F, Ogasawara MA, Huang P: Small mitochondria-targeting molecules as anti-cancer agents. Mol Aspects Med. 2010, 31: 75-92. 10.1016/j.mam.2009.12.003.CrossRefPubMed
18.
Dhanasekaran A, Kotamraju S, Kalivendi SV, Matsunaga T, Shang T, Keszler A, Joseph J, Kalyanaraman B: Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem. 2004, 279: 37575-37587. 10.1074/jbc.M404003200.CrossRefPubMed
19.
20.
Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C, Guise TA, Massague J: A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003, 3: 537-549. 10.1016/S1535-6108(03)00132-6.CrossRefPubMed
21.
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J: Genes that mediate breast cancer metastasis to lung. Nature. 2005, 436: 518-524. 10.1038/nature03799.CrossRefPubMedPubMedCentral
22.
Wendt MK, Cooper AN, Dwinell MB: Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene. 2008, 27: 1461-1471. 10.1038/sj.onc.1210751.CrossRefPubMed
23.
Fischer EG, Stingl A, Kirkpatrick CJ: Migration assay for endothelial cells in multiwells. Application to studies on the effect of opioids. J Immunol Methods. 1990, 128: 235-239. 10.1016/0022-1759(90)90215-H.CrossRefPubMed
24.
Franken NA, Rodermond HM, Stap J, Haveman J, van Bree C: Clonogenic assay of cells in vitro. Nat Protoc. 2006, 1: 2315-2319. 10.1038/nprot.2006.339.CrossRefPubMed
25.
Dranka BP, Hill BG, Rley-Usmar VM: Mitochondrial reserve capacity in endothelial cells: the impact of nitric oxide and reactive oxygen species. Free Radic Biol Med. 2010, 48: 905-914. 10.1016/j.freeradbiomed.2010.01.015.CrossRefPubMedPubMedCentral
26.
Nicholls DG, Rley-Usmar VM, Wu M, Jensen PB, Rogers GW, Ferrick DA: Bioenergetic profile experiment using C2C12 myoblast cells. J Vis Exp. 2010, 46: e2511-10.3791/2511.
27.
Nadakavukaren KK, Nadakavukaren JJ, Chen LB: Increased rhodamine 123 uptake by carcinoma cells. Cancer Res. 1985, 45: 6093-6099.PubMed
28.
Kurtoglu M, Lampidis TJ: From delocalized lipophilic cations to hypoxia: blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors. Mol Nutr Food Res. 2009, 53: 68-75. 10.1002/mnfr.200700457.CrossRefPubMedPubMedCentral
29.
Summerhayes IC, Lampidis TJ, Bernal SD, Nadakavukaren JJ, Nadakavukaren KK, Shepherd EL, Chen LB: Unusual retention of rhodamine 123 by mitochondria in muscle and carcinoma cells. Proc Natl Acad Sci USA. 1982, 79: 5292-5296. 10.1073/pnas.79.17.5292.CrossRefPubMedPubMedCentral
30.
Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O’Sullivan JD, Fung V, Smith RA, Murphy MP, Taylor KM: A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov Disord. 2010, 25: 1670-1674. 10.1002/mds.23148.CrossRefPubMed
31.
Pelicano H, Martin DS, Xu RH, Huang P: Glycolysis inhibition for anticancer treatment. Oncogene. 2006, 25: 4633-4646. 10.1038/sj.onc.1209597.CrossRefPubMed
32.
Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB: Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004, 64: 3892-3899. 10.1158/0008-5472.CAN-03-2904.CrossRefPubMed
33.
34.
Marin-Hernandez A, Gallardo-Perez JC, Rodriguez-Enriquez S, Encalada R, Moreno-Sanchez R, Saavedra E: Modeling cancer glycolysis. Biochim Biophys Acta. 1807, 2011: 755-767.
35.
Fan Y, Dickman KG, Zong WX: Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition. J Biol Chem. 2010, 285: 7324-7333. 10.1074/jbc.M109.035584.CrossRefPubMed
36.
Cairns RA, Harris IS, Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 2011, 11: 85-95.CrossRefPubMed
37.
Pathania D, Millard M, Neamati N: Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev. 2009, 61: 1250-1275. 10.1016/j.addr.2009.05.010.CrossRefPubMed
38.
Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS: Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 2010, 107: 8788-8793. 10.1073/pnas.1003428107.CrossRefPubMedPubMedCentral
39.
40.
Sauna ZE, Smith MM, Muller M, Kerr KM, Ambudkar SV: The mechanism of action of multidrug-resistance-linked P-glycoprotein. J Bioenerg Biomembr. 2001, 33: 481-491. 10.1023/A:1012875105006.CrossRefPubMed
41.
Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, Gao G, Zhang A, Xia X, Brasher H, Widger W, Ellis LM, Weihua Z: Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 2012, 72: 304-314. 10.1158/0008-5472.CAN-11-1674.CrossRefPubMed
42.
Prochazka L, Koudelka S, Dong LF, Stursa J, Goodwin J, Neca J, Slavik J, Ciganek M, Masek J, Kluckova K, Nguyen M, Turanek J, Neuzil J: Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to alpha-tocopheryl succinate. Apoptosis. 2013, 18: 286-299. 10.1007/s10495-012-0795-1.CrossRefPubMed
43.
Lopes MA, Meisel A, Carvalho FD, Bastos ML: Neuronal nitric oxide synthase is a key factor in doxorubicin-induced toxicity to rat-isolated cortical neurons. Neurotox Res. 2011, 19: 14-22. 10.1007/s12640-009-9135-9.CrossRefPubMed
44.
Gianni L, Salvatorelli E, Minotti G: Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes. Cardiovasc Toxicol. 2007, 7: 67-71. 10.1007/s12012-007-0013-5.CrossRefPubMed
45.
Mao G, Kraus GA, Kim I, Spurlock ME, Bailey TB, Beitz DC: Effect of a mitochondria-targeted vitamin E derivative on mitochondrial alteration and systemic oxidative stress in mice. Br J Nutr. 2011, 106: 87-95. 10.1017/S0007114510005830.CrossRefPubMed
46.
Chandran K, Aggarwal D, Migrino RQ, Joseph J, McAllister D, Konorev EA, Antholine WE, Zielonka J, Srinivasan S, Avadhani NG, Kalyanaraman B: Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophys J. 2009, 96: 1388-1398. 10.1016/j.bpj.2008.10.042.CrossRefPubMedPubMedCentral
47.
Mukhopadhyay P, Horvath B, Zsengeller Z, Zielonka J, Tanchian G, Holovac E, Kechrid M, Patel V, Stillman IE, Parikh SM, Joseph J, Kalyanaraman B, Pacher P: Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy. Free Radic Biol Med. 2012, 52: 497-506. 10.1016/j.freeradbiomed.2011.11.001.CrossRefPubMed
48.
Gohil VM, Sheth SA, Nilsson R, Wojtovich AP, Lee JH, Perocchi F, Chen W, Clish CB, Ayata C, Brookes PS, Mootha VK: Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nat Biotechnol. 2010, 28: 249-255.PubMedPubMedCentral
49.
Hernlund E, Ihrlund LS, Khan O, Ates YO, Linder S, Panaretakis T, Shoshan MC: Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir. Int J Cancer. 2008, 123: 476-483. 10.1002/ijc.23525.CrossRefPubMed
Metadata
Title
Mitochondria-targeted vitamin E analogs inhibit breast cancer cell energy metabolism and promote cell death
Authors
Gang Cheng
Jacek Zielonka
Donna M McAllister
A Craig Mackinnon Jr
Joy Joseph
Michael B Dwinell
Balaraman Kalyanaraman
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-285

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