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DOI: 10.1055/s-0043-112343
Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A
Publication History
received 29 March 2017
revised 02 May 2017
accepted 20 May 2017
Publication Date:
08 June 2017 (online)
Abstract
In a recent study, several new derivatives of antimycin A (AMA) were produced by means of a novel transacylation reaction, and these were shown to mediate selective toxicity toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether the analogues all expressed their cytotoxicity by the same mechanism. This was done by studying the effects of the compounds in several types of cell lines. In comparison with 2-O-methylantimycin, which acts at the locus of Bcl-2, none of the new derivatives exhibited a difference in cytotoxicity toward cells expressing different levels of Bcl-2. In cell lines that over- or underexpress estrogen or Her2 receptors, AMA analogue 2 exhibited Her2 receptor dependency at low concentration. Three compounds (1, 4, and 6) exhibited concentration-dependent increases in reactive oxygen species, with 6 being especially potent. Compounds 5 and 6 diminished mitochondrial membrane potential more potently than AMA, and 1 also displayed enhanced activity relative to 2–4. Interestingly, only 1 and AMA displayed strong inhibition of the respiratory chain, as measured by monitoring NADH (reduced nicotinamide adenine dinucleotide) oxidase. Because four of the analogues have positively charged substituents, two of these (4 and 6) were studied to see whether the observed effects were due to much higher level of accumulation within the mitochondria. Their presence in the mitochondria was not dramatically enhanced. Neither of the two presently characterized mechanisms of cell killing by AMA can fully account for the observed results.
Key words
antimycin A - cytotoxicity - Bcl-2 expression - NADH oxidase inhibition - reactive oxygen species - mitochondrial membrane potentialSupporting Information
- Supporting Information
Fluorescence microscopy images of A549 cells after a 4 h incubation with compounds AMA, 4, and 6, histograms illustrating the dose-dependent cytotoxicity of 1–6 in six cell lines, and complete data for IC50 determination of compounds 1–6.
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References
- 1 Rohlena J, Dong LF, Ralph SJ, Neuzil J. Anticancer drugs targeting the mitochondrial electron transport chain. Antioxid Redox Signal 2011; 15: 2951-2974
- 2 Rohlena J, Dong LF, Neuzil J. Targeting the mitochondrial electron transport chain complexes for the induction of apoptosis and cancer treatment. Curr Pharm Biotechnol 2013; 14: 377-389
- 3 Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS, Chandel NS. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife 2014; 3: e02242
- 4 Sun X, Ai M, Wang Y, Shen S, Gu Y, Jin Y, Zhou Z, Long Y, Yu Q. Selective induction of tumor cell apoptosis by a novel P450-mediated reactive oxygen species (ROS) inducer methyl 3-(4-nitrophenyl) propiolate. J Biol Chem 2013; 288: 8826-8837
- 5 Lessene G, Czabotar PE, Colman PM. BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discovery 2008; 7: 989-1000
- 6 Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 2009; 15: 1126-1132
- 7 Sullivan LB, Chandel NS. Mitochondrial reactive oxygen species and cancer. Cancer Metab 2014; 2: 17
- 8 Chevalier A, Zhang YM, Khdour OM, Hecht SM. Selective functionalization of antimycin A through an N-transacylation reaction. Org Lett 2016; 18: 2395-2398
- 9 Tzung SP, Kim KM, Basanez G, Giedt CD, Simon J, Zimmerberg J, Zhang KY, Hockenbery DM. Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 2001; 3: 183-191
- 10 Ubah OC, Wallace HM. Cancer therapy: targeting mitochondria and other sub-cellular organelles. Curr Pharm Des 2014; 20: 201-222
- 11 Zhang YM, Jiang Q, Wang N, Dai BL, Chen YN, He LC. Effects of taspine on proliferation and apoptosis by regulating caspase-3 expression and the ratio of Bax/Bcl-2 in A431 cells. Phytother Res 2011; 25: 357-364
- 12 Murphy MP. Targeting lipophilic cations to mitochondria. Biochim Biophys Acta 2008; 1777: 1028-1031
- 13 Bernardi P, Krauskopf A, Basso E, Petronilli V, Blachly-Dyson E, Di Lisa F, Forte MA. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J 2006; 273: 2077-2099
- 14 Huang LS, Cobessi D, Tung EY, Berry EA. Binding of the respiratory chain inhibitor antimycin to the mitochondrial bc1 complex: a new crystal structure reveals an altered intramolecular hydrogen-bonding pattern. J Mol Biol 2005; 351: 573-597
- 15 Jean SR, Tulumello DV, Wisnovsky SP, Lei EK, Pereira MP, Kelley SO. Molecular vehicles for mitochondrial chemical biology and drug delivery. ACS Chem Biol 2014; 9: 323-333
- 16 Ma J, Lim C, Sacher JR, Van Houten B, Qian W, Wipf P. Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells. Bioorg Med Chem Lett 2015; 25: 4828-4833
- 17 Xu Z, Xu L. Fluorescent probes for the selective detection of chemical species inside mitochondria. Chem Commun 2016; 52: 1094-1119
- 18 Ma X, Jin M, Cai Y, Xia H, Long K, Liu J, Yu Q, Yuan J. Mitochondrial electron transport chain complex III is required for antimycin A to inhibit autophagy. Chem Biol 2011; 18: 1474-1481
- 19 Park WH, Han YW, Kim SW, Kim SH, Cho KW, Kim SZ. Antimycin A induces apoptosis in As4.1 juxtaglomerular cells. Cancer Lett 2007; 251: 68-77
- 20 Schwartz PS, Manion MK, Emerson CB, Fry JS, Schulz CM, Sweet IR, Hockenbery DM. 2-Methoxy antimycin reveals a unique mechanism for Bcl-x(L) inhibition. Mol Cancer Ther 2007; 6: 2073-2080
- 21 Schwartz PS, Hockenbery DM. Targeted therapies for epithelial cancers: in vivo efficacy of the Bcl-2/Bcl-xL inhibitor 2-MeAA. Cancer Biol Ther 2007; 6: 465-466
- 22 Minn AJ, Rudin CM, Boise LH, Thompson CB. Expression of Bcl-xL can confer a multidrug resistance phenotype. Blood 1995; 86: 1903-1910
- 23 Decaudin D, Geley S, Hirsch T, Castedo M, Marchetti P, Macho A, Kofler R, Kroemer G. Bcl-2 and Bcl-xL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents. Cancer Res 1997; 57: 62-67
- 24 Alam MP, Khdour OM, Arce PM, Chen Y, Roy B, Johnson WG, Dey S, Hecht SM. Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases. Bioorg Med Chem 2014; 22: 4935-4947
- 25 Fash DM, Khdour OM, Sahdeo SJ, Goldschmidt R, Jaruvangsanti J, Dey S, Arce PM, Collin VC, Cortopassi GA, Hecht SM. Effects of alkyl side chain modification of coenzyme Q10 on mitochondrial respiratory chain function and cytoprotection. Bioorg Med Chem 2013; 21: 2346-2354