Effect of tetrahydroquinoline derivatives on the intracellular Ca2+ homeostasis in breast cancer cells (MCF-7) and its relationship with apoptosis.
Efecto de derivados de tetrahidroquinolinas sobre la homeostasis del Ca2+ intracelular en células de cáncer de mama (MCF-7) y su relación con la apoptosis.
Keywords:
Ca2, apoptosis, tetrahydroquinolines, mitocondria, SERCA, NF-κB
Abstract
Tetrahydroquinoline derivatives are interesting structures exhibiting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92 on apoptosis, intracellular Ca2+ concentration ([Ca2+]i), and the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity was determined on MCF-7 breast cancer cells. Colorimetric assays were used to assess MCF-7 cells viability and SERCA activity. Fura-2 and rhodamine 123 were used to measure the intracellular Ca2+ concentration and the mitochondrial electrochemical potential, respec-tively. TUNEL assay was used to analyze DNA fragmentation, while caspase activity and NF-κB-dependent gene expression were assessed by luminescence. In silico models were used for molecular docking analysis. These compounds increase intracellular Ca2+ concentration; the main contribution is the Ca2+ entry from the extracellular milieu. Both JS-56 and JS-92 inhibit the activity of SERCA and dissipate the mitochondrial electrochemical potential through processes dependent and independent of the Ca2+ uptake by this organelle. Furthermore, JS-56 and JS-92 generate cytotoxicity in MCF-7 cells. The effect of JS-92 is higher than JS-56. Both compounds activate caspases 7 and 9, cause DNA fragmentation, and potentiate the effect of phorbol 12-myristate-13-acetate on NF-κB-dependent gene expression. Molecular docking analysis suggests that both compounds have a high interaction for SERCA, similar to thapsigargin. Both tetrahydroquinoline derivatives induced cell death through a combination of apoptotic events, increase [Ca2+]i, and inhibit SERCA activity by direct interaction.
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References
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Kagawa S, Gu J, Honda T, McDonnell TJ, Swisher SG, Roth JA, Fang B. Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation but not cell death. Clin Cancer Res 2001;7:1474–1480.
Obara K, Miyashita N, Xu C, Toyoshima I, Sugita Y, Inesi G, Toyoshima C. Structural role of countertransport revealed in Ca2+ pump crystal structure in the absence of Ca2+. Proc Natl Acad Sci 2005;102:14489– 14496.
Guex N, Peitsch MC. SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling. Electrophoresis 1997;18:2714–2723.
Fusi F, Saponara S, Gagov H, Sgaragli G. 2,5-Di-t-butyl-1,4 benzohydroquinone (BHQ) inhibits vascular L -type Ca2+ channel via superoxide anion generation. Br J Pharmacol 2001;133:988–996.
Lytton J, Westlin M, Hanley MR. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem 1991;266:17067– 17071.
Thompson M. ArgusLab 4.0 Planaria Software. LLC: Seatle, WA. 2004. Becke AD. A new mixing of Hartree–Fock and local density‐functional theories. J Chem Phys 1993;98:1372–1377.
Young DC. Computational Drug Design. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2009.
Colina C, Flores A, Rojas H, Acosta A, Castillo C, Rosario Garrido M del, Israel A, DiPolo R, Benaim G. Ceramide increase cytoplasmic Ca2+ concentration in Jurkat T cells by liberation of calcium from intracellular stores and activation of a store-operated calcium channel. Arch Biochem Biophys 2005;436:333–345.
Moore GA, McConkey DJ, Kass GEN, O’Brien PJ, Orrenius S. 2,5-Di(tertbutyl)-1,4-benzohydroquinone - a novel inhibitor of liver microsomal Ca2+ sequestration. FEBS Lett 1987;224:331–336.
Tang D, Lahti JM, Kidd VJ. Caspase-8 activation and bid cleavage contribute to MCF7 cellular execution in a caspase-3-dependent manner during staurosporine-mediated apoptosis. J Biol Chem 2000;275:9303– 9307.
Schmitz ML, Bacher S, Dienz O. NF‐ĸB activation pathways induced by T cell costimulation. FASEB J 2003;17:2187–2193.
Lee WJ, Monteith GR, Roberts-Thomson SJ. Calcium transport and signaling in the mammary gland: Targets for breast cancer. Biochim Biophys Acta - Rev Cancer 2006;1765:235–255.
Tadini-Buoninsegni F, Smeazzetto S, Gualdani R, Moncelli MR. Drug interactions with the Ca2+-ATPase from sarco (endo) plasmic reticulum (SERCA). Front Mol Biosci 2018;5:36.
Demaurex N. Cell biology: Apoptosis--the calcium connection. Science 2003;300:65– 67.
Vercesi AE, Moreno SN, Bernardes CF, Meinicke AR, Fernandes EC, Docampo R. Thapsigargin causes Ca2+ release and collapse of the membrane potential of Trypanosoma brucei mitochondria in situ and of isolated rat liver mitochondria. J Biol Chem 1993;268:8564–8568.
Peart O. Breast intervention and breast cancer treatment options. Radiol Technol 2015;86:535M-558M; quiz 559–62.
Sergeev IN, Li S, Colby J, Ho C-T, Dushenkov S. Polymethoxylated flavones induce Ca2+-mediated apoptosis in breast cancer cells. Life Sci 2006;80:245–253.
Sareen D, Darjatmoko SR, Albert DM, Polans AS. Mitochondria, calcium, and calpain are key mediators of Resveratrol-induced apoptosis in breast cancer. Mol Pharmacol 2007;72:1466–1475.
Lee J-H, Li Y-C, Ip S-W, Hsu S-C, Chang N-W, Tang N-Y, Yu C-S, Chou S-T, Lin S-S, Lino C-C, Yang J-S, Chung J-G. The role of Ca2+ in baicalein-induced apopto- sis in human breast MDA-MB-231 cancer cells through mitochondria- and caspa- se-3-dependent pathway. Anticancer Res 2008;28:1701–1711.
Pimentel AA, Felibertt P, Sojo F, Colman L, Mayora A, Silva ML, Rojas H, Dipolo R, Suarez AI, Compagnone RS, Arvelo F, Galindo-Castro I, De Sanctis JB, Chirino P, Benaim G. The marine sponge toxin agelasine B increases the intracellular Ca2+ concentration and induces apoptosis in human breast cancer cells (MCF-7). Cancer Chemother Pharmacol 2012;69:71–83.
Zhang Z, Teruya K, Eto H, Shirahata S. Induction of apoptosis by low molecular-weight fucoidan through calcium and caspase-dependent mitochondrial pathways in MDA-MB-231 breast cancer cells. Biosci Biotechnol Biochem 2013;77:235–242.
Al-Taweel N, Varghese E, Florea A-M, Büsselberg D. Cisplatin (CDDP) triggers cell death of MCF-7 cells following disruption of intracellular calcium ([Ca2+]i) homeostasis. J Toxicol Sci 2014;39:765–774.
Sehgal P, Szalai P, Olesen C, Praetorius HA, Nissen P, Christensen SB, Engedal N, Møller J V. Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response. J Biol Chem 2017;292:19656– 19673.
Carafoli E. Calcium signaling: A tale for all seasons. Proc Natl Acad Sci 2002;99:1115– 1122.
Carafoli E. Intracellular calcium homeostasis. Annu Rev Biochem 1987;56:395–433.
Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003;22:8608–8618.
Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress‐induced apoptosis. EMBO Rep 2006;7:880–885.
Rizzuto R, Bernardi P, Pozzan T. Mitochondria as all‐round players of the calcium game. J Physiol 2000;529:37–47.
Hengartner MO. The biochemistry of apoptosis. Nature 2000;407:770–776.
Kouznetsov V V, Bello Forero JS, Amado Torres DF. A simple entry to novel spiro dihydroquinoline-oxindoles using Povarov reaction between 3-N-aryliminoisatins and isoeugenol. Tetrahedron Lett 2008; doi: 10.1016/j.tetlet.2008.07.096.
Kouznetsov V, R. Merchan Arenas D, Arvelo F, S. Bello Forero J, Sojo F, Munoz 4-Hydroxy-3-methoxyphenyl substituted 3-methyl-tetrahydroquinoline derivatives obtained through Imino Diels-Alder reactions as potential antitumoral agents. Lett Drug Des Discov 2010;7:632–639.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63.
Colina C, Flores A, Castillo C, Rosario Garrido M del, Israel A, DiPolo R, Benaim G. Ceramide-1-P induces Ca2+ mobilization in Jurkat T-cells by elevation of Ins(1,4,5)-P3 and activation of a store-operated calcium channel. Biochem Biophys Res Commun 2005;336:54–60.
Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985;260:3440–3450.
Eletr S, Inesi G. Phospholipid orientation in sacroplasmic membranes: Spin-label ESR and proton NMR studies. Biochim Biophys Acta - Biomembr 1972;282:174–179.
Fiske CH, Subbarow Y. The colorimetric determination of phosphorus. J Biol Chem 1925;66:375–400.
Benaim G, Cervino V, Lopez-Estraño C, Weitzman C. Ethanol stimulates the plasma membrane calcium pump from human erythrocytes. Biochim Biophys Acta Bio membr 1994;1195:141–148.
Benaim G, Sanders JM, Garcia-Marchán Y, Colina C, Lira R, Caldera AR, Payares G, Sanoja C, Burgos JM, Leon-Rossell A, Concepcion JL, Schijman AG, Levin M, Oldfield E, Urbina JA. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole. J Med Chem 2006;49:892–899.
Kagawa S, Gu J, Honda T, McDonnell TJ, Swisher SG, Roth JA, Fang B. Deficiency of caspase-3 in MCF7 cells blocks Bax-mediated nuclear fragmentation but not cell death. Clin Cancer Res 2001;7:1474–1480.
Obara K, Miyashita N, Xu C, Toyoshima I, Sugita Y, Inesi G, Toyoshima C. Structural role of countertransport revealed in Ca2+ pump crystal structure in the absence of Ca2+. Proc Natl Acad Sci 2005;102:14489– 14496.
Guex N, Peitsch MC. SWISS-MODEL and the Swiss-Pdb Viewer: An environment for comparative protein modeling. Electrophoresis 1997;18:2714–2723.
Fusi F, Saponara S, Gagov H, Sgaragli G. 2,5-Di-t-butyl-1,4 benzohydroquinone (BHQ) inhibits vascular L -type Ca2+ channel via superoxide anion generation. Br J Pharmacol 2001;133:988–996.
Lytton J, Westlin M, Hanley MR. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem 1991;266:17067– 17071.
Thompson M. ArgusLab 4.0 Planaria Software. LLC: Seatle, WA. 2004. Becke AD. A new mixing of Hartree–Fock and local density‐functional theories. J Chem Phys 1993;98:1372–1377.
Young DC. Computational Drug Design. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2009.
Colina C, Flores A, Rojas H, Acosta A, Castillo C, Rosario Garrido M del, Israel A, DiPolo R, Benaim G. Ceramide increase cytoplasmic Ca2+ concentration in Jurkat T cells by liberation of calcium from intracellular stores and activation of a store-operated calcium channel. Arch Biochem Biophys 2005;436:333–345.
Moore GA, McConkey DJ, Kass GEN, O’Brien PJ, Orrenius S. 2,5-Di(tertbutyl)-1,4-benzohydroquinone - a novel inhibitor of liver microsomal Ca2+ sequestration. FEBS Lett 1987;224:331–336.
Tang D, Lahti JM, Kidd VJ. Caspase-8 activation and bid cleavage contribute to MCF7 cellular execution in a caspase-3-dependent manner during staurosporine-mediated apoptosis. J Biol Chem 2000;275:9303– 9307.
Schmitz ML, Bacher S, Dienz O. NF‐ĸB activation pathways induced by T cell costimulation. FASEB J 2003;17:2187–2193.
Lee WJ, Monteith GR, Roberts-Thomson SJ. Calcium transport and signaling in the mammary gland: Targets for breast cancer. Biochim Biophys Acta - Rev Cancer 2006;1765:235–255.
Tadini-Buoninsegni F, Smeazzetto S, Gualdani R, Moncelli MR. Drug interactions with the Ca2+-ATPase from sarco (endo) plasmic reticulum (SERCA). Front Mol Biosci 2018;5:36.
Demaurex N. Cell biology: Apoptosis--the calcium connection. Science 2003;300:65– 67.
Vercesi AE, Moreno SN, Bernardes CF, Meinicke AR, Fernandes EC, Docampo R. Thapsigargin causes Ca2+ release and collapse of the membrane potential of Trypanosoma brucei mitochondria in situ and of isolated rat liver mitochondria. J Biol Chem 1993;268:8564–8568.
Published
2022-08-22
How to Cite
Maksoud, S., Mayora, A., Colman, L., Sojo, F., Pimentel, A. A., Kouznetsov, V. V., Merchán-Arenas, D. R., Romero, Ángel H., Arvelo, F., De Sanctis, J. B., & Benaim, G. (2022). Effect of tetrahydroquinoline derivatives on the intracellular Ca2+ homeostasis in breast cancer cells (MCF-7) and its relationship with apoptosis.: Efecto de derivados de tetrahidroquinolinas sobre la homeostasis del Ca2+ intracelular en células de cáncer de mama (MCF-7) y su relación con la apoptosis. Investigación Clínica, 63(3), 243-261. https://doi.org/10.54817/IC.v63n3a04
Section
Original Works
