Diterpenylhydroquinones from Natural ent-Labdanes Induce Apoptosis through Decreased Mitochondrial Membrane Potential
Abstract
:1. Introduction
- (1)
- redox cycling of quinones, resulting in generation of reactive oxygen species which can damage biomolecules, and inhibition of the mitochondrial function;
- (2)
- electrophilic arylation of critical cellular nucleophiles, either by quinones or quinonemethides formed after bioreductive activation of quinones [27].
2. Results and Discussion
Compounds | MDA-MB 231 | DU-145 | DHF |
---|---|---|---|
1 | 21.3 ± 3.1 * | 22.7 ± 3.5 * | 10.1 ± 2.0 |
2 | 29.4 ± 4.3 * | 21.4 ± 3.3 * | 7.7 ± 1.1 |
3 | 18.9 ± 2.1 * | 24.5 ± 3.4 * | 8.4 ± 1.3 |
6 | 4.2 ± 0.9 | 6.8 ± 0.8 | 6.1 ± 0.9 |
7 | 8.7 ± 1.2 | 11.0 ± 1.3 | 8.9 ± 1.4 |
EtOH 1% | 7.0 ± 1.3 | 8.6 ± 1.0 | 5.0 ± 1.0 |
Staurosporin | 35.4 ± 5.1 * | 42.9 ± 4.9 * | 36.8 ± 5.0 * |
3. Experimental
3.1. Cell Lines
3.2. Morphological Assessment of Cell Apoptosis
Hoechst 33342
3.3. Analysis of Mitochondrial Transmembrane Potential
3.4. Caspase 3 Activity Assay
3.5. Statistical Analyses
4. Conclusions
Acknowledgments
Conflicts of Interest
References
- Reddy, L.; Odhav, B.; Bhoola, K.D. Natural products for cancer prevention: A global perspective. Pharmacol. Ther. 2003, 99, 1–13. [Google Scholar] [CrossRef]
- Mann, J. Natural products in cancer chemotherapy: Past, present and future. Nat. Rev. Cancer 2002, 2, 143–148. [Google Scholar] [CrossRef]
- Li, W.; Lam, M.S.; Birkeland, A.; Riffel, A.; Montana, L.; Sullivan, M.E.; Post, J.M. Cell-based assays for profiling activity and safety properties of cancer drugs. J. Pharmacol. Toxicol. Methods 2006, 54, 313–319. [Google Scholar] [CrossRef]
- Guy, M.; John, A.H. Apoptosis and cancer chemotherapy. Cell Tissue Res. 2000, 301, 143–152. [Google Scholar] [CrossRef]
- Ghobrial, I.M.; Witzig, T.E.; Adjei, A.A. Targeting apoptosis pathways in cancer therapy. CA Cancer J. Clin. 2005, 55, 178–194. [Google Scholar] [CrossRef]
- Wyllie, A.H. Apoptosis: An overview. Br. Med. Bull. 1997, 53, 451–465. [Google Scholar] [CrossRef]
- Fleischer, A.; Ghadiri, A.; Dessauge, A.F.; Duhamela, M.; Rebollo, M.P.; Alvarez-Franco, F.; Rebollo, A. Modulating apoptosis as a target for effective therapy. Mol. Immunol. 2006, 43, 1065–1079. [Google Scholar] [CrossRef]
- Kim, R.; Emi, M.; Tanabe, K. Role of mitochondria as the gardens of cell death. Cancer Chemother. Pharmacol. 2006, 57, 545–553. [Google Scholar] [CrossRef]
- Guimaraes, A.C.; Linden, R. Programmed cell death. Apoptosis and alternative death styles. Eur. J. Biochem. 2004, 271, 1638–1650. [Google Scholar] [CrossRef]
- Lemasters, J.J.; Nieminen, A.L.; Qian, T.; Trost, L.C.; Elmore, S.P.; Nishimura, Y.; Crowe, R.A.; Cascio, W.E.; Bradham, C.A.; Brenner, D.A.; Herman, B. The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta 1998, 1366, 177–196. [Google Scholar] [CrossRef]
- Mattson, M.P.; Kroemer, G. Mitochondria in cell death: Novel targets for neuroprotection and cardioprotection. Trends Mol. Med. 2003, 9, 196–205. [Google Scholar] [CrossRef]
- Reed, J.C.; Tomaselli, K.J. Drug discovery opportunities from apoptosis research. Curr. Opin. Biotechnol. 2000, 11, 586–592. [Google Scholar] [CrossRef]
- Fesik, S.W. Promoting apoptosis as a strategy for cancer drug discovery. Nat. Rev. Cancer. 2005, 5, 876–885. [Google Scholar] [CrossRef]
- Fischer, U.; Janssen, K.; Schulze-Osthoff, K. Cutting-edge apoptosis-based therapeutics: A panacea for cancer? BioDrugs 2007, 21, 273–297. [Google Scholar] [CrossRef]
- Fischer, U.; Schulze-Osthoff, K. New approaches and therapeutics targeting apoptosis in disease. Pharmacol. Rev. 2005, 57, 187–215. [Google Scholar] [CrossRef]
- Garbarino, J.A.; Chamy, M.C.; Piovano, M. Chemistry of the calceolaria genus. Structural and biological aspects. Molecules 2000, 5, 302–303. [Google Scholar] [CrossRef]
- Woldemichael, G.M.; Wachter, G.; Singh, M.P.; Maiese, W.M.; Timmermann, B.N. Antibacterial Diterpenes from Calceolaria pinifolia. J. Nat. Prod. 2003, 66, 242–246. [Google Scholar] [CrossRef]
- Villagran, C.; Romo, M.; Castro, V. Etnobotánica del sur de los andes de la primera región de Chile: un enlace entre las culturas altiplánicas y las de quebradas altas del loa superior. Chungará (Arica) 2003, 35, 73–124. [Google Scholar]
- Garbarino, J.A.; Chamy, M.C.; Piovano, M.; Espinoza, L.; Belmonte, E. Diterpenoids from Calceolaria inamoena. Phytochemistry 2004, 65, 903–908. [Google Scholar]
- Espinoza, L.; Carrasco, H.; Cuellar, M.; Gallardo, C.; Catalán, K. Oxidative degradations of the side chain of unsaturated Ent-labdanes. Part I. Molecules 2007, 12, 318–327. [Google Scholar] [CrossRef]
- Espinoza, L.; Catalán, K.; Carrasco, H.; Cuellar, M.; Chamy, M.C. Oxidative degradations of the side chain of unsaturated Ent-labdanes. Part II. Molecules 2007, 12, 2605–2620. [Google Scholar] [CrossRef]
- Espinoza, L.; Catalán, K.; Madrid, A.; Carrasco, H.; Villena, J.; Cuellar, M. Synthesis of two new hemisynthetic diterpenylhydroquinones from natural Ent-labdanes. Molecules 2009, 14, 2181–2194. [Google Scholar] [CrossRef]
- Espinoza, L.; Baeza, E.; Catalán, K.; Osorio, M.; Carrasco, H.; Cuellar, M.; Villena, J. Synthesis and antitumor activity of diterpenylhydroquinone derivatives of natural Ent-labdanes. Molecules 2010, 15, 6502–6511. [Google Scholar] [CrossRef]
- Del Corral, J.M.; Gordaliza, M.; Castro, M.A.; Mahiques, M.M.; Chamorro, P.; Molinari, A.; García-Grávalos, M.D.; Broughton, H.B.; San Feliciano, A. New selective cytotoxic diterpenylquinones and diterpenylhydroquinones. J. Med. Chem. 2001, 44, 1257–1267. [Google Scholar] [CrossRef]
- O'Brien, P.J. Molecular mechanisms of quinone cytotoxicity. Chem. Biol. Interact. 1991, 80, 1–41. [Google Scholar] [CrossRef]
- Henry, R.T.; Wallace, B.K. Different mechanisms of cell killing by redox cycling and arylating quinones. Arch. Toxicol. 1996, 70, 482–489. [Google Scholar] [CrossRef]
- Guilivi, C.; Cadenas, E. One- and two-electron reduction of 2-methyl-1,4-naphthoquinone bioreductive alkylating agents: Kinetic studies, free-radical production, thiol oxidation and DNAstrand-break formation. Biochem. J. 1994, 301, 21–30. [Google Scholar]
- Kamb, A.; Lassota, P. Disease models of cancer: Apoptosis. Drug Discov. Today Dis. Models 2004, 1, 31–36. [Google Scholar] [CrossRef]
- Kobayashi, J.; Naitoh, K.; Sasaki, T.; Shigemori, H. Metachromins D-H, new cytotoxic sesquiterpenoids from the Okinawan marine sponge Hippospongia metachromia. J. Org. Chem. 1992, 57, 5773–5776. [Google Scholar] [CrossRef]
- Brüggemann, M.; Holst, C.; Hoppe, D. First enantioselective total synthesis of both (+)- and (−)-Metachromin A. Eur. J. Org. Chem. 2001, 4, 647–654. [Google Scholar]
- Emaus, R.K.; Grunwald, R.; Lemaster, J.J. Rhodamine 123 as a probe of transmembrane potential in isolated rat-liver mitochondria: Spectral and metabolic properties. Biochim. Biophys. Acta 1986, 850, 436–448. [Google Scholar] [CrossRef]
- Day, T.W.; Wu, C.H.; Safa, A.R. Etoposide induces protein kinase C Cδ- and caspase 3 dependent apoptosis in neuroblastoma cancer cells. Mol. Pharmacol. 2009, 76, 632–640. [Google Scholar] [CrossRef]
- Sample Availability: Samples of the compounds 1–7 are available from the authors.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Share and Cite
Villena, J.; Madrid, A.; Montenegro, I.; Werner, E.; Cuellar, M.; Espinoza, L. Diterpenylhydroquinones from Natural ent-Labdanes Induce Apoptosis through Decreased Mitochondrial Membrane Potential. Molecules 2013, 18, 5348-5359. https://doi.org/10.3390/molecules18055348
Villena J, Madrid A, Montenegro I, Werner E, Cuellar M, Espinoza L. Diterpenylhydroquinones from Natural ent-Labdanes Induce Apoptosis through Decreased Mitochondrial Membrane Potential. Molecules. 2013; 18(5):5348-5359. https://doi.org/10.3390/molecules18055348
Chicago/Turabian StyleVillena, Joan, Alejandro Madrid, Iván Montenegro, Enrique Werner, Mauricio Cuellar, and Luis Espinoza. 2013. "Diterpenylhydroquinones from Natural ent-Labdanes Induce Apoptosis through Decreased Mitochondrial Membrane Potential" Molecules 18, no. 5: 5348-5359. https://doi.org/10.3390/molecules18055348