Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Assessment of the Cytotoxic and Apoptotic Effects of Chaetominine in a Human Leukemia Cell Line

  • Yao, Jingyun (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Jiao, Ruihua (Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University) ;
  • Liu, Changqing (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Zhang, Yupeng (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Yu, Wanguo (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Lu, Yanhua (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Tan, Renxiang (Institute of Functional Biomolecules, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University)
  • Received : 2015.07.06
  • Accepted : 2016.01.07
  • Published : 2016.03.01
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Abstract

Chaetominine is a quinazoline alkaloid originating from the endophytic fungus Aspergillus fumigatus CY018. In this study, we showed evidence that chaetominine has cytotoxic and apoptotic effects on human leukemia K562 cells and investigated the pathway involved in chaetominine-induced apoptosis in detail. Chaetominine inhibited K562 cell growth, with an $IC_{50}$ value of 35 nM, but showed little inhibitory effect on the growth of human peripheral blood mononuclear cells. The high apoptosis rates, morphological apoptotic features, and DNA fragmentation caused by chaetominine indicated that the cytotoxicity was partially caused by its pro-apoptotic effect. Under chaetominine treatment, the Bax/Bcl-2 ratio was upregulated (from 0.3 to 8), which was followed by a decrease in mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, and stimulation of Apaf-1. Furthermore, activation of caspase-9 and caspase-3, which are the main executers of the apoptotic process, was observed. These results demonstrated that chaetominine induced cell apoptosis via the mitochondrial pathway. Chaetominine inhibited K562 cell growth and induced apoptotic cell death through the intrinsic pathway, which suggests that chaetominine might be a promising therapeutic for leukemia.

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References

  1. Adams, J. M. and Cory, S. (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26,1324-1337. https://doi.org/10.1038/sj.onc.1210220
  2. Araujo, A. J., de Souza, A. A., da Silva Junior, E. N., Marinho-Filho, J. D., de Moura, M. A., Rocha, D. D., Vasconcellos, M. C., Costa, C. O., Pessoa, C., de Moraes, M. O., Ferreira, V. F., de Abreu, F. C., Pinto, A. V., Montenegro, R. C., Costa-Lotufo, L. V. and Goulart, M. O. (2012) Growth inhibitory effects of 3'-nitro-3-phenylamino norbeta- lapachone against HL-60: a redox-dependent mechanism. Toxicol. In Vitro 26, 585-594. https://doi.org/10.1016/j.tiv.2012.02.003
  3. Babu, Y. R., Bhagavanraju, M., Reddy, G. D., Peters, G. J. and Prasad, V. V. (2014) Design and synthesis of quinazolinone tagged acridones as cytotoxic agents and their effects on EGFR tyrosine kinase. Arch. Pharm. (Weinheim) 347, 624-634. https://doi.org/10.1002/ardp.201400065
  4. Beesoo, R., Neergheen-Bhujun, V., Bhagooli, R. and Bahorun, T. (2014) Apoptosis inducing lead compounds isolated from marine organisms of potential relevance in cancer treatment. Mutat. Res. 768, 84-97. https://doi.org/10.1016/j.mrfmmm.2014.03.005
  5. Belofsky, G. N., Anguera, M., Jensen, P. R., Fenical, W. and Köck, M. (2000) Oxepinamides A-C and fumiquinazolines H-I: bioactive metabolites from a marine isolate of a fungus of the genus Acremonium. Chemistry 6, 1355-1360. https://doi.org/10.1002/(SICI)1521-3765(20000417)6:8<1355::AID-CHEM1355>3.0.CO;2-S
  6. Brown, J. M. and Attardi, L. D. (2005) The role of apoptosis in cancer development and treatment response. Nat. Rev. Cancer 5, 231-237. https://doi.org/10.1038/nrc1560
  7. Chau, M., Phan, K. and Nguyen, D. (2005) Marine natural products and their potential application in the future. AJSTD 22, 297-311.
  8. Choi, D. W., Lim, M. S., Lee, J. W., Chun, W., Lee, S. H., Nam, Y. H., Park, J. M., Choi, D. H., Kang, C. D., Lee, S. J. and Park, S. C. (2015) The Cytotoxicity of Kahweol in HT-29 Human Colorectal Cancer Cells Is Mediated by Apoptosis and Suppression of Heat Shock Protein 70 Expression. Biomol. Ther. (Seoul) 23, 128-133. https://doi.org/10.4062/biomolther.2014.133
  9. Czabotar, P. E., Lessene, G., Strasser, A. and Adams, J. M. (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49-63. https://doi.org/10.1038/nrm3722
  10. Dalla Via, L., Garcia-Argaez, A. N., Martinez-Vazquez, M., Grancara, S., Martinis, P. and Toninello, A. (2014) Mitochondrial permeability transition as target of anticancer drugs. Curr. Pharm. Des. 20, 223-244. https://doi.org/10.2174/13816128113199990033
  11. Danial, N. N. and Korsmeyer, S. J. (2004) Cell death: critical control points. Cell 116, 205-219. https://doi.org/10.1016/S0092-8674(04)00046-7
  12. Finkel, T., Serrano, M. and Blasco, M. A. (2007) The common biology of cancer and ageing. Nature 448, 767-774. https://doi.org/10.1038/nature05985
  13. Helleday, T., Petermann, E., Lundin, C., Hodgson, B. and Sharma, R. A. (2008) DNA repair pathways as targets for cancer therapy. Nat. Rev. Cancer 8, 193-204. https://doi.org/10.1038/nrc2342
  14. Jang, Y. J., Won, J. H., Back, M. J., Fu, Z., Jang, J. M., Ha, H. C., Hong, S., Chang, M. and Kim, D. K. (2015) Paraquat Induces Apoptosis through a Mitochondria-Dependent Pathway in RAW264.7 Cells. Biomol. Ther. (Seoul) 23, 407-413. https://doi.org/10.4062/biomolther.2015.075
  15. Jiao, R. H., Xu, S., Liu, J. Y., Ge, H. M., Ding, H., Xu, C., Zhu, H. L. and Tan, R. X. (2006) Chaetominine, a cytotoxic alkaloid produced by endophytic chaetomium sp. IFB-E015. Org. Lett. 8, 5709-5712. https://doi.org/10.1021/ol062257t
  16. Kaminskyy, V., Kulachkovskyy, O. and Stoika, R. (2008) A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids. Toxicol. Lett. 177, 168-181. https://doi.org/10.1016/j.toxlet.2008.01.009
  17. Kroemer, G., Galluzzi, L. and Brenner, C. (2007) Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99-163. https://doi.org/10.1152/physrev.00013.2006
  18. Lamkanfi, M., Festjens, N., Declercq, W., Vanden Berghe, T. and Vandenabeele, P. (2007) Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 14, 44-55. https://doi.org/10.1038/sj.cdd.4402047
  19. Lemasters, J. J. (2005) Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis. Gastroenterology 129, 351-360. https://doi.org/10.1053/j.gastro.2005.06.006
  20. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S. M., Ahmad, M., Alnemri, E. S. and Wang, X. (1997) Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479-489. https://doi.org/10.1016/S0092-8674(00)80434-1
  21. Liu, Z., Zhao, Y., Li, J., Xu, S., Liu, C., Zhu, Y. and Liang, S. (2012) The venom of the spider Macrothele raveni induces apoptosis in the myelogenous. Leuk. Res. 36, 1063-1066. https://doi.org/10.1016/j.leukres.2012.02.025
  22. Lu, Y., Zhu, Y., Jiao, R., Tan, R., Yao, L. And Hu, W., inventors; Univ. East. China Science & Tech. and Univ. Nanjing, assignee. [Method of preparing fumigaclavine C by symbiotic aspergillus fumigatus of sea crab and culture medium of fumigaclavine C]. Chinese patent CN 103849663. 2014 Jun 11. Chinese.
  23. Luo, M., Liu, X., Zu, Y., Fu, Y., Zhang, S., Yao, L. and Efferth, T. (2010) Cajanol, a novel anticancer agent from Pigeonpea [Cajanus cajan (L.) Millsp.] roots, induces apoptosis in human breast cancer cells through a ROS-mediated mitochondrial pathway. Chem. Biol. Interact. 188, 151-160. https://doi.org/10.1016/j.cbi.2010.07.009
  24. Luo, S.-P., Peng, Q.-L., Xu, C.-P., Wang, A.-E. and Huang, P.-Q. (2014) Bio-inspired step-economical, redox-economical and protectinggroup- free enantioselective total syntheses of (-)-chaetominine and analogues. Chin. J. Chem. 32, 757-770. https://doi.org/10.1002/cjoc.201400413
  25. Martinou, J. C. and Youle, R. J. (2011) Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev. Cell 21, 92-101. https://doi.org/10.1016/j.devcel.2011.06.017
  26. Nakao Y, Kuo J, Yoshida, W. Y., Kelly, M. and Scheuer, P. J. (2003) More kapakahines from the marine sponge Cribrochalina olemda. Org. Lett. 5, 1387-1390. https://doi.org/10.1021/ol026830u
  27. Newman, D. J. and Cragg, G. M. (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75, 311-335. https://doi.org/10.1021/np200906s
  28. Pradelli, L. A., Beneteau, M. and Ricci, J. E. (2010) Mitochondrial control of caspase-dependent and -independent cell death. Cell. Mol. Life Sci. 67, 1589-1597. https://doi.org/10.1007/s00018-010-0285-y
  29. Riedl, S. J. and Salvesen, G. S. (2007) The apoptosome: signalling platform of cell death. Nat. Rev. Mol. Cell Biol. 8, 405-413.
  30. Rieger, A. M., Nelson, K. L., Konowalchuk, J. D. and Barreda, D. R. (2011) Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. J. Vis. Exp. 50, e2597.
  31. Rovini, A., Savry, A., Braguer, D. and Carre, M. (2011) Microtubuletargeted agents: When mitochondria become essential to chemotherapy. Biochim. Biophys. Acta 1807, 679-688. https://doi.org/10.1016/j.bbabio.2011.01.001
  32. Sarfaraj, H. M., Sheeba, F., Saba, A. and Mohd, S. K. (2012) Marine natural products: a lead for anti-cancer. Indian J. Geomarine Sci. 41, 27-39.
  33. Urra, F. A., Cordova-Delgado, M., Pessoa-Mahana, H., Ramirez-Rodriguez, O., Weiss-Lopez, B., Ferreira, J. and Araya-Maturana, R. (2013) Mitochondria: a promising target for anticancer alkaloids. Curr. Top. Med. Chem. 13, 2171-2183. https://doi.org/10.2174/15680266113139990150
  34. Vinothkumar, S. and Parameswaran, P. S. (2013) Recent advances in marine drug research. Biotechnol. Adv. 31, 1826-1845. https://doi.org/10.1016/j.biotechadv.2013.02.006
  35. Wink, M. (2007) Molecular modes of action of cytotoxic alkaloids: from DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance. Alkaloids Chem. Biol. 64, 1-47. https://doi.org/10.1016/S1099-4831(07)64001-2
  36. Zhang, L., Wang, H., Xu, J., Zhu, J. and Ding, K. (2014) Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways. Toxicol. Lett. 228, 248-259. https://doi.org/10.1016/j.toxlet.2014.05.015

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