Assessment of the Cytotoxic and Apoptotic Effects of Chaetominine in a Human Leukemia Cell Line

다국어 초록 (Multilingual 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 IC50 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.

참고문헌 (Reference)

1 Liu, Z, "The venom of the spider Macrothele raveni induces apoptosis in the myelogenous" 36 : 1063-1066, 2012

2 Brown, J. M, "The role of apoptosis in cancer development and treatment response" 5 : 231-237, 2005

3 Finkel, T, "The common biology of cancer and ageing" 448 : 767-774, 2007

4 Riedl, S. J, "The apoptosome: signalling platform of cell death" 8 : 405-413, 2007

5 최동욱, "The Cytotoxicity of Kahweol in HT-29 Human Colorectal Cancer Cells Is Mediated by Apoptosis and Suppression of Heat Shock Protein 70 Expression" 한국응용약물학회 23 (23): 128-133, 2015

6 Adams, J. M, "The Bcl-2 apoptotic switch in cancer development and therapy" 26 : 1324-1337, 2007

7 Vinothkumar, S, "Recent advances in marine drug research" 31 : 1826-1845, 2013

8 Luo, S.-P, "QBio-inspired step-economical, redox-economical and protectinggroup-free enantioselective total syntheses of (-)-chaetominine and analogues" 32 : 757-770, 2014

9 장여진, "Paraquat Induces Apoptosis through a Mitochondria-Dependent Pathway in RAW264.7 Cells" 한국응용약물학회 23 (23): 407-413, 2015

10 Belofsky, G. N, "Oxepinamides A-C and fumiquinazolines H-I: bioactive metabolites from a marine isolate of a fungus of the genus Acremonium" 6 : 1355-1360, 2000

11 Newman, D. J, "Natural products as sources of new drugs over the 30 years from 1981 to 2010" 75 : 311-335, 2010

12 Nakao Y, "More kapakahines from the marine sponge Cribrochalina olemda" 5 : 1387-1390, 2003

13 Wink, M, "Molecular modes of action of cytotoxic alkaloids: from DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance" 64 : 1-47, 2007

14 Rieger, A. M, "Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death" 50 : e2597-, 2011

15 Dalla Via, L, "Mitochondrial permeability transition as target of anticancer drugs" 20 : 223-244, 2014

16 Pradelli, L. A, "Mitochondrial control of caspase-dependent and -independent cell death" 67 : 1589-1597, 2010

17 Urra, F. A, "Mitochondria: a promising target for anticancer alkaloids" 13 : 2171-2183, 2013

18 Martinou, J. C, "Mitochondria in apoptosis: Bcl-2family members and mitochondrial dynamics" 21 : 92-101, 2011

19 Rovini, A, "Microtubuletargeted agents: When mitochondria become essential to chemotherapy" 1807 : 679-688, 2011

20 Lu, Y, "Method of preparing fumigaclavine C by symbiotic aspergillus fumigatus of sea crab and culture medium of fumigaclavine C, Chinese patent CN 103849663"

21 Sarfaraj, H. M, "Marine natural products: a lead for anti-cancer" 41 : 27-39, 2012

22 Chau, M, "Marine natural products and their potential application in the future" 22 : 297-311, 2005

23 Kroemer, G, "Kroemer, G., Galluzzi, L. and Brenner, C. (2007) Mitochondrial membrane permeabilization in cell death" 87 : 99-163, 2007

24 Zhang, L, "Inhibition of cathepsin S induces autophagy and apoptosis in human glioblastoma cell lines through ROS-mediated PI3K/AKT/mTOR/p70S6K and JNK signaling pathways" 228 : 248-259, 2014

25 Araújo, A. J, "Growth inhibitory effects of 3'-nitro-3-phenylamino norbeta-lapachone against HL-60: a redox-dependent mechanism" 26 : 585-594, 2012

26 Lemasters, J. J, "Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis" 129 : 351-360, 2005

27 Babu, Y. R, "Design and synthesis of quinazolinone tagged acridones as cytotoxic agents and their effects on EGFR tyrosine kinase" 347 : 624-634, 2014

28 Helleday, T, "DNA repair pathways as targets for cancer therapy" 8 : 193-204, 2008

29 Li, P, "Cytochrome c and dATP-dependent formation of Apaf-1/Caspase-9 complex initiates an apoptotic protease cascade" 479 (479): 1997

30 Czabotar, P. E, "Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy" 15 : 49-63, 2014

31 Jiao, R. H, "Chaetominine, a cytotoxic alkaloid produced by endophytic chaetomium sp" 8 : 5709-5712, 2006

32 Danial, N. N, "Cell death: critical control points" 116 : 205-219, 2004

33 Lamkanfi, M, "Caspases in cell survival, proliferation and differentiation" 14 : 44-55, 2007

34 Luo, M, "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" 188 : 151-160, 2010

35 Beesoo, R, "Apoptosis inducing lead compounds isolated from marine organisms of potential relevance in cancer treatment" 768 : 84-97, 2014

36 Kaminskyy, V, "A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids" 177 : 168-181, 2008