An indolylquinoline derivative activates DNA damage response and apoptosis in human hepatocellular carcinoma cells

Liu,Chun-Yen; Hsieh,Chang-Hung; Kim,Seung-Hun; Wang,Jing-Ping; Ni,Yu-Lin; Su,Chun-Li; Yao,Ching-Fa; Fang,Kang

doi:10.3892/ijo.2016.3717

An indolylquinoline derivative activates DNA damage response and apoptosis in human hepatocellular carcinoma cells

Authors:
- Chun-Yen Liu
- Chang-Hung Hsieh
- Seung-Hun Kim
- Jing-Ping Wang
- Yu-Lin Ni
- Chun-Li Su
- Ching-Fa Yao
- Kang Fang
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Affiliations: Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C., Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C., Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan, R.O.C.
Published online on: October 5, 2016 https://doi.org/10.3892/ijo.2016.3717
Pages: 2431-2441

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Abstract

Human liver cancer is one of the most frequently diagnosed cancers worldwide. The development of resistance to therapy limits the application against the disease. To improve treatment, new effective anticancer agents are constantly pursued. Previously, we reported that an indolylquinoline, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), is effective in suppressing the growth of human lung cancer by impairing mitochondria functions. The present study revealed that EMMQ inhibited cell growth and induced apoptosis in liver cancer cells, but not in normal cells. This study demonstrated that EMMQ induced DNA damage by activating p53 and γ-H2AX and cell arrest by suppressing cyclin D1 and CDK2. Damaged DNA injured mitochondrial functions by lowering the membrane potential and producing reactive oxygen species. The subsequent mitochondrial cytochrome c release attenuated pro-survival signals and increased apoptotic characteristics. Introduction of p53 shRNA abrogated drug effects by reducing DNA damage while maintaining mitochondria integrity. In brief, the study demonstrates that the effectiveness of EMMQ accentuated apoptosis of hepatocarcinoma cells by activating p53. Based on these collective findings, the study offered a new perspective of EMMQ that was shown to be a promising candidate to treat liver cancer.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
3	Kumar M, Zhao X and Wang XW: Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: One step closer to personalized medicine? Cell Biosci. 1:52011. View Article : Google Scholar : PubMed/NCBI
4	Brown KS: Chemotherapy and other systemic therapies for hepatocellular carcinoma and liver metastases. Semin Intervent Radiol. 23:99–108. 2006. View Article : Google Scholar : PubMed/NCBI
5	Cao H, Phan H and Yang LX: Improved chemotherapy for hepatocellular carcinoma. Anticancer Res. 32:1379–1386. 2012.PubMed/NCBI
6	Terazawa T, Kondo S, Hosoi H, Morizane C, Shimizu S, Mitsunaga S, Ikeda M, Ueno H and Okusaka T: Transarterial infusion chemotherapy with cisplatin plus S-1 for hepatocellular carcinoma treatment: A phase I trial. BMC Cancer. 14:3012014. View Article : Google Scholar : PubMed/NCBI
7	Jiang L, Zhang Q, Ren H, Ma S, Lu C, Liu B, Liu J, Liang J, Li M and Zhu R: Dihydromyricetin enhances the chemo-sensitivity of nedaplatin via regulation of the p53/Bcl-2 pathway in hepatocellular carcinoma cells. PLoS One. 10:e01249942015. View Article : Google Scholar : PubMed/NCBI
8	Liu CY, Wu PT, Wang JP, Fan PW, Hsieh CH, Su CL, Chiu CC, Yao CF and Fang K: An indolylquinoline derivative promotes apoptosis in human lung cancer cells by impairing mitochondrial functions. Apoptosis. 20:1471–1482. 2015. View Article : Google Scholar : PubMed/NCBI
9	Lee WY, Cheung CC, Liu KW, Fung KP, Wong J, Lai PB and Yeung JH: Cytotoxic effects of tanshinones from Salvia miltior-rhiza on doxorubicin-resistant human liver cancer cells. J Nat Prod. 73:854–859. 2010. View Article : Google Scholar : PubMed/NCBI
10	Gauthier A and Ho M: Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update. Hepatol Res. 43:147–154. 2013. View Article : Google Scholar
11	Hartmann JT and Kanz L: Sunitinib and periodic hair depigmentation due to temporary c-KIT inhibition. Arch Dermatol. 144:1525–1526. 2008. View Article : Google Scholar : PubMed/NCBI
12	Sukowati CH, Rosso N, Crocè LS and Tiribelli C: Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma. World J Hepatol. 2:114–126. 2010.PubMed/NCBI
13	Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, et al: Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science. 281:1674–1677. 1998. View Article : Google Scholar : PubMed/NCBI
14	Hamer G, Roepers-Gajadien HL, van Duyn-Goedhart A, Gademan IS, Kal HB, van Buul PP and de Rooij DG: DNA double-strand breaks and gamma-H2AX signaling in the testis. Biol Reprod. 68:628–634. 2003. View Article : Google Scholar : PubMed/NCBI
15	Yuan J and Chen J: MRE11-RAD50-NBS1 complex dictates DNA repair independent of H2AX. J Biol Chem. 285:1097–1104. 2010. View Article : Google Scholar :
16	Di Leonardo A, Linke SP, Clarkin K and Wahl GM: DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8:2540–2551. 1994. View Article : Google Scholar : PubMed/NCBI
17	Agarwal ML, Agarwal A, Taylor WR and Stark GR: p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc Natl Acad Sci USA. 92:8493–8497. 1995. View Article : Google Scholar : PubMed/NCBI
18	Innocente SA, Abrahamson JL, Cogswell JP and Lee JM: p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci USA. 96:2147–2152. 1999. View Article : Google Scholar : PubMed/NCBI
19	Lakin ND and Jackson SP: Regulation of p53 in response to DNA damage. Oncogene. 18:7644–7655. 1999. View Article : Google Scholar
20	Assunção Guimarães C and Linden R: Programmed cell deaths. Apoptosis and alternative death styles. Eur J Biochem. 271:1638–1650. 2004. View Article : Google Scholar
21	Shi A, Nguyen TA, Battina SK, Rana S, Takemoto DJ, Chiang PK and Hua DH: Synthesis and anti-breast cancer activities of substituted quinolines. Bioorg Med Chem Lett. 18:3364–3368. 2008. View Article : Google Scholar : PubMed/NCBI
22	Ding Y and Nguyen TA: PQ1, a quinoline derivative, induces apoptosis in T47D breast cancer cells through activation of caspase-8 and caspase-9. Apoptosis. 18:1071–1082. 2013. View Article : Google Scholar : PubMed/NCBI
23	Bernzweig J, Heiniger B, Prasain K, Lu J, Hua DH and Nguyen TA: Anti-breast cancer agents, quinolines, targeting gap junction. Med Chem. 7:448–453. 2011. View Article : Google Scholar : PubMed/NCBI
24	Nakamura Y, Yogosawa S, Izutani Y, Watanabe H, Otsuji E and Sakai T: A combination of indol-3-carbinol and genistein synergistically induces apoptosis in human colon cancer HT-29 cells by inhibiting Akt phosphorylation and progression of autophagy. Mol Cancer. 8:1002009. View Article : Google Scholar : PubMed/NCBI
25	Chakrabarti G, Basu A, Manna PP, Mahato SB, Mandal NB and Bandyopadhyay S: Indolylquinoline derivatives are cytotoxic to Leishmania donovani promastigotes and amastigotes in vitro and are effective in treating murine visceral leishmaniasis. J Antimicrob Chemother. 43:359–366. 1999. View Article : Google Scholar : PubMed/NCBI
26	Pal C, Raha M, Basu A, Roy KC, Gupta A, Ghosh M, Sahu NP, Banerjee S, Mandal NB and Bandyopadhyay S: Combination therapy with indolylquinoline derivative and sodium antimony gluconate cures established visceral leishmaniasis in hamsters. Antimicrob Agents Chemother. 46:259–261. 2002. View Article : Google Scholar
27	Brambilla E and Negoescu A: Analysis of Bax and Bcl-2 expression in p53-immunopositive breast cancers. Clin Cancer Res. 3:2181–2183. 1997.
28	Vaseva AV and Moll UM: The mitochondrial p53 pathway. Biochimica et Biophysica Acta. 1787:414–420. 2009. View Article : Google Scholar
29	Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, et al: Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 244:217–221. 1989. View Article : Google Scholar : PubMed/NCBI
30	Linke SP, Clarkin KC, Di Leonardo A, Tsou A and Wahl GM: A reversible, p53-dependent G₀/G₁ cell cycle arrest induced by ribo-nucleotide depletion in the absence of detectable DNA damage. Genes Dev. 10:934–947. 1996. View Article : Google Scholar : PubMed/NCBI
31	Saha S, Bhattacharjee P, Mukherjee S, Mazumdar M, Chakraborty S, Khurana A, Nayak D, Manchanda R, Chakrabarty R, Das T, et al: Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells. Oncol Rep. 31:1589–1598. 2014.PubMed/NCBI
32	Macip S, Igarashi M, Berggren P, Yu J, Lee SW and Aaronson SA: Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Mol Cell Biol. 23:8576–8585. 2003. View Article : Google Scholar : PubMed/NCBI
33	Raha S and Robinson BH: Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci. 25:502–508. 2000. View Article : Google Scholar : PubMed/NCBI
34	Holley AK and St Clair DK: Watching the watcher: Regulation of p53 by mitochondria. Future Oncol. 5:117–130. 2009. View Article : Google Scholar : PubMed/NCBI
35	Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P and Moll UM: p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 11:577–590. 2003. View Article : Google Scholar : PubMed/NCBI
36	Ji H, Ding Z, Hawke D, Xing D, Jiang BH, Mills GB and Lu Z: AKT-dependent phosphorylation of Niban regulates nucleo-phosmin- and MDM2-mediated p53 stability and cell apoptosis. EMBO Rep. 13:554–560. 2012. View Article : Google Scholar : PubMed/NCBI
37	Qian J, Zou Y, Rahman JS, Lu B and Massion PP: Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung. Mol Cancer Ther. 8:101–109. 2009. View Article : Google Scholar : PubMed/NCBI
38	Malki A and El Ashry S: In vitro and in vivo efficacy of a novel quinuclidinone derivative against breast cancer. Anticancer Res. 34:1367–1376. 2014.PubMed/NCBI