N-benzyl-N-methyldecan-1-amine, a phenylamine derivative isolated from garlic cloves, induces G2/M phase arrest and apoptosis in U937 human leukemia cells

Jeong,Jin-Woo; Park,Sejin; Park,Cheol; Chang,Young-Chae; Moon,Dong-Oh; Kim,Sung  Ok; Kim,Gi-Young; Cha,Hee-Jae; Kim,Heui-Soo; Choi,Young-Whan; Kim,Wun-Jae; Yoo,Young  Hyun; Choi,Yung  Hyun

doi:10.3892/or.2014.3215

N-benzyl-N-methyldecan-1-amine, a phenylamine derivative isolated from garlic cloves, induces G2/M phase arrest and apoptosis in U937 human leukemia cells

Authors:
- Jin-Woo Jeong
- Sejin Park
- Cheol Park
- Young-Chae Chang
- Dong-Oh Moon
- Sung Ok Kim
- Gi-Young Kim
- Hee-Jae Cha
- Heui-Soo Kim
- Young-Whan Choi
- Wun-Jae Kim
- Young Hyun Yoo
- Yung Hyun Choi
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Affiliations: Center for Core Research Facilities, Daegu Gyeongbuk Institute of Science and Technology, Daegu 711-873, Republic of Korea, Department of Horticultural Bioscience, College of Natural Resource and Life Sciences, Busan National University, Miryang 627-706, Republic of Korea, Department of Molecular Biology, Dongeui University, Busan 614-714, Republic of Korea, Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705‑718, Republic of Korea, Department of Biology Education, Daegu University, Gyeongbuk 712-714, Republic of Korea , Team for Scientification of Korean Medical Intervention (BK21 Plus) and Department of Herbal Pharmacology, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Republic of Korea, Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Jeju 690‑756, Republic of Korea , Departments of Parasitology and Genetics, Kosin University College of Medicine, Seo-gu, Busan 602‑702, Republic of Korea , Department of Biological Sciences, College of Natural Sciences, Busan National University, Busan 609‑735, Republic of Korea , Department of Urology, Chungbuk National University College of Medicine, Cheongju 361-804, Republic of Korea , Department of Anatomy and Cell Biology, Dong-A University College of Medicine and Mitochondria Hub Regulation Center, Busan 602‑714, Republic of Korea, Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614‑052, Republic of Korea
Published online on: May 23, 2014 https://doi.org/10.3892/or.2014.3215
Pages: 373-381

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Abstract

Epidemiological studies indicate that components of garlic (Allium sativum) have anti-proliferative effects against various types of cancer. In the present study, we investigated the effect of newly isolated phenylamine derivative N-benzyl-N-methyldecan-1-amine (NBNMA) from garlic cloves on the inhibition of the growth and apoptosis of human leukemia U937 cells and its potential anticancer mechanism. NBNMA exhibited an antiproliferative effect in U937 cells by inducing cell cycle arrest at the G2/M phase and apoptotic cell death. Western blot analyses revealed that NBNMA decreased the expression of the regulator genes of G2/M phase progression, cyclin dependent kinase (Cdk) 2 and Cdc2 and elevated the expression of the Cdk inhibitor p21WAF1/CIP1 in a p53-independent manner. In addition, NBNMA activated caspase-8 and caspase-9, initiator caspases of the extrinsic and intrinsic pathways of apoptosis, respectively, which led to activation of executioner caspase-3 along with degradation of poly(ADP-ribose) polymerase. NBNMA-induced apoptosis was observed in parallel with an increased ratio of pro-apoptotic Bax and Bad/anti-apoptotic Bcl-2 and Bcl-xL, and inhibition of inhibitor of apoptosis protein (IAP) family members XIAP and cIAP-1. Furthermore, NBNMA-treated cells displayed enhanced release of cytochrome c from the mitochondria into the cytosol concomitant with a loss of mitochondrial membrane potential and downregulation of Bid, suggesting that NBNMA-induced apoptosis occurred via the extrinsic and intrinsic apoptotic pathways with a possible link to Bid protein activity between the two pathways. These results indicate that NBNMA has promising potential to become a novel anticancer agent for the treatment of leukemia. We provide new insight into the mechanisms underlying the anticancer effect of NBNMA.

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1	Tsubura A, Lai YC, Kuwata M, Uehara N and Yoshizawa K: Anticancer effects of garlic and garlic-derived compounds for breast cancer control. Anticancer Agents Med Chem. 11:249–253. 2011. View Article : Google Scholar : PubMed/NCBI
2	Bianchini F and Vainio H: Allium vegetables and organosulfur compounds: do they help prevent cancer? Environ Health Perspect. 109:893–902. 2001. View Article : Google Scholar : PubMed/NCBI
3	Milner JA: Mechanisms by which garlic and allyl sulfur compounds suppress carcinogen bioactivation. Garlic and carcinogenesis. Adv Exp Med Biol. 492:69–81. 2001. View Article : Google Scholar : PubMed/NCBI
4	Kim JY and Kwon O: Garlic intake and cancer risk: an analysis using the Food and Drug Administration’s evidence-based review system for the scientific evaluation of health claims. Am J Clin Nutr. 89:257–264. 2009.
5	Fleischauer AT and Arab L: Garlic and cancer: a critical review of the epidemiologic literature. J Nutr. 131:S1032–S1040. 2001.PubMed/NCBI
6	Ngo SN, Williams DB, Cobiac L and Head RJ: Does garlic reduce risk of colorectal cancer? A systematic review. J Nutr. 137:2264–2269. 2007.PubMed/NCBI
7	Sperka T, Wang J and Rudolph KL: DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol. 13:579–590. 2012. View Article : Google Scholar : PubMed/NCBI
8	Canavese M, Santo L and Raje N: Cyclin dependent kinases in cancer: potential for therapeutic intervention. Cancer Biol Ther. 13:451–457. 2012. View Article : Google Scholar : PubMed/NCBI
9	Modem S, Dicarlo SE and Reddy TR: Fresh garlic extract induces growth arrest and morphological differentiation of MCF7 breast cancer cells. Genes Cancer. 3:177–186. 2012. View Article : Google Scholar : PubMed/NCBI
10	Lund T, Stokke T, Olsen ØE and Fodstad Ø: Garlic arrests MDA-MB-435 cancer cells in mitosis, phosphorylates the proapoptotic BH3-only protein BimEL and induces apoptosis. Br J Cancer. 92:1773–1781. 2005. View Article : Google Scholar : PubMed/NCBI
11	Frantz DJ, Hughes BG, Nelson DR, Murray BK and Christensen MJ: Cell cycle arrest and differential gene expression in HT-29 cells exposed to an aqueous garlic extract. Nutr Cancer. 38:255–264. 2000. View Article : Google Scholar : PubMed/NCBI
12	Su CC, Chen GW, Tan TW, Lin JG and Chung JG: Crude extract of garlic induced caspase-3 gene expression leading to apoptosis in human colon cancer cells. In Vivo. 20:85–90. 2006.PubMed/NCBI
13	Kim HJ, Han MH, Kim GY, Choi YW and Choi YH: Hexane extracts of garlic cloves induce apoptosis through the generation of reactive oxygen species in Hep3B human hepatocarcinoma cells. Oncol Rep. 28:1757–1763. 2012.
14	Na HK, Kim EH, Choi MA, Park JM, Kim DH and Surh YJ: Diallyl trisulfide induces apoptosis in human breast cancer cells through ROS-mediated activation of JNK and AP-1. Biochem Pharmacol. 84:1241–1250. 2012. View Article : Google Scholar : PubMed/NCBI
15	Xiao D, Herman-Antosiewicz A, Antosiewicz J, Xiao H, Brisson M, Lazo JS and Singh SV: Diallyl trisulfide-induced G(2)-M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc 25C. Oncogene. 24:6256–6268. 2005. View Article : Google Scholar
16	Di X, Andrews DM, Tucker CJ, Yu L, Moore AB, Zheng X, Castro L, Hermon T, Xiao H and Dixon D: A high concentration of genistein down-regulates activin A, Smad3 and other TGF-β pathway genes in human uterine leiomyoma cells. Exp Mol Med. 44:281–292. 2012.PubMed/NCBI
17	Medema RH and Macůrek L: Checkpoint control and cancer. Oncogene. 31:2601–2613. 2012. View Article : Google Scholar : PubMed/NCBI
18	Rozenblat S, Grossman S, Bergman M, Gottlieb H, Cohen Y and Dovrat S: Induction of G2/M arrest and apoptosis by sesquiterpene lactones in human melanoma cell lines. Biochem Pharmacol. 75:369–382. 2008. View Article : Google Scholar : PubMed/NCBI
19	Lim S and Kaldis P: Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development. 140:3079–3093. 2013. View Article : Google Scholar : PubMed/NCBI
20	Sánchez I and Dynlacht BD: New insights into cyclins, CDKs, and cell cycle control. Semin Cell Dev Biol. 16:311–321. 2005.PubMed/NCBI
21	Jeong AL and Yang Y: PP2A function toward mitotic kinases and substrates during the cell cycle. BMB Rep. 46:289–294. 2013. View Article : Google Scholar : PubMed/NCBI
22	Lindqvist A, Rodríguez-Bravo V and Medema RH: The decision to enter mitosis: feedback and redundancy in the mitotic entry network. J Cell Biol. 185:193–202. 2009. View Article : Google Scholar : PubMed/NCBI
23	Porter LA and Donoghue DJ: Cyclin B1 and CDK1: nuclear localization and upstream regulators. Prog Cell Cycle Res. 5:335–347. 2003.PubMed/NCBI
24	Abbas T and Dutta A: p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI
25	Brown L, Boswell S, Raj L and Lee SW: Transcriptional targets of p53 that regulate cellular proliferation. Crit Rev Eukaryot Gene Expr. 17:73–85. 2007. View Article : Google Scholar : PubMed/NCBI
26	Danova M, Giordano M, Mazzini G and Riccardi A: Expression of p53 protein during the cell cycle measured by flow cytometry in human leukemia. Leuk Res. 14:417–422. 1990. View Article : Google Scholar : PubMed/NCBI
27	Burz C, Berindan-Neagoe I, Balacescu O and Irimie A: Apoptosis in cancer: key molecular signaling pathways and therapy targets. Acta Oncol. 48:811–821. 2009. View Article : Google Scholar : PubMed/NCBI
28	Fulda S and Debatin KM: Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 25:4798–4811. 2006. View Article : Google Scholar : PubMed/NCBI
29	Liu Y, Bertram CC, Shi Q and Zinkel SS: Proapoptotic Bid mediates the Atr-directed DNA damage response to replicative stress. Cell Death Differ. 18:841–852. 2011. View Article : Google Scholar : PubMed/NCBI
30	Shamas-Din A, Brahmbhatt H, Leber B and Andrews DW: BH3-only proteins: Orchestrators of apoptosis. Biochim Biophys Acta. 1813:508–520. 2011. View Article : Google Scholar : PubMed/NCBI
31	Tewari M, Quan LT, O’Rourke K, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS and Dixit VM: Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell. 81:801–809. 1995. View Article : Google Scholar : PubMed/NCBI
32	Low IC, Kang J and Pervaiz S: Bcl-2: a prime regulator of mitochondrial redox metabolism in cancer cells. Antioxid Redox Signal. 15:2975–2987. 2011. View Article : Google Scholar : PubMed/NCBI
33	Galluzzi L, Larochette N, Zamzami N and Kroemer G: Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene. 25:4812–4830. 2006. View Article : Google Scholar : PubMed/NCBI
34	LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S and Korneluk RG: IAP-targeted therapies for cancer. Oncogene. 27:6252–6275. 2008. View Article : Google Scholar : PubMed/NCBI
35	Hunter AM, LaCasse EC and Korneluk RG: The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis. 12:1543–1568. 2007. View Article : Google Scholar : PubMed/NCBI