The molecular mechanism of luteolin-induced apoptosis is potentially related to inhibition of angiogenesis in human pancreatic carcinoma cells

Cai,Xueting; Lu,Wuguang; Ye,Tingmei; Lu,Min; Wang,Jianhua; Huo,Jiege; Qian,Shihui; Wang,Xiaoning; Cao,Peng

doi:10.3892/or.2012.1914

The molecular mechanism of luteolin-induced apoptosis is potentially related to inhibition of angiogenesis in human pancreatic carcinoma cells

Authors:
- Xueting Cai
- Wuguang Lu
- Tingmei Ye
- Min Lu
- Jianhua Wang
- Jiege Huo
- Shihui Qian
- Xiaoning Wang
- Peng Cao
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Affiliations: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, P.R. China, Department of Biology, School of Chemistry and Life Sciences, Lishui University, Lishui 323000, P.R. China, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
Published online on: July 16, 2012 https://doi.org/10.3892/or.2012.1914
Pages: 1353-1361

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Abstract

Luteolin has been shown to have a strong anticancer effect on various cancer models via programmed cell death (apoptosis). However, the fundamental mechanisms of these effects are still unclear. In the present study, we examined the question of whether or not luteolin can inhibit proliferation of pancreatic carcinoma cells, via apoptosis. We used three human pancreatic carcinoma cell lines, PANC-1, CoLo‑357 and BxPC-3 in our study. In luteolin-treated pancreatic carcinoma cells, typical features of apoptosis were observed. Luteolin increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptotic protein Bcl-2, with a concomitant increase in the levels of caspase-3 and cleaved PARP after treatment for 24 h. Luteolin inhibited HUVEC proliferation and vessel growth in CAM in vivo. In addition, the concentration of VEGF in the conditioned medium from human pancreatic carcinoma cells was downregulated by luteolin. Pancreatic carcinoma cells, pretreated with luteolin, could decrease the capillary-like structure formation by HUVEC, which was analyzed by a co-culture system. The abatement of VEGF secretion was related to the inhibition of VEGF mRNA expression, which may be regulated by inhibiting the transcription activity of nuclear transcription factor NF-κB.

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1	Neesse A, Gress TM and Michl P: Therapeutic targeting of apoptotic pathways: novel aspects in pancreatic cancer. Curr Pharm Biotechnol. May 24–2011.(Epub ahead of print).
2	Kato H, Ishikura H, Kawarada Y, Furuya M, Kondo S and Yoshiki T: Anti-angiogenic treatment for peritoneal dissemination of pancreas adenocarcinoma: a study using TNP-470. Jpn J Cancer Res. 92:67–73. 2001. View Article : Google Scholar : PubMed/NCBI
3	Saif MW: Anti-angiogenesis therapy in pancreatic carcinoma. JOP. 7:163–173. 2006.PubMed/NCBI
4	Lin Y, Shi R, Wang X and Shen HM: Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 8:634–646. 2008. View Article : Google Scholar : PubMed/NCBI
5	Jaffe EA, Nachman RL, Becker CG and Minick CR: Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 52:2745–2756. 1973. View Article : Google Scholar : PubMed/NCBI
6	Cai X, Ye T, Liu C, et al: Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol In Vitro. 25:1385–1391. 2011. View Article : Google Scholar : PubMed/NCBI
7	Minchenko A, Bauer T, Salceda S and Caro J: Hypoxic stimulation of vascular endothelial growth factor expression in vitro and in vivo. Lab Invest. 71:374–379. 1994.PubMed/NCBI
8	Nagineni CN, Samuel W, Nagineni S, et al: Transforming growth factor-β induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: involvement of mitogen-activated protein kinases. J Cell Physiol. 197:453–462. 2003.
9	Das A and McGuire PG: Retinal and choroidal angiogenesis: pathophysiology and strategies for inhibition. Prog Retin Eye Res. 22:721–748. 2003. View Article : Google Scholar : PubMed/NCBI
10	McDougall SR, Anderson AR and Chaplain MA: Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies. J Theor Biol. 241:564–589. 2006. View Article : Google Scholar
11	Joussen AM, Rohrschneider K, Reichling J, Kirchhof B and Kruse FE: Treatment of corneal neovascularization with dietary isoflavonoids and flavonoids. Exp Eye Res. 71:483–487. 2000. View Article : Google Scholar : PubMed/NCBI
12	Bagli E, Stefaniotou M, Morbidelli L, et al: Luteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3′-kinase activity. Cancer Res. 64:7936–7946. 2004.PubMed/NCBI
13	Ramos S: Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem. 18:427–442. 2007. View Article : Google Scholar : PubMed/NCBI
14	Chang J, Hsu Y, Kuo P, Kuo Y, Chiang L and Lin C: Increase of Bax/Bcl-XL ratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line. Life Sci. 76:1883–1893. 2005. View Article : Google Scholar : PubMed/NCBI
15	Lee HJ, Wang CJ, Kuo HC, Chou FP, Jean LF and Tseng TH: Induction apoptosis of luteolin in human hepatoma HepG2 cells involving mitochondria translocation of Bax/Bak and activation of JNK. Toxicol Appl Pharmacol. 203:124–131. 2005. View Article : Google Scholar : PubMed/NCBI
16	Lee WJ, Wu LF, Chen WK, Wang CJ and Tseng TH: Inhibitory effect of luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K-Akt pathways. Chem Biol Interact. 160:123–133. 2006. View Article : Google Scholar : PubMed/NCBI
17	Lim do Y, Jeong Y, Tyner AL and Park JH: Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin. Am J Physiol Gastrointest Liver Physiol. 292:G66–G75. 2007.PubMed/NCBI
18	Plaumann B, Fritsche M, Rimpler H, Brandner G and Hess RD: Flavonoids activate wild-type p53. Oncogene. 13:1605–1614. 1996.PubMed/NCBI
19	Zhang Q, Zhao XH and Wang ZJ: Flavones and flavonols exert cytotoxic effects on a human oesophageal adenocarcinoma cell line (OE33) by causing G2/M arrest and inducing apoptosis. Food Chem Toxicol. 46:2042–2053. 2008. View Article : Google Scholar
20	Schutte ME, Boersma MG, Verhallen DA, Groten JP and Rietjens IM: Effects of flavonoid mixtures on the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers: an in vitro and kinetic modeling approach to predict the combined effects on transporter inhibition. Food Chem Toxicol. 46:557–566. 2008.PubMed/NCBI
21	Xavier CP, Lima CF, Preto A, Seruca R, Fernandes-Ferreira M and Pereira-Wilson C: Luteolin, quercetin and ursolic acid are potent inhibitors of proliferation and inducers of apoptosis in both KRAS and BRAF mutated human colorectal cancer cells. Cancer Lett. 281:162–170. 2009. View Article : Google Scholar : PubMed/NCBI
22	Yang SF, Yang WE, Chang HR, Chu SC and Hsieh YS: Luteolin induces apoptosis in oral squamous cancer cells. J Dent Res. 87:401–406. 2008. View Article : Google Scholar : PubMed/NCBI
23	Yee SB, Lee JH, Chung HY, et al: Inhibitory effects of luteolin isolated from Ixeris sonchifolia Hance on the proliferation of HepG2 human hepatocellular carcinoma cells. Arch Pharm Res. 26:151–156. 2003. View Article : Google Scholar : PubMed/NCBI
24	Shi RX, Ong CN and Shen HM: Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells. Oncogene. 23:7712–7721. 2004. View Article : Google Scholar : PubMed/NCBI
25	Ando C, Takahashi N, Hirai S, et al: Luteolin, a food-derived flavonoid, suppresses adipocyte-dependent activation of macrophages by inhibiting JNK activation. FEBS Lett. 583:3649–3654. 2009. View Article : Google Scholar : PubMed/NCBI
26	Jang S, Kelley KW and Johnson RW: Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci USA. 105:7534–7539. 2008. View Article : Google Scholar : PubMed/NCBI
27	Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N and Nagai H: Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy. 30:501–508. 2000. View Article : Google Scholar : PubMed/NCBI