Total alkaloids of Rubus alceifolius Poir inhibit tumor angiogenesis through suppression of the Notch signaling pathway in a mouse model of hepatocellular carcinoma

Zhao,Jinyan; Lin,Wei; Cao,Zhiyun; Zhuang,Qunchuan; Zheng,Liangpu; Peng,Jun; Hong,Zhenfeng

doi:10.3892/mmr.2014.2702

Total alkaloids of Rubus alceifolius Poir inhibit tumor angiogenesis through suppression of the Notch signaling pathway in a mouse model of hepatocellular carcinoma

Authors:
- Jinyan Zhao
- Wei Lin
- Zhiyun Cao
- Qunchuan Zhuang
- Liangpu Zheng
- Jun Peng
- Zhenfeng Hong
View Affiliations

Affiliations: Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
Published online on: October 20, 2014 https://doi.org/10.3892/mmr.2014.2702
Pages: 357-361

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Angiogenesis, which has a critical role in human tumor growth and development, is tightly regulated by the Notch signaling pathway. Total alkaloids are active components of the plant Rubus alceifolius Poir, which is used for the treatment of various types of cancer. A previous study by our group showed that the total alkaloids of Rubus alceifolius Poir (TARAP) induced hepatocellular carcinoma (HCC) cell apoptosis through the activation of the mitochondria‑dependent pathway in vitro and in vivo, as well as inhibited angiogenesis in a chick embryo chorioallantoic membrane model. In the present study, to further analyze the specific mechanisms underlying the antitumor activity of TARAP, a HCC xenograft mouse model was used to assess the effect of TARAP on angiogenesis in vivo. TARAP was found to suppress the expression of vascular endothelial growth factor (VEGF) A and VEGF receptor‑2 in tumor tissues, which resulted in the inhibition of tumor angiogenesis. In addition, TARAP treatment was observed to inhibit the expression of Notch1, delta‑like ligand 4 and jagged 1, which are key mediators of the Notch signaling pathway. The present study identified that the inhibition of tumor angiogenesis through the suppression of the Notch signaling pathway may be one of the mechanisms through which TARAP may be effective in the treatment of cancer.

View Figures

View References

1	Tsai WL and Chung RT: Viral hepatocarcinogenesis. Oncogene. 29:2309–2324. 2010. View Article : Google Scholar : PubMed/NCBI
2	Schütte K, Bornschein J and Malfertheiner P: Hepatocellular carcinoma - epidemiological trends and risk factors. Dig Dis. 27:80–92. 2009.PubMed/NCBI
3	Bikfalvi A: Significance of angiogenesis in tumour progression and metastasis. Eur J Cancer. 31A:1101–1104. 1995. View Article : Google Scholar : PubMed/NCBI
4	Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 82:4–6. 1990. View Article : Google Scholar : PubMed/NCBI
5	Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H and Folkman J: Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature. 348:555–557. 1990. View Article : Google Scholar : PubMed/NCBI
6	Folkman J and Shing Y: Angiogenesis. J Biol Chem. 267:10931–10934. 1992.
7	Pluda JM: Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies. Semin Oncol. 24:203–218. 1997.PubMed/NCBI
8	Folkman J: Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg. 175:409–416. 1972. View Article : Google Scholar : PubMed/NCBI
9	Brem H and Folkman J: Inhibition of tumor angiogenesis mediated by cartilage. J Exp Med. 141:427–439. 1975. View Article : Google Scholar : PubMed/NCBI
10	Voest EE: Inhibitors of angiogenesis in a clinical perspective. Anticancer Drugs. 7:723–727. 1996. View Article : Google Scholar : PubMed/NCBI
11	Jung YD, Ahmad SA, Liu W, Reinmuth N, Parikh A, Stoeltzing O, Fan F and Ellis LM: The role of the microenvironment and intercellular cross-talk in tumor angiogenesis. Semin Cancer Biol. 12:105–112. 2002. View Article : Google Scholar : PubMed/NCBI
12	Krebs LT, Xue Y, Norton CR, et al: Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 14:1343–1352. 2000.PubMed/NCBI
13	Krebs LT, Shutter JR, Tanigaki K, Honio T, Stark KL and Gridley T: Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev. 18:2469–2473. 2004. View Article : Google Scholar : PubMed/NCBI
14	Xue Y, Gao X, Lindsell CE, et al: Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. Hum Mol Genet. 8:723–730. 1999. View Article : Google Scholar : PubMed/NCBI
15	Artavanis-Tsakonas S, Rand MD and Lake RJ: Notch signaling: cell fate control and signal integration in development. Science. 284:770–776. 1999. View Article : Google Scholar : PubMed/NCBI
16	Guo S, Liu M and Gonzalez-Perez RR: Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim Biophys Acta. 1815:197–213. 2011.PubMed/NCBI
17	Li JL and Harris AL: Notch signaling from tumor cells: a new mechanism of angiogenesis. Cancer Cell. 8:1–3. 2005. View Article : Google Scholar : PubMed/NCBI
18	Taylor KL, Henderson AM and Hughes CC: Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res. 64:372–383. 2002. View Article : Google Scholar
19	Williams CK, Li JL, Murga M, Harris AL and Tosato G: Upregulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood. 107:931–939. 2006. View Article : Google Scholar : PubMed/NCBI
20	Zimrin AB, Pepper MS, McMahon GA, Nguyen F, Montesano R and Maciag T: An antisense oligonucleotide to the notch ligand jagged enhances fibroblast growth factor-induced angiogenesis in vitro. J Biol Chem. 271:32499–32502. 1996. View Article : Google Scholar
21	Zhao J, Chen X, Lin W, et al: Total alkaloids of Rubus aleaefolius Poir inhibit hepatocellular carcinoma growth in vivo and in vitro via activation of mitochondrial-dependent apoptosis. Int J Oncol. 42:971–978. 2013.
22	Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other diseases. Nat Med. 1:27–31. 1995. View Article : Google Scholar : PubMed/NCBI
23	Folkman J: Angiogenesis. Annu Rev Med. 57:1–18. 2006. View Article : Google Scholar
24	Yancopoulos GD, Davis S, Gale NW, et al: Vascular-specific growth factors and blood vessel formation. Nature. 407:242–248. 2000. View Article : Google Scholar : PubMed/NCBI
25	Ishiwata I, Sudo T, Kiguchi K and Ishikawa H: Tumor angiogenesis factors produced by cancer cells. Hum Cell. 12:37–46. 1999.PubMed/NCBI
26	Risau W: Mechanisms of angiogenesis. Nature. 386:671–674. 1997. View Article : Google Scholar : PubMed/NCBI
27	Jain RK: Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. Semin Oncol. 29(6 Suppl 16): 3–9. 2002. View Article : Google Scholar : PubMed/NCBI
28	Ferrara N: Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications. Semin Oncol. 29(6 Suppl 16): 10–14. 2002. View Article : Google Scholar : PubMed/NCBI
29	Houck KA, Ferrara N, Winer J, et al: The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 5:1806–1814. 1991. View Article : Google Scholar : PubMed/NCBI