Isorhamnetin suppresses colon cancer cell growth through the PI3K‑Akt‑mTOR pathway

Li,Chuan; Yang,Xi; Chen,Cheng; Cai,Shaoxin; Hu,Junbo

doi:10.3892/mmr.2014.1886

Isorhamnetin suppresses colon cancer cell growth through the PI3K‑Akt‑mTOR pathway

Authors:
- Chuan Li
- Xi Yang
- Cheng Chen
- Shaoxin Cai
- Junbo Hu
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Affiliations: Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: January 7, 2014 https://doi.org/10.3892/mmr.2014.1886
Pages: 935-940

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Abstract

Isorhamnetin, a flavonoid isolated from the fruits of herbal medicinal plants, such as Hippophae rhamnoides L., exerts anticancer effects similar to other flavonoids. However, the effect of isorhamnetin on colorectal cancer (CRC) and the underlying molecular mechanism are unclear. This study aimed to determine the effect of isorhamnetin on the proliferation of cells from the human CRC cell lines, HT‑29, HCT116 and SW480. It was demonstrated that isorhamnetin suppressed the proliferation of cells from all three cell lines, induced cell cycle arrest at the G2/M phase and suppressed cell proliferation by inhibiting the PI3K‑Akt‑mTOR pathway. Isorhamnetin also reduced the phosphorylation levels of Akt (ser473), phosph‑p70S6 kinase and phosph‑4E‑BP1 (t37/46) protein, and enhanced the expression of Cyclin B1 protein. Therefore, this compound was revealed to be a selective PI3K‑Akt‑mTOR pathway inhibitor, and may be a potent anticancer agent for the treatment of CRC, as it restrains the proliferation of CRC cells.

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1	Murtaza I, Adhami VM, Hafeez BB, Saleem M and Mukhtar H: Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-κB. Int J Cancer. 125:2465–2473. 2009.PubMed/NCBI
2	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
3	Devi VG, Rooban BN, Sasikala V, Sahasranamam V and Abraham A: Isorhamnetin-3-glucoside alleviates oxidative stress and opacification in selenite cataract in vitro. Toxicol In Vitro. 24:1662–1669. 2010. View Article : Google Scholar : PubMed/NCBI
4	Lee J, Jung E, Kim S, et al: Isorhamnetin represses adipogenesis in 3T3-L1 cells. Obesity (Silver Spring). 17:226–232. 2009. View Article : Google Scholar : PubMed/NCBI
5	Jaramillo S, Lopez S, Varela LM, et al: The flavonol isorhamnetin exhibits cytotoxic effects on human colon cancer cells. J Agric Food Chem. Oct 5–2010.(Epub ahead of print).
6	Kim JE, Lee DE, Lee KW, et al: Isorhamnetin suppresses skin cancer through direct inhibition of MEK1 and PI3-K. Cancer Prev Res (Phila). 4:582–591. 2011. View Article : Google Scholar : PubMed/NCBI
7	Kong CS, Kim YA, Kim MM, et al: Flavonoid glycosides isolated from Salicornia herbacea inhibit matrix metalloproteinase in HT1080 cells. Toxicol In Vitro. 22:1742–1748. 2008.PubMed/NCBI
8	Ma G, Yang C, Qu Y, Wei H, Zhang T and Zhang N: The flavonoid component isorhamnetin in vitro inhibits proliferation and induces apoptosis in Eca-109 cells. Chem Biol Interact. 167:153–160. 2007. View Article : Google Scholar : PubMed/NCBI
9	Teng BS, Lu YH, Wang ZT, Tao XY and Wei DZ: In vitro anti-tumor activity of isorhamnetin isolated from Hippophae rhamnoides L. against BEL-7402 cells. Pharmacol Res. 54:186–194. 2006.PubMed/NCBI
10	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
11	Sartore-Bianchi A, Martini M, Molinari F, et al: PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 69:1851–1857. 2009. View Article : Google Scholar : PubMed/NCBI
12	Samuels Y and Velculescu VE: Oncogenic mutations of PIK3CA in human cancers. Cell Cycle. 3:1221–1224. 2004. View Article : Google Scholar : PubMed/NCBI
13	Mosmann T: Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 65:55–63. 1983. View Article : Google Scholar : PubMed/NCBI
14	Yang Y, Zhou X, Xiao M, et al: Discovery of chrysoeriol, a PI3K-AKT-mTOR pathway inhibitor with potent antitumor activity against human multiple myeloma cells in vitro. J Huazhong Univ Sci Technolog Med Sci. 30:734–740. 2010. View Article : Google Scholar : PubMed/NCBI
15	Jacinto E, Loewith R, Schmidt A, et al: Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 6:1122–1128. 2004. View Article : Google Scholar : PubMed/NCBI
16	Sarbassov DD, Guertin DA, Ali SM and Sabatini DM: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 307:1098–1101. 2005. View Article : Google Scholar : PubMed/NCBI
17	Morgensztern D and McLeod HL: PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs. 16:797–803. 2005. View Article : Google Scholar : PubMed/NCBI
18	Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS and Workman P: Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol. 8:393–412. 2008. View Article : Google Scholar : PubMed/NCBI
19	Tokunaga E, Oki E, Egashira A, et al: Deregulation of the Akt pathway in human cancer. Curr Cancer Drug Targets. 8:27–36. 2008. View Article : Google Scholar : PubMed/NCBI
20	Cheng JQ, Lindsley CW, Cheng GZ, Yang H and Nicosia SV: The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene. 24:7482–7492. 2005. View Article : Google Scholar : PubMed/NCBI
21	Hidalgo M and Rowinsky EK: The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 19:6680–6686. 2000. View Article : Google Scholar : PubMed/NCBI
22	Huang WY, Cai YZ and Zhang Y: Natural phenolic compounds from medicinal herbs and dietary plants: potential use for cancer prevention. Nutr Cancer. 62:1–20. 2010. View Article : Google Scholar : PubMed/NCBI
23	Jeong JH, An JY, Kwon YT, Rhee JG and Lee YJ: Effects of low dose quercetin: cancer cell-specific inhibition of cell cycle progression. J Cell Biochem. 106:73–82. 2009. View Article : Google Scholar : PubMed/NCBI
24	Shan BE, Wang MX and Li RQ: Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/β-catenin signaling pathway. Cancer Invest. 27:604–612. 2009.PubMed/NCBI
25	Wang W, VanAlstyne PC, Irons KA, Chen S, Stewart JW and Birt DF: Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest in human colon carcinoma cell lines. Nutr Cancer. 48:106–114. 2004. View Article : Google Scholar : PubMed/NCBI
26	Wan X, Harkavy B, Shen N, Grohar P and Helman LJ: Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene. 26:1932–1940. 2007. View Article : Google Scholar : PubMed/NCBI
27	Hyun J, Shin SY, So KM, Lee YH and Lim Y: Isoflavones inhibit the clonogenicity of human colon cancer cells. Bioorg Med Chem Lett. 22:2664–2669. 2012. View Article : Google Scholar : PubMed/NCBI
28	Abdul-Ghani R, Serra V, Gyorffy B, et al: The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1. Oncogene. 25:1743–1752. 2006. View Article : Google Scholar : PubMed/NCBI
29	Hoeffer CA and Klann E: mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33:67–75. 2010. View Article : Google Scholar : PubMed/NCBI
30	Bjornsti MA and Houghton PJ: The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 4:335–348. 2004. View Article : Google Scholar : PubMed/NCBI
31	Nasmyth K: Viewpoint: putting the cell cycle in order. Science. 274:1643–1645. 1996. View Article : Google Scholar : PubMed/NCBI
32	Cappelletti V, Fioravanti L, Miodini P and Di Fronzo G: Genistein blocks breast cancer cells in the G(2)M phase of the cell cycle. J Cell Biochem. 79:594–600. 2000. View Article : Google Scholar : PubMed/NCBI