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Investigational New Drugs

Erschienen in:

01.02.2010 | PRECLINICAL STUDIES

Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell

verfasst von: Kathy Ka-Wai Auyeung, Joshua Ka-Shun Ko

Erschienen in: Investigational New Drugs | Ausgabe 1/2010

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Summary

Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus, a medicinal plant that possesses antitumorigenic property. We attempted to compare the anticarcinogenic mechanism of formononetin with that of the known proapoptotic flavonoid isoliquiritigenin (ISL) in human cancer cells. We first evaluated the effects of formononetin and ISL on HCT 116 colon cancer cell viability. Immunofluorescence staining was then performed to observe the morphological changes of cancer cells undergoing apoptosis, which had been substantiated using Annexin V-FITC/propidium iodide staining. Western immunoblotting and flow cytometry were also employed to study parameters associated with apoptosis and cell proliferation. Our data show that formononetin and ISL both inhibited the growth of colon cancer cells and promoted apoptosis. These processes were accompanied by caspase activation and downregulation of the antiapoptotic proteins Bcl-2 and Bcl-x_L. Besides, the novel proapoptotic protein NSAID-activated gene (NAG-1) and its upstream regulator were overexpressed in drug-treated cells. Nevertheless, only ISL was found to induce a G2 arrest. These findings exemplify that both formononetin and ISL could cause growth inhibition and facilitate apoptosis in colon cancer cells, while only ISL is capable of inducing phase-specific cell cycle arrest. This suggests that the anticarcinogenic activities of different herbal flavonoids may involve both common and differential mechanisms of action, which could be developed as potential anticancer drugs.

Kuo SM (1997) Dietary flavonoids and cancer prevention: Evidence and potential mechanisms. Crit Rev Oncog 8:47–69PubMed

Richter M, Ebermann R, Marian B (1999) Quercetin-induced apoptosis in colorectal tumor cells: possible role of EGF receptor signaling. Nutr Cancer 34:88–99, doi:10.1207/S15327914NC340113 CrossRefPubMed

Kawabata K, Murakami A, Ohigashi H (2005) Nobiletin, a citrus flavonoid, down-regulates matrix metalloproteinase-7 (matrilysin) expression in HT-29 human colorectal cancer cells. Biosci Biotechnol Biochem 69:307–314, doi:10.1271/bbb.69.307 CrossRefPubMed

Shi RX, Ong CN, Shen HM (2004) Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells. Oncogene 23:7712–7721, doi:10.1038/sj.onc.1208046 CrossRefPubMed

Tin MMY, Cho CH, Chan K, James AE, Ko JKS (2007) Astragalus saponins induce growth inhibition and apoptosis in human colon cancer cells and tumor xenograft. Carcinogenesis 28:1347–1355, doi:10.1093/carcin/bgl238 CrossRefPubMed

Ma XQ, Shi Q, Duan JA, Dong TTX, Tsim KWK (2002) Chemical analysis of Radix Astragali (Huangq i) in China: a comparison with its adulterants and seasonal variations. J Agric Food Chem 50:4861–4866, doi:10.1021/jf0202279 CrossRefPubMed

Shen P, Liu MH, Ng TY, Chan YH, Yong EL (2006) Differential effects of isoflavones, from Astragalus membranaceus and Pueraria thomsonii, on the activation of PPARα, PPARγ, and adipocyte differentiation in vitro. J Nutr 136:899–905PubMed

Vaya J, Belinky PA, Aviram M (1997) Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidant capacity toward LDL oxidation. Free Radic Biol Med 23:302–312, doi:10.1016/S0891-5849(97)00089-0 CrossRefPubMed

Dong TTX, Zhao KJ, Gao QT, Ji ZN, Zhu TT, Li J, Duan R, Cheung AWH, Tsim KWK (2006) Chemical and biological assessment of a Chinese herbal decoction containing Radix astragali and Radix angelicae sinensis: determination of drug ratio in having optimized properties. J Agric Food Chem 54:2767–2774, doi:10.1021/jf053163l CrossRefPubMed

10.

Roberts-Thomson SJ (2000) Peroxisome proliferator-activated receptors in tumorigenesis: targets of tumour promotion and treatment. Immunol Cell Biol 78:436–441, doi:10.1046/j.1440-1711.2000.00921.x CrossRefPubMed

11.

Auyeung KK, Liu P, Chan C, Wu W, Lee SS, Ko JKS (2008) Herbal isoprenols induce apoptosis in human colon cancer cells through transcriptional activation of PPARγ. Cancer Invest 26:708–717, doi:10.1080/07357900801898656 CrossRef

12.

Gupta RA, Dubois RN (2002) Controversy: PPARgamma as a target for treatment of colorectal cancer. Am J Physiol Gastrointest Liver Physiol 283:G266–G269PubMed

13.

Hsu Y, Kuo P, Lin C (2005) Isoliquiritigenin induces apoptosis and cell cycle arrest through p53-dependent pathway in Hep G2 cells. Life Sci 77:279–292, doi:10.1016/j.lfs.2004.09.047 CrossRefPubMed

14.

Ma J, Fu NY, Pang DB, Wu WY, Xu AL (2001) Apoptosis induced by isoliquiritigenin in human gastric cancer MGC-803 cells. Planta Med 67:754–757, doi:10.1055/s-2001-11533 CrossRefPubMed

15.

Jung JI, Lim SS, Choi HJ, Cho HJ, Shin H, Kim EJ, Chung W, Park K, Park JHY (2006) Isoliquiritigenin induces apoptosis by depolarizing mitochondrial membranes in prostate cancer cells. J Nutr Biochem 17:689–696, doi:10.1016/j.jnutbio.2005.11.006 CrossRefPubMed

16.

Hsu Y, Kuo P, Chiang L, Lin C (2004) Isoliquiritigenin inhibits the proliferation and induces the apoptosis of human non-small cell lung cancer a549 cells. Clin Exp Pharmacol Physiol 31:414–418, doi:10.1111/j.1440-1681.2004.04016.x CrossRefPubMed

17.

Maggiolini M, Statti G, Vivacqua A, Gabriele S, Rago V, Loizzo M, Menichini F, Amdo S (2002) Estrogenic and antiproliferative activities of isoliquiritigenin in MCF7 breast cancer cells. J Steroid Biochem Mol Biol 82:315–322, doi:10.1016/S0960-0760(02)00230-3 CrossRefPubMed

18.

Takahashi T, Takasuka N, Ligo M, Baba M, Nishino H, Tsuda H, Okuyama T (2004) Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development. Cancer Sci 95:448–453, doi:10.1111/j.1349-7006.2004.tb03230.x CrossRefPubMed

19.

Baek SJ, Wilson LC, Eling TE (2002) Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53. Carcinogenesis 23:425–434, doi:10.1093/carcin/23.3.425 CrossRefPubMed

20.

Ko JKS, Leung WC, Ho WK, Chiu P (2007) Herbal diterpenoids induce growth arrest and apoptosis in colon cancer cells with increased expression of the nonsteroidal anti-inflammatory drug-activated gene. Eur J Pharmacol 559:1–13, doi:10.1016/j.ejphar.2006.12.004 CrossRefPubMed

21.

Baek SJ, Kim JS, Nixon JB, Di Augustine RP, Eling TE (2004) Expression of NAG-1, a transforming growth factor-beta superfamily member, by troglitazone requires the early growth response gene EGR-1. J Biol Chem 279:6883–6892, doi:10.1074/jbc.M305295200 CrossRefPubMed

22.

Lin J, Dong HF, Oppenheim JJ, Howard OM (2003) Effects of astragali radix on the growth of different cancer cell lines. World J Gastroenterol 9(4):670–673PubMed

23.

Park J, Kim SH, Cho D, Kim TS (2005) Formononetin, a phyto-oestrogen, and its metabolites up-regulate interleukin-4 production in activated T cells via increased AP-1 DNA binding activity. Immunology 116(1):71–81, doi:10.1111/j.1365-2567.2005.02199.x CrossRefPubMed

24.

Nestel P, Fujii A, Zhang L (2007) An isoflavone metabolite reduces arterial stiffness and blood pressure in overweight men and postmenopausal women. Atherosclerosis 192:184–189, doi:10.1016/j.atherosclerosis.2006.04.033 CrossRefPubMed

25.

Shen P, Liu MH, Ng TY, Chan YH, Yong EL (2006) Differential effects of isoflavones, from Astragalus membranaceus and Pueraria thomsonii, on the activation of PPARalpha, PPARgamma, and adipocyte differentiation in vitro. J Nutr 136(4):899–905PubMed

26.

Huo Y, Guo C, Zhang QY, Chen WS, Zheng HC, Rahman K, Qin LP (2007) Antinociceptive activity and chemical composition of constituents from Caragana microphylla seeds. Phytomedicine 14(2-3):143–146, doi:10.1016/j.phymed.2006.03.008 CrossRefPubMed

27.

Ko JKS, Lam FYL, Cheung APL (2005) Amelioration of experimental colitis by Astragalus membranaceus through anti-oxidation and inhibition of adhesion molecule synthesis. World J Gastroenterol 11(37):5787–5794PubMed

28.

Jun M, Hong J, Jeong WS, Ho CT (2005) Suppression of arachidonic acid metabolism and nitric oxide formation by kudzu isoflavones in murine macrophages. Mol Nutr Food Res 49(12):1154–1159, doi:10.1002/mnfr.200500103 CrossRefPubMed

29.

Ho PK, Hawkins CJ (2005) Mammalian initiator apoptotic caspases. FEBS J 272(21):5436–5453, doi:10.1111/j.1742-4658.2005.04966.x CrossRefPubMed

30.

Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S, Smulson M (1999) Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem 274(33):22932–22940, doi:10.1074/jbc.274.33.22932 CrossRefPubMed

31.

Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326, doi:10.1126/science.281.5381.1322 CrossRefPubMed

32.

Chao DT, Korsmeyer SJ (1998) Bcl-2 family: regulators of cell death. Annu Rev Immunol 16:395–419, doi:10.1146/annurev.immunol.16.1.395 CrossRefPubMed

33.

Iwashita K, Kobori M, Yamaki K, Tsushida T (2000) Flavonoids inhibit cell growth and induce apoptosis in B16 melanoma 4A5 cells. Biosci Biotechnol Biochem 64:1813–1820, doi:10.1271/bbb.64.1813 CrossRefPubMed

34.

Vermeulen K, van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36:131–149, doi:10.1046/j.1365-2184.2003.00266.x CrossRefPubMed

35.

Ford HL, Pardee AB (1998) The S phase: beginning, middle, and end: a perspective. J Cell Biol Suppl 30–31:1–7

36.

O’Connell MJ, Cimprich KA (2005) G2 damage checkpoints: what is the turn-on? J Cell Sci 118(pt 1):1–6, doi:10.1242/jcs.01626 CrossRefPubMed

37.

Walker DH, Maller JL (1991) Role for cyclin A in the dependence of mitosis on completion of DNA replication. Nature 354:314–317, doi:10.1038/354314a0 CrossRefPubMed

38.

Borboule N, Baldin V, Jozan S, Vidal S, Valette A (1998) Increased level of p21 in human ovarian tumors is associated with increased expression of cdk2, cyclin A and PCNA. Int J Cancer 76:891–896, doi:10.1002/(SICI)1097-0215(19980610)76:6<891::AID-IJC20>3.0.CO;2-4 CrossRef

39.

Baek SJ, Kim JS, Moore SM, Lee SH, Martinez J, Eling TE (2004) Cyclooxygenase inhibitors induce the expression of the tumor suppressor gene Egr-1, which results in the up-regulation of NAG-1, an antitumorigenic protein. Mol Pharmacol 67(2):356–364, doi:10.1124/mol.104.005108 CrossRefPubMed

40.

Eling TE, Baek SJ, Shim M, Lee CH (2006) NSAID activated gene (NAG-1), a modulator of tumorigenesis. J Biochem Mol Biol 39(6):649–655PubMed

Titel: Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell
verfasst von: Kathy Ka-Wai Auyeung
Joshua Ka-Shun Ko
Publikationsdatum: 01.02.2010
Verlag: Springer US
Erschienen in: Investigational New Drugs / Ausgabe 1/2010
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-008-9207-3

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Novel herbal flavonoids promote apoptosis but differentially induce cell cycle arrest in human colon cancer cell

Summary

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