Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2011

Open Access 01-12-2011 | Research

Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway

Authors: Xiaoman Xu, Yi Zhang, Dan Qu, Tingshu Jiang, Shengqi Li

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2011

Login to get access

Abstract

Background

To explore the effects of Osthole on the proliferation, cell cycle and apoptosis of human lung cancer A549 cells.

Methods

Human lung cancer A549 cells were treated with Osthole at different concentrations. Cell proliferation was measured using the MTT assay. Cell cycle was evaluated using DNA flow cytometry analysis. Induction of apoptosis was determined by flow cytometry and fluorescent microscopy. The expressions of Cyclin B1, p-Cdc2, Bcl-2, Bax, t-Akt and p-Akt were evaluated by Western blotting.

Results

Osthole inhibited the growth of human lung cancer A549 cells by inducing G2/M arrest and apoptosis. Western blotting demonstrated that Osthole down-regulated the expressions of Cyclin B1, p-Cdc2 and Bcl-2 and up-regulated the expressions of Bax in A549 cells. Inhibition of PI3K/Akt signaling pathway was also observed after treating A549 cells with Osthole.

Conclusions

Our findings suggest that Osthole may have a therapeutic application in the treatment of human lung cancer.
Appendix
Available only for authorised users
Literature
1.
go back to reference Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005, 55: 74-108. 10.3322/canjclin.55.2.74.CrossRefPubMed Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005, 55: 74-108. 10.3322/canjclin.55.2.74.CrossRefPubMed
2.
go back to reference Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96. 10.3322/CA.2007.0010.CrossRefPubMed Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96. 10.3322/CA.2007.0010.CrossRefPubMed
3.
go back to reference Erridge SC, Moller H, Price A, Brewster D: International comparisons of survival from lung cancer: pitfalls and warnings. Nat Clin Pract Oncol. 2007, 4: 570-7. 10.1038/ncponc0932.CrossRefPubMed Erridge SC, Moller H, Price A, Brewster D: International comparisons of survival from lung cancer: pitfalls and warnings. Nat Clin Pract Oncol. 2007, 4: 570-7. 10.1038/ncponc0932.CrossRefPubMed
4.
go back to reference Hsu SC, Ou CC, Chuang TC, Li JW, Lee YJ, Wang V, Liu JY, Chen CS, Lin SC, Kao MC: Ganoderma tsugae extract inhibits expression of epidermal growth factor receptor and angiogenesis in human epidermoid carcinoma cells: In vitro and in vivo. Cancer Lett. 2009, 281: 108-16. 10.1016/j.canlet.2009.02.032.CrossRefPubMed Hsu SC, Ou CC, Chuang TC, Li JW, Lee YJ, Wang V, Liu JY, Chen CS, Lin SC, Kao MC: Ganoderma tsugae extract inhibits expression of epidermal growth factor receptor and angiogenesis in human epidermoid carcinoma cells: In vitro and in vivo. Cancer Lett. 2009, 281: 108-16. 10.1016/j.canlet.2009.02.032.CrossRefPubMed
5.
go back to reference Su CC, Lin YH: Tanshinone IIA down-regulates the protein expression of ErbB-2 and up-regulates TNF-alpha in colon cancer cells in vitro and in vivo. Int J Mol Med. 2008, 22: 847-51.PubMed Su CC, Lin YH: Tanshinone IIA down-regulates the protein expression of ErbB-2 and up-regulates TNF-alpha in colon cancer cells in vitro and in vivo. Int J Mol Med. 2008, 22: 847-51.PubMed
6.
go back to reference Carter BZ, Mak DH, Schober WD, Dietrich MF, Pinilla C, Vassilev LT, Reed JC, Andreeff M: Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5. Blood. 2008, 111: 3742-50. 10.1182/blood-2007-05-091504.PubMedCentralCrossRefPubMed Carter BZ, Mak DH, Schober WD, Dietrich MF, Pinilla C, Vassilev LT, Reed JC, Andreeff M: Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5. Blood. 2008, 111: 3742-50. 10.1182/blood-2007-05-091504.PubMedCentralCrossRefPubMed
7.
go back to reference Guh JH, Yu SM, Ko FN, Wu TS, Teng CM: Antiproliferative effect in rat vascular smooth muscle cells by osthole, isolated from Angelica pubescens. Eur J Pharmacol. 1996, 298: 191-7. 10.1016/0014-2999(95)00812-8.CrossRefPubMed Guh JH, Yu SM, Ko FN, Wu TS, Teng CM: Antiproliferative effect in rat vascular smooth muscle cells by osthole, isolated from Angelica pubescens. Eur J Pharmacol. 1996, 298: 191-7. 10.1016/0014-2999(95)00812-8.CrossRefPubMed
8.
go back to reference Ko FN, Wu TS, Liou MJ, Huang TF, Teng CM: Vasorelaxation of rat thoracic aorta caused by osthole isolated from Angelica pubescens. Eur J Pharmacol. 1992, 219: 29-34. 10.1016/0014-2999(92)90576-P.CrossRefPubMed Ko FN, Wu TS, Liou MJ, Huang TF, Teng CM: Vasorelaxation of rat thoracic aorta caused by osthole isolated from Angelica pubescens. Eur J Pharmacol. 1992, 219: 29-34. 10.1016/0014-2999(92)90576-P.CrossRefPubMed
9.
go back to reference Zimecki M, Artym J, Cisowski W, Mazol I, Wlodarczyk M, Glensk M: Immunomodulatory and anti-inflammatory activity of selected osthole derivatives. Z Naturforsch C. 2009, 64: 361-8.CrossRefPubMed Zimecki M, Artym J, Cisowski W, Mazol I, Wlodarczyk M, Glensk M: Immunomodulatory and anti-inflammatory activity of selected osthole derivatives. Z Naturforsch C. 2009, 64: 361-8.CrossRefPubMed
10.
go back to reference Cai J, Yu B, Xu G, Wu J: Studies on the quality of fructus Cnidii--comparison of antibacterial action. Zhongguo Zhong Yao Za Zhi. 1991, 16: 451-3. 510PubMed Cai J, Yu B, Xu G, Wu J: Studies on the quality of fructus Cnidii--comparison of antibacterial action. Zhongguo Zhong Yao Za Zhi. 1991, 16: 451-3. 510PubMed
11.
go back to reference Matsuda H, Tomohiro N, Ido Y, Kubo M: Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium monnieri) and its major component, osthol. Biol Pharm Bull. 2002, 25: 809-12. 10.1248/bpb.25.809.CrossRefPubMed Matsuda H, Tomohiro N, Ido Y, Kubo M: Anti-allergic effects of cnidii monnieri fructus (dried fruits of Cnidium monnieri) and its major component, osthol. Biol Pharm Bull. 2002, 25: 809-12. 10.1248/bpb.25.809.CrossRefPubMed
12.
go back to reference Okamoto T, Yoshida S, Kobayashi T, Okabe S: Inhibition of concanavalin A-induced mice hepatitis by coumarin derivatives. Jpn J Pharmacol. 2001, 85: 95-7. 10.1254/jjp.85.95.CrossRefPubMed Okamoto T, Yoshida S, Kobayashi T, Okabe S: Inhibition of concanavalin A-induced mice hepatitis by coumarin derivatives. Jpn J Pharmacol. 2001, 85: 95-7. 10.1254/jjp.85.95.CrossRefPubMed
13.
go back to reference Yang LL, Wang MC, Chen LG, Wang CC: Cytotoxic activity of coumarins from the fruits of Cnidium monnieri on leukemia cell lines. Planta Med. 2003, 69: 1091-5. 10.1055/s-2003-45188.CrossRefPubMed Yang LL, Wang MC, Chen LG, Wang CC: Cytotoxic activity of coumarins from the fruits of Cnidium monnieri on leukemia cell lines. Planta Med. 2003, 69: 1091-5. 10.1055/s-2003-45188.CrossRefPubMed
14.
go back to reference Chou SY, Hsu CS, Wang KT, Wang MC, Wang CC: Antitumor effects of Osthol from Cnidium monnieri: an in vitro and in vivo study. Phytother Res. 2007, 21: 226-30. 10.1002/ptr.2044.CrossRefPubMed Chou SY, Hsu CS, Wang KT, Wang MC, Wang CC: Antitumor effects of Osthol from Cnidium monnieri: an in vitro and in vivo study. Phytother Res. 2007, 21: 226-30. 10.1002/ptr.2044.CrossRefPubMed
15.
go back to reference Yang D, Gu T, Wang T, Tang Q, Ma C: Effects of osthole on migration and invasion in breast cancer cells. Biosci Biotechnol Biochem. 2010, 74: 1430-4. 10.1271/bbb.100110.CrossRefPubMed Yang D, Gu T, Wang T, Tang Q, Ma C: Effects of osthole on migration and invasion in breast cancer cells. Biosci Biotechnol Biochem. 2010, 74: 1430-4. 10.1271/bbb.100110.CrossRefPubMed
16.
go back to reference Riviere C, Goossens L, Pommery N, Fourneau C, Delelis A, Henichart JP: Antiproliferative effects of isopentenylated coumarins isolated from Phellolophium madagascariense Baker. Nat Prod Res. 2006, 20: 909-16. 10.1080/14786410500277787.CrossRefPubMed Riviere C, Goossens L, Pommery N, Fourneau C, Delelis A, Henichart JP: Antiproliferative effects of isopentenylated coumarins isolated from Phellolophium madagascariense Baker. Nat Prod Res. 2006, 20: 909-16. 10.1080/14786410500277787.CrossRefPubMed
17.
go back to reference Okamoto T, Kobayashi T, Yoshida S: Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. Curr Med Chem Anticancer Agents. 2005, 5: 47-51. 10.2174/1568011053352622.CrossRefPubMed Okamoto T, Kobayashi T, Yoshida S: Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. Curr Med Chem Anticancer Agents. 2005, 5: 47-51. 10.2174/1568011053352622.CrossRefPubMed
18.
go back to reference Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G: Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature. 1997, 385: 544-8. 10.1038/385544a0.CrossRefPubMed Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G: Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature. 1997, 385: 544-8. 10.1038/385544a0.CrossRefPubMed
19.
go back to reference Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002, 2: 489-501. 10.1038/nrc839.CrossRefPubMed Vivanco I, Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002, 2: 489-501. 10.1038/nrc839.CrossRefPubMed
20.
go back to reference Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridandapani S, Anant S, Kuppusamy P: Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther. 2007, 6: 178-84. 10.4161/cbt.6.2.3577.PubMedCentralCrossRefPubMed Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridandapani S, Anant S, Kuppusamy P: Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther. 2007, 6: 178-84. 10.4161/cbt.6.2.3577.PubMedCentralCrossRefPubMed
21.
go back to reference Katayama K, Fujita N, Tsuruo T: Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol. 2005, 25: 5725-37. 10.1128/MCB.25.13.5725-5737.2005.PubMedCentralCrossRefPubMed Katayama K, Fujita N, Tsuruo T: Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol Cell Biol. 2005, 25: 5725-37. 10.1128/MCB.25.13.5725-5737.2005.PubMedCentralCrossRefPubMed
22.
go back to reference Asnaghi L, Calastretti A, Bevilacqua A, D'Agnano I, Gatti G, Canti G, Delia D, Capaccioli S, Nicolin A: Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene. 2004, 23: 5781-91. 10.1038/sj.onc.1207698.CrossRefPubMed Asnaghi L, Calastretti A, Bevilacqua A, D'Agnano I, Gatti G, Canti G, Delia D, Capaccioli S, Nicolin A: Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt. Oncogene. 2004, 23: 5781-91. 10.1038/sj.onc.1207698.CrossRefPubMed
23.
go back to reference Xavier CP, Lima CF, Preto A, Seruca R, Fernandes-Ferreira M, 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. 2009, 281: 162-70. 10.1016/j.canlet.2009.02.041.CrossRefPubMed Xavier CP, Lima CF, Preto A, Seruca R, Fernandes-Ferreira M, 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. 2009, 281: 162-70. 10.1016/j.canlet.2009.02.041.CrossRefPubMed
24.
go back to reference Pu L, Amoscato AA, Bier ME, Lazo JS: Dual G1 and G2 phase inhibition by a novel, selective Cdc25 inhibitor 6-chloro-7-[corrected](2-morpholin-4-ylethylamino)-quinoline-5,8-dione. J Biol Chem. 2002, 277: 46877-85. 10.1074/jbc.M207902200.CrossRefPubMed Pu L, Amoscato AA, Bier ME, Lazo JS: Dual G1 and G2 phase inhibition by a novel, selective Cdc25 inhibitor 6-chloro-7-[corrected](2-morpholin-4-ylethylamino)-quinoline-5,8-dione. J Biol Chem. 2002, 277: 46877-85. 10.1074/jbc.M207902200.CrossRefPubMed
25.
go back to reference Chao JI, Kuo PC, Hsu TS: Down-regulation of survivin in nitric oxide-induced cell growth inhibition and apoptosis of the human lung carcinoma cells. J Biol Chem. 2004, 279: 20267-76. 10.1074/jbc.M312381200.CrossRefPubMed Chao JI, Kuo PC, Hsu TS: Down-regulation of survivin in nitric oxide-induced cell growth inhibition and apoptosis of the human lung carcinoma cells. J Biol Chem. 2004, 279: 20267-76. 10.1074/jbc.M312381200.CrossRefPubMed
26.
go back to reference Wang Y, Ji P, Liu J, Broaddus RR, Xue F, Zhang W: Centrosome-associated regulators of the G(2)/M checkpoint as targets for cancer therapy. Mol Cancer. 2009, 8: 8-10.1186/1476-4598-8-8.PubMedCentralCrossRefPubMed Wang Y, Ji P, Liu J, Broaddus RR, Xue F, Zhang W: Centrosome-associated regulators of the G(2)/M checkpoint as targets for cancer therapy. Mol Cancer. 2009, 8: 8-10.1186/1476-4598-8-8.PubMedCentralCrossRefPubMed
27.
go back to reference Dash BC, El-Deiry WS: Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Mol Cell Biol. 2005, 25: 3364-87. 10.1128/MCB.25.8.3364-3387.2005.PubMedCentralCrossRefPubMed Dash BC, El-Deiry WS: Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Mol Cell Biol. 2005, 25: 3364-87. 10.1128/MCB.25.8.3364-3387.2005.PubMedCentralCrossRefPubMed
28.
go back to reference Yang CJ, Wang CS, Hung JY, Huang HW, Chia YC, Wang PH, Weng CF, Huang MS: Pyrogallol induces G2-M arrest in human lung cancer cells and inhibits tumor growth in an animal model. Lung Cancer. 2009, 66: 162-8. 10.1016/j.lungcan.2009.01.016.CrossRefPubMed Yang CJ, Wang CS, Hung JY, Huang HW, Chia YC, Wang PH, Weng CF, Huang MS: Pyrogallol induces G2-M arrest in human lung cancer cells and inhibits tumor growth in an animal model. Lung Cancer. 2009, 66: 162-8. 10.1016/j.lungcan.2009.01.016.CrossRefPubMed
29.
go back to reference Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH: An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005, 435: 677-81. 10.1038/nature03579.CrossRefPubMed Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH: An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005, 435: 677-81. 10.1038/nature03579.CrossRefPubMed
30.
go back to reference Thees S, Hubbard GB, Winckler J, Schultz C, Rami A: Specific alteration of the Bax/Bcl2 ratio and cytochrome c without execution of apoptosis in the hippocampus of aged baboons. Restor Neurol Neurosci. 2005, 23: 1-9.PubMed Thees S, Hubbard GB, Winckler J, Schultz C, Rami A: Specific alteration of the Bax/Bcl2 ratio and cytochrome c without execution of apoptosis in the hippocampus of aged baboons. Restor Neurol Neurosci. 2005, 23: 1-9.PubMed
31.
go back to reference Gupta S, Afaq F, Mukhtar H: Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene. 2002, 21: 3727-38. 10.1038/sj.onc.1205474.CrossRefPubMed Gupta S, Afaq F, Mukhtar H: Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene. 2002, 21: 3727-38. 10.1038/sj.onc.1205474.CrossRefPubMed
32.
go back to reference Emi M, Kim R, Tanabe K, Uchida Y, Toge T: Targeted therapy against Bcl-2-related proteins in breast cancer cells. Breast Cancer Res. 2005, 7: R940-52. 10.1186/bcr1323.PubMedCentralCrossRefPubMed Emi M, Kim R, Tanabe K, Uchida Y, Toge T: Targeted therapy against Bcl-2-related proteins in breast cancer cells. Breast Cancer Res. 2005, 7: R940-52. 10.1186/bcr1323.PubMedCentralCrossRefPubMed
33.
go back to reference Luo J, Manning BD, Cantley LC: Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003, 4: 257-62. 10.1016/S1535-6108(03)00248-4.CrossRefPubMed Luo J, Manning BD, Cantley LC: Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003, 4: 257-62. 10.1016/S1535-6108(03)00248-4.CrossRefPubMed
Metadata
Title
Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway
Authors
Xiaoman Xu
Yi Zhang
Dan Qu
Tingshu Jiang
Shengqi Li
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2011
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-30-33

Other articles of this Issue 1/2011

Journal of Experimental & Clinical Cancer Research 1/2011 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine