Skip to main content
Top
Published in: Journal of Experimental & Clinical Cancer Research 1/2016

Open Access 01-12-2016 | Research

Anti-tumor effects of Atractylenolide I on bladder cancer cells

Authors: Rui Yu, Bi-xia Yu, Jun-feng Chen, Xiu-yi Lv, Ze-jun Yan, Yue Cheng, Qi Ma

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2016

Login to get access

Abstract

Background

Atractylenolide I (ATR-1), an active component of Rhizoma Atractylodis Macrocephalae, possesses cytotoxicity against various carcinomas. However, little is known about the effects of ATR-1on bladder cancer. In the present study, the anti-tumor activity of ATR-1 was examined on bladder cancer cells both in vivo and in vitro.

Methods

MTT assay was used to assess the cytotoxic effect of ATR-1. Cell cycle distribution and apoptosis levels were evaluated using flow cytometry. Western blotting assay was applied to measure the levels of proteins associated with the apoptotic pathway, cell cycle progression and PI3K/Akt/mTOR signaling pathway. Tumor models in nude mice were induced by injection of T-24 and 253J human bladder cancer cells.

Results

ATR-1 inhibited bladder cancer cell proliferation, arrested cell cycle in G2/M phase through up-regulation of p21 and down-regulation of cyclin B1, CDK1 and Cdc25c. Meanwhile, ATR-1 also triggered cellular apoptosis depending on the activation of mitochondrial apoptotic pathway. Mechanism investigation indicated that ATR-1 exerts its anti-tumor effect also relies on the inhibition of PI3K/Akt/mTOR signaling pathway. Finally, mice studies showed that ATR-1 blocked the T-24 or 253J-induced xenograft tumor growth without noticeable toxicity.

Conclusions

ATR-1 may be served as a potential therapeutic agent for the treatment of bladder cancer.
Literature
1.
go back to reference Carneiro BA, Meeks JJ, Kuzel TM, Scaranti M, Abdulkadir SA, Giles FJ. Emerging therapeutic targets in bladder cancer. Cancer Treat Rev. 2015;41:170–8.CrossRef Carneiro BA, Meeks JJ, Kuzel TM, Scaranti M, Abdulkadir SA, Giles FJ. Emerging therapeutic targets in bladder cancer. Cancer Treat Rev. 2015;41:170–8.CrossRef
2.
go back to reference Bellmunt J, Orsola A, Leow JJ, Wiegel T, De Santis M, Horwich A, et al. Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii40–48.CrossRef Bellmunt J, Orsola A, Leow JJ, Wiegel T, De Santis M, Horwich A, et al. Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii40–48.CrossRef
3.
go back to reference Pal SK, Milowsky MI, Plimack ER. Optimizing systemic therapy for bladder cancer. J Natl Compr Canc Netw. 2013;11:793–804.CrossRef Pal SK, Milowsky MI, Plimack ER. Optimizing systemic therapy for bladder cancer. J Natl Compr Canc Netw. 2013;11:793–804.CrossRef
4.
go back to reference van Kessel KE, Zuiverloon TC, Alberts AR, Boormans JL, Zwarthoff EC. Targeted therapies in bladder cancer: an overview of in vivo research. Nat Rev Urol. 2015;12:681–94.CrossRef van Kessel KE, Zuiverloon TC, Alberts AR, Boormans JL, Zwarthoff EC. Targeted therapies in bladder cancer: an overview of in vivo research. Nat Rev Urol. 2015;12:681–94.CrossRef
5.
go back to reference Wang A, Xiao Z, Zhou L, Zhang J, Li X, He Q. The protective effect of atractylenolide I on systemic inflammation in the mouse model of sepsis created by cecal ligation and puncture. Pharm Biol. 2016;54:146–50.CrossRef Wang A, Xiao Z, Zhou L, Zhang J, Li X, He Q. The protective effect of atractylenolide I on systemic inflammation in the mouse model of sepsis created by cecal ligation and puncture. Pharm Biol. 2016;54:146–50.CrossRef
6.
go back to reference Zhao H, Ji ZH, Liu C, Yu XY. Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats. Neuroscience. 2015;290:485–91.CrossRef Zhao H, Ji ZH, Liu C, Yu XY. Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats. Neuroscience. 2015;290:485–91.CrossRef
7.
go back to reference Wang KT, Chen LG, Wu CH, Chang CC, Wang CC. Gastroprotective activity of atractylenolide III from Atractylodes ovata on ethanol-induced gastric ulcer in vitro and in vivo. J Pharm Pharmacol. 2010;62:381–8.CrossRef Wang KT, Chen LG, Wu CH, Chang CC, Wang CC. Gastroprotective activity of atractylenolide III from Atractylodes ovata on ethanol-induced gastric ulcer in vitro and in vivo. J Pharm Pharmacol. 2010;62:381–8.CrossRef
8.
go back to reference Wang CC, Chen LG, Yang LL. Cytotoxic activity of sesquiterpenoids from Atractylodes ovata on leukemia cell lines. Planta Med. 2002;68:204–8.CrossRef Wang CC, Chen LG, Yang LL. Cytotoxic activity of sesquiterpenoids from Atractylodes ovata on leukemia cell lines. Planta Med. 2002;68:204–8.CrossRef
9.
go back to reference Yan Y, Chou GX, Hui W, Chu JH, Fong WF, Yu ZL. Effects of sesquiterpenes isolated from largehead atractylodes rhizome on growth, migration, and differentiation of B16 melanoma cells. Integr Cancer Ther. 2011;10:92–100.CrossRef Yan Y, Chou GX, Hui W, Chu JH, Fong WF, Yu ZL. Effects of sesquiterpenes isolated from largehead atractylodes rhizome on growth, migration, and differentiation of B16 melanoma cells. Integr Cancer Ther. 2011;10:92–100.CrossRef
10.
go back to reference Ye Y, Chao XJ, Wu JF, Cheng BC, Su T, Fu XQ, et al. ERK/GSK3beta signaling is involved in atractylenolide I-induced apoptosis and cell cycle arrest in melanoma cells. Oncol Rep. 2015;34:1543–8.CrossRef Ye Y, Chao XJ, Wu JF, Cheng BC, Su T, Fu XQ, et al. ERK/GSK3beta signaling is involved in atractylenolide I-induced apoptosis and cell cycle arrest in melanoma cells. Oncol Rep. 2015;34:1543–8.CrossRef
11.
go back to reference Liu H, Zhu Y, Zhang T, Zhao Z, Zhao Y, Cheng P, et al. Anti-tumor effects of atractylenolide I isolated from Atractylodes macrocephala in human lung carcinoma cell lines. Molecules. 2013;18:13357–68.CrossRef Liu H, Zhu Y, Zhang T, Zhao Z, Zhao Y, Cheng P, et al. Anti-tumor effects of atractylenolide I isolated from Atractylodes macrocephala in human lung carcinoma cell lines. Molecules. 2013;18:13357–68.CrossRef
12.
go back to reference Liu Y, Jia Z, Dong L, Wang R, Qiu G. A randomized pilot study of atractylenolide I on gastric cancer cachexia patients. Evid Based Complement Alternat Med. 2008;5:337–44.CrossRef Liu Y, Jia Z, Dong L, Wang R, Qiu G. A randomized pilot study of atractylenolide I on gastric cancer cachexia patients. Evid Based Complement Alternat Med. 2008;5:337–44.CrossRef
13.
go back to reference Molinari M. Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif. 2000;33:261–74.CrossRef Molinari M. Cell cycle checkpoints and their inactivation in human cancer. Cell Prolif. 2000;33:261–74.CrossRef
14.
go back to reference Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11:621–32.CrossRef Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010;11:621–32.CrossRef
15.
go back to reference Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–62.CrossRef Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–62.CrossRef
16.
go back to reference Burris 3rd HA. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71:829–42.CrossRef Burris 3rd HA. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71:829–42.CrossRef
17.
go back to reference Pinto-Leite R, Botelho P, Ribeiro E, Oliveira P, Santos L. Effect of sirolimus on urinary bladder cancer T24 cell line. J Exp Clin Cancer Res. 2009;28:3.CrossRef Pinto-Leite R, Botelho P, Ribeiro E, Oliveira P, Santos L. Effect of sirolimus on urinary bladder cancer T24 cell line. J Exp Clin Cancer Res. 2009;28:3.CrossRef
18.
go back to reference Mansure JJ, Nassim R, Chevalier S, Rocha J, Scarlata E, Kassouf W. Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer. Cancer Biol Ther. 2009;8:2339–47.CrossRef Mansure JJ, Nassim R, Chevalier S, Rocha J, Scarlata E, Kassouf W. Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer. Cancer Biol Ther. 2009;8:2339–47.CrossRef
19.
go back to reference Liu M, Qi Z, Liu B, Ren Y, Li H, Yang G, et al. RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway. Oncotarget. 2015;6:25281–94.PubMedPubMedCentral Liu M, Qi Z, Liu B, Ren Y, Li H, Yang G, et al. RY-2f, an isoflavone analog, overcomes cisplatin resistance to inhibit ovarian tumorigenesis via targeting the PI3K/AKT/mTOR signaling pathway. Oncotarget. 2015;6:25281–94.PubMedPubMedCentral
20.
go back to reference Briest F, Grabowski P. PI3K-AKT-mTOR-signaling and beyond: the complex network in gastroenteropancreatic neuroendocrine neoplasms. Theranostics. 2014;4:336–65.CrossRef Briest F, Grabowski P. PI3K-AKT-mTOR-signaling and beyond: the complex network in gastroenteropancreatic neuroendocrine neoplasms. Theranostics. 2014;4:336–65.CrossRef
21.
go back to reference Jin D, Cao M, Mu X, Yang G, Xue W, Huang Y, et al. Catalpol inhibited the proliferation of T24 human bladder cancer cells by inducing apoptosis through the blockade of Akt-mediated anti-apoptotic signaling. Cell Biochem Biophys. 2015;71,1349-56.CrossRef Jin D, Cao M, Mu X, Yang G, Xue W, Huang Y, et al. Catalpol inhibited the proliferation of T24 human bladder cancer cells by inducing apoptosis through the blockade of Akt-mediated anti-apoptotic signaling. Cell Biochem Biophys. 2015;71,1349-56.CrossRef
22.
go back to reference Xu X, Zhang Y, Qu D, Jiang T, Li S. Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway. J Exp Clin Cancer Res. 2011;30:33.CrossRef Xu X, Zhang Y, Qu D, Jiang T, Li S. Osthole induces G2/M arrest and apoptosis in lung cancer A549 cells by modulating PI3K/Akt pathway. J Exp Clin Cancer Res. 2011;30:33.CrossRef
23.
go back to reference Bernhard EJ, Maity A, Muschel RJ, McKenna WG. Effects of ionizing radiation on cell cycle progression. A review. Radiat Environ Biophys. 1995;34:79–83.CrossRef Bernhard EJ, Maity A, Muschel RJ, McKenna WG. Effects of ionizing radiation on cell cycle progression. A review. Radiat Environ Biophys. 1995;34:79–83.CrossRef
24.
go back to reference Wani ZA, Guru SK, Rao AV, Sharma S, Mahajan G, Behl A, et al. A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells. Food Chem Toxicol. 2015;87:1–11.CrossRef Wani ZA, Guru SK, Rao AV, Sharma S, Mahajan G, Behl A, et al. A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells. Food Chem Toxicol. 2015;87:1–11.CrossRef
25.
go back to reference Kumar S, Yedjou CG, Tchounwou PB. Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells. J Exp Clin Cancer Res. 2014;33:42.CrossRef Kumar S, Yedjou CG, Tchounwou PB. Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells. J Exp Clin Cancer Res. 2014;33:42.CrossRef
26.
go back to reference Yuan L, Wang J, Xiao H, Xiao C, Wang Y, Liu X. Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells. Toxicol Appl Pharmacol. 2012;265:83–92.CrossRef Yuan L, Wang J, Xiao H, Xiao C, Wang Y, Liu X. Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells. Toxicol Appl Pharmacol. 2012;265:83–92.CrossRef
27.
go back to reference Wong R. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30:87.CrossRef Wong R. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30:87.CrossRef
28.
go back to reference Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–510.CrossRef Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–510.CrossRef
29.
go back to reference Meng Q, Xia C, Fang J, Rojanasakul Y, Jiang BH. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal. 2006;18:2262–71.CrossRef Meng Q, Xia C, Fang J, Rojanasakul Y, Jiang BH. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal. 2006;18:2262–71.CrossRef
30.
go back to reference Calderaro J, Rebouissou S, de Koning L, Masmoudi A, Herault A, Dubois T, et al. PI3K/AKT pathway activation in bladder carcinogenesis. Int J Cancer. 2014;134:1776–84.CrossRef Calderaro J, Rebouissou S, de Koning L, Masmoudi A, Herault A, Dubois T, et al. PI3K/AKT pathway activation in bladder carcinogenesis. Int J Cancer. 2014;134:1776–84.CrossRef
31.
go back to reference Yuge K, Kikuchi E, Hagiwara M, Yasumizu Y, Tanaka N, Kosaka T, et al. Nicotine induces tumor growth and chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer. Mol Cancer Ther. 2015;14:2112–20.CrossRef Yuge K, Kikuchi E, Hagiwara M, Yasumizu Y, Tanaka N, Kosaka T, et al. Nicotine induces tumor growth and chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer. Mol Cancer Ther. 2015;14:2112–20.CrossRef
32.
go back to reference Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22:8983–98.CrossRef Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene. 2003;22:8983–98.CrossRef
33.
go back to reference Huang JM, Zhang GN, Shi Y, Zha X, Zhu Y, Wang MM, et al. Atractylenolide-I sensitizes human ovarian cancer cells to paclitaxel by blocking activation of TLR4/MyD88-dependent pathway. Sci Rep. 2014;4:3840.CrossRef Huang JM, Zhang GN, Shi Y, Zha X, Zhu Y, Wang MM, et al. Atractylenolide-I sensitizes human ovarian cancer cells to paclitaxel by blocking activation of TLR4/MyD88-dependent pathway. Sci Rep. 2014;4:3840.CrossRef
34.
go back to reference Sun W, Meng K, Qi C, Yang X, Wang Y, Fan W, et al. Immune-enhancing activity of polysaccharides isolated from Atractylodis macrocephalae Koidz. Carbohydr Polym. 2015;126:91–6.CrossRef Sun W, Meng K, Qi C, Yang X, Wang Y, Fan W, et al. Immune-enhancing activity of polysaccharides isolated from Atractylodis macrocephalae Koidz. Carbohydr Polym. 2015;126:91–6.CrossRef
Metadata
Title
Anti-tumor effects of Atractylenolide I on bladder cancer cells
Authors
Rui Yu
Bi-xia Yu
Jun-feng Chen
Xiu-yi Lv
Ze-jun Yan
Yue Cheng
Qi Ma
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2016
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-016-0312-4

Other articles of this Issue 1/2016

Journal of Experimental & Clinical Cancer Research 1/2016 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