title: Guizhi Fuling Wan as a Novel Agent for Intravesical Treatment for Bladder Cancer in a Mouse Model.
abstract: Alternative intravesical agents are required to overcome the side effects currently associated with the treatment of bladder cancer. This study used an orthotopic bladder cancer mouse model to evaluate Guizhi Fuling Wan (GFW) as an intravesical agent. The effects of GFW were compared with those of mitomycin-C (Mito-C) and bacille Calmette-Guérin (BCG). We began by evaluating the response of the mouse bladder cancer cell line MB49 to GFW treatment, with regard to cell viability, cell cycle progression and apoptosis. MB49 cells were subsequently implanted into the urothelial walls of the bladder in female C57BL/6 mice. The success of the model was confirmed by the appearance of hematuria and tumor growth in the bladder. Intravesical chemotherapy was administered in accordance with a published protocol.In vitrodata revealed that GFW arrested MB49 cell cycle in the G0/G1 phase, resulting in the suppression of cell proliferation and induced apoptosis. One possible mechanism underlying these effects is an increase in intracellular reactive oxygen species (ROS) levels leading to the activation of ataxia telangiectasia-mutated (ATM)/checkpoint kinase 2 (CHK2) and ATM/P53 pathways, thereby mediating cell cycle progression and apoptosis, respectively. This mouse model demonstrates the effectiveness of GFW in the tumor growth, with results comparable to those achieved by using BCG and Mito-C. Furthermore, GFW was shown to cause only mild hematuria. The low toxicity of the compound was confirmed by a complete lack of lesions on bladder tissue, even after 10 consecutive treatments using high concentrations of GFW. These results demonstrate the potential of GFW for the intravesical therapy of bladder cancer.
authors.affiliation: Department of Chinese Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.|Graduate Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.|Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan.
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.|Department of Urology, and Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Cheng-Huang
authors.initials: CH
authors.lastname: Shen
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.|Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan.
authors.forename: Chia-Bin
authors.initials: CB
authors.lastname: Chang
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.|Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan.|Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Hsiao-Yen
authors.initials: HY
authors.lastname: Hsieh
authors.affiliation: Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Jiann-Der
authors.initials: JD
authors.lastname: Wu
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.
authors.forename: Ling-Huei
authors.initials: LH
authors.lastname: Tseng
authors.affiliation: Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, Taiwan.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Hwang
authors.affiliation: Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Syue-Yi
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.|Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Wu
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.|Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan.
authors.forename: Michael W Y
authors.initials: MWY
authors.lastname: Chan
authors.affiliation: Graduate Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.|Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.|Department of Urology, and Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Cheng-Da
authors.initials: CD
authors.lastname: Hsu
references.citation: J Clin Pathol. 2002 Sep;55(9):641-7
references.pmid: 12194991
references.citation: J Biol Chem. 2014 Feb 28;289(9):5730-46
references.pmid: 24421316
references.citation: J Ethnopharmacol. 2008 Oct 30;120(1):25-35
references.pmid: 18761069
references.citation: Free Radic Biol Med. 2002 May 1;32(9):790-6
references.pmid: 11978480
references.citation: J Urol. 2003 Jan;169(1):90-5
references.pmid: 12478111
references.citation: Urology. 2007 Sep;70(3):591.e9-10
references.pmid: 17905131
references.citation: In Vivo. 2010 May-Jun;24(3):287-91
references.pmid: 20555000
references.citation: Cancer Res. 2002 Mar 15;62(6):1876-83
references.pmid: 11912168
references.citation: Biochem J. 1996 Jan 1;313 ( Pt 1):17-29
references.pmid: 8546679
references.citation: Apoptosis. 2008 Dec;13(12 ):1465-78
references.pmid: 19002586
references.citation: Adv Cancer Res. 2010;108:73-112
references.pmid: 21034966
references.citation: Molecules. 2011 Sep 28;16(10):8228-42
references.pmid: 21959296
references.citation: Mol Cancer Ther. 2004 Jul;3(7):877-84
references.pmid: 15252149
references.citation: J Clin Invest. 1997 Aug 15;100(4):839-46
references.pmid: 9259583
references.citation: World J Urol. 1997;15(2):84-8
references.pmid: 9144896
references.citation: Mol Cell Biol. 2003 Dec;23(23):8576-85
references.pmid: 14612402
references.citation: Carcinogenesis. 2009 Jan;30(1):2-10
references.pmid: 18978338
references.citation: Curr Opin Oncol. 2008 May;20(3):307-14
references.pmid: 18391631
references.citation: Science. 1994 Dec 16;266(5192):1821-8
references.pmid: 7997877
references.citation: Am J Clin Pathol. 1993 Mar;99(3):244-8
references.pmid: 8447285
references.citation: Science. 2010 Oct 22;330(6003):517-21
references.pmid: 20966255
references.citation: J Urol. 2007 Dec;178(6):2314-30
references.pmid: 17993339
references.citation: Cell Prolif. 2003 Jun;36(3):165-75
references.pmid: 12814432
references.citation: Ann N Y Acad Sci. 1999;893:13-8
references.pmid: 10672226
references.citation: Front Biosci. 2008 May 01;13:5016-29
references.pmid: 18508566
references.citation: J Clin Invest. 2004 Jan;113(2):169-74
references.pmid: 14722606
references.citation: Science. 1988 Apr 29;240(4852):640-2
references.pmid: 2834821
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3110-5
references.pmid: 24520177
references.citation: Carcinogenesis. 2009 Oct;30(10):1744-53
references.pmid: 19549704
references.citation: Nutrition. 2002 Oct;18(10):872-9
references.pmid: 12361782
references.citation: Immunopharmacol Immunotoxicol. 2004 Feb;26(1):103-12
references.pmid: 15106735
references.citation: Br J Pharmacol. 2010 Aug;160(8):2008-27
references.pmid: 20649598
references.citation: Eur Urol. 2011 Apr;59(4):584-94
references.pmid: 21269756
references.citation: CA Cancer J Clin. 2010 Jul-Aug;60(4):244-72
references.pmid: 20566675
references.citation: Molecules. 2014 Jan 27;19(2):1576-91
references.pmid: 24473214
references.citation: Mutat Res. 2009 Apr 26;663(1-2):22-31
references.pmid: 19475715
references.citation: Free Radic Biol Med. 2014 May;70:182-93
references.pmid: 24583460
references.citation: BMC Complement Altern Med. 2013 Feb 23;13:44
references.pmid: 23433042
references.citation: PLoS Genet. 2013 May;9(5):e1003546
references.pmid: 23737759
references.citation: Science. 1998 Sep 11;281(5383):1677-9
references.pmid: 9733515
references.citation: Int Urol Nephrol. 1996;28(6):755-9
references.pmid: 9089042
references.citation: PLoS One. 2014 Jan 30;9(1):e87299
references.pmid: 24498068
references.citation: Immunopharmacol Immunotoxicol. 2005;27(3):473-83
references.pmid: 16237957
references.citation: Oncogene. 1998 Feb 12;16(6):721-36
references.pmid: 9488036
references.citation: Carcinogenesis. 2005 May;26(5):958-67
references.pmid: 15705601