title: Hirsutanol A, a novel sesquiterpene compound from fungus Chondrostereum sp., induces apoptosis and inhibits tumor growth through mitochondrial-independent ROS production: hirsutanol A inhibits tumor growth through ROS production.
abstract: BACKGROUND
  Hirsutanol A is a novel sesquiterpene compound purified from fungus Chondrostereum sp. in Sarcophyton tortuosum. Our previous studies had demonstrated that hirsutanol A exhibited potent cytotoxic effect on many kinds of cancer cell lines. In the current study, the antitumor activity of hirsutanol A and its molecular mechanisms were investigated.
  
  
  METHODS
  Hirsutanol A induced growth inhibition and apoptotic cell death of human colon cancer SW620 cells and human breast cancer MDA-MB-231cells were determined using MTT assay and flow cytometry assay, respectively. The effect of hirsutanol A on intrinsic ROS level and change in mitochondrial membrane potential (△ψm) of different cell lines were also measured by flow cytometry assay. The function of JNK was compromised by JNK siRNA or JNK inhibitor SP600125. The expression of cytochrome c, p-JNK, p-c-Jun after treatment with hirsutanol A were detected by Western blot analysis. Finally, the in vivo anti-tumor effect of hirsutanol A was examined in human cancer cell SW620 xenograft model.
  
  
  RESULTS
  The results showed that hirsutanol A significantly induced apoptosis, mitochondrial-independent increase of Reactive Oxygen Species (ROS) level, change of mitochondrial membrane potential, release of cytochrome c in human cancer cells. Preventing increase of ROS level using the potent antioxidant N-acetyl-L-cysteine (NAC) markedly decreased hirsutanol A-induced apoptosis. In addition, JNK signaling pathway was activated by hirsutanol A through elevating ROS level. Blockade of JNK signaling pathway by JNK specific inhibitor SP600125 enhanced apoptosis and hirsutanol A-induced ROS accumulation. Also, hirsutanol A exhibited antitumor activity in human cancer cell SW620 xenograft model.
  
  
  CONCLUSIONS
  These data suggested that hirsutanol A inhibited tumor growth through triggering ROS production and apoptosis.
authors: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, 651 Dongfeng Road East, Guangzhou 510060, China.
authors: Fen
authors: F
authors: Yang
authors: Wen-Dan
authors: WD
authors: Chen
authors: Rong
authors: R
authors: Deng
authors: Hui
authors: H
authors: Zhang
authors: Jun
authors: J
authors: Tang
authors: Ke-Wei
authors: KW
authors: Wu
authors: Dan-Dan
authors: DD
authors: Li
authors: Gong-Kan
authors: GK
authors: Feng
authors: Wen-Jian
authors: WJ
authors: Lan
authors: Hou-Jin
authors: HJ
authors: Li
authors: Xiao-Feng
authors: XF
authors: Zhu
mesh_terms: D000363:Agaricales / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D013778:Tetrazolium Salts; D013844:Thiazoles; C569055:hirsutanol A; D045304:Cytochromes c; C022616:thiazolyl blue
references: J Signal Transduct. 2012;2012:329635
references: 22175013
references: Cell. 2004 Jun 11;117(6):773-86
references: 15186778
references: Eur J Cancer. 2005 Jul;41(11):1637-44
references: 15953713
references: Med Hypotheses. 2007;69(6):1293-8
references: 17509774
references: Cancer Lett. 2010 Oct 1;296(1):96-105
references: 20580989
references: Chem Biodivers. 2011 Feb;8(2):317-24
references: 21337504
references: Nat Rev Drug Discov. 2009 Jul;8(7):579-91
references: 19478820
references: Brain Res. 1994 Jan 28;635(1-2):113-7
references: 8173945
references: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
references: 11717429
references: J Neurosci. 1996 Feb 15;16(4):1324-36
references: 8778284
references: Biol Pharm Bull. 2006 Apr;29(4):648-54
references: 16595895
references: Cancer Cell. 2006 Sep;10(3):241-52
references: 16959615
references: World J Gastroenterol. 2009 Apr 14;15(14):1702-7
references: 19360913
references: EMBO Rep. 2002 May;3(5):420-5
references: 11991946
references: Oncol Res. 2004;14(7-8):355-62
references: 15301426
references: Oncol Rep. 2009 Aug;22(2):385-91
references: 19578781
references: Leukemia. 2008 Jun;22(6):1191-9
references: 18385754
references: Mol Cancer Ther. 2009 Apr;8(4):873-82
references: 19372560
references: Cancer Biol Ther. 2007 Sep;6(9):1413-21
references: 17786034
references: Oncogene. 2009 Feb 12;28(6):886-98
references: 19060920
references: Oncogene. 2006 Nov 9;25(53):7070-7
references: 16715131
references: Adv Drug Deliv Rev. 2009 Apr 28;61(4):290-302
references: 19249331
references: Chin J Cancer. 2010 Jul;29(7):655-60
references: 20591217
references: Chem Biol Interact. 2006 Mar 10;160(1):1-40
references: 16430879
references: Nature. 2000 Sep 21;407(6802):390-5
references: 11014196
references: Trends Cell Biol. 2001 Aug;11(8):343-8
references: 11489640
references: Drug Resist Updat. 2004 Apr;7(2):97-110
references: 15158766
references: Cancer Cell. 2006 Sep;10(3):175-6
references: 16959608
references: J Clin Biochem Nutr. 2008 Sep;43(2):51-7
references: 18818753
references: Cytometry. 1997 Jan 1;27(1):1-20
references: 9000580
references: Oncogene. 2006 Jan 26;25(4):503-11
references: 16170347
references: Curr Protoc Neurosci. 2010 Jul;Chapter 7:Unit 7.22
references: 20578034
references: Cancer Biol Ther. 2009 Apr;8(8):739-43
references: 19242112
references: Nature. 2002 Sep 19;419(6904):316-21
references: 12239572
references: Curr Opin Struct Biol. 2005 Dec;15(6):690-9
references: 16263267
references: Int J Biochem Cell Biol. 2010 Oct;42(10):1634-50
references: 20601089
references: Cell. 2004 Jan 23;116(2):205-19
references: 14744432
references: Cancer Res. 2007 Apr 15;67(8):3512-7
references: 17440056
references: Leukemia. 2007 Jun;21(6):1300-2
references: 17392822