title: Dichloroacetate enhances adriamycin-induced hepatoma cell toxicity in vitro and in vivo by increasing reactive oxygen species levels.
abstract: A unique bioenergetic feature of cancer, aerobic glycolysis is considered an attractive therapeutic target for cancer therapy. Recently, dichloroacetate (DCA), a small-molecule metabolic modulator, was shown to reverse the glycolytic phenotype, induce reactive oxygen species (ROS) generation, and trigger apoptosis in various tumor cells. In this work, the capacity of DCA to enhance Adriamycin (ADM) efficacy in hepatoma cells by modulating glucose metabolism and redox status was evaluated. Two human hepatoma (HCC-LM3 and SMMC-7721) and a normal liver (LO2) cell lines were treated with DCA or ADM alone, or in combination. Exposure of hepatoma cells to DCA/ADM combination resulted in significantly decreased cell viability and increased percentage of apoptotic cells as well as intracellular ROS levels, in comparison with treatment with DCA or ADM alone. However, simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC, 10 mmol/L) reduced the elevated ROS levels and protected hepatoma cells from the cytotoxic effects of DCA/ADM combination. L-buthionine-[S,R]-sulfoximine, an inhibitor of glutathione synthesis, enhanced hepatoma cell sensitivity to DCA/ADM combination. Interestingly, treatment with DCA/ADM combination did not significantly increase cytotoxicity in normal hepatocytes in comparison with the drugs administered individually. Finally, DCA reduced tumor growth and enhanced ADM efficacy on HCC-LM3 hepatoma in mice. Overall, our data suggest that DCA enhances ADM cytotoxicity in hepatoma cells by increasing intracellular ROS levels and provide a strong biochemical rationale for the use of DCA in combination with ADM for treatment of hepatoma.
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Yunhai
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
authors.forename: Shile
authors.initials: S
authors.lastname: Sheng
authors.affiliation: Department of Gastroenterology, Sixth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Wang
authors.affiliation: National Laboratory for Oncogenes and Related Genes, WHO Collaborating Center for Research on Cancer, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D004317:Doxorubicin; D003999:Dichloroacetic Acid; D000111:Acetylcysteine
references.citation: Hypertension. 2001 Sep;38(3 Pt 2):576-80
references.pmid: 11566934
references.citation: PLoS One. 2012;7(7):e39949
references.pmid: 22866174
references.citation: Mol Cell Biol. 2005 Aug;25(15):6391-403
references.pmid: 16024778
references.citation: Cancer Cell. 2007 Jan;11(1):37-51
references.pmid: 17222789
references.citation: Cancer Chemother Pharmacol. 1989;24(3):181-6
references.pmid: 2736709
references.citation: Nat Rev Drug Discov. 2009 Jul;8(7):579-91
references.pmid: 19478820
references.citation: Cancer Res. 1983 Jul;43(7):3417-21
references.pmid: 6850648
references.citation: J Clin Oncol. 2008 Aug 1;26(22):3777-84
references.pmid: 18669466
references.citation: Breast Cancer Res Treat. 2010 Feb;120(1):253-60
references.pmid: 19543830
references.citation: Zhonghua Zhong Liu Za Zhi. 1997 Jul;19(4):260-3
references.pmid: 11038753
references.citation: Free Radic Biol Med. 2008 Feb 1;44(3):322-31
references.pmid: 18215740
references.citation: Oncogene. 2006 Aug 7;25(34):4633-46
references.pmid: 16892078
references.citation: Br J Cancer. 2013 Apr 30;108(8):1624-33
references.pmid: 23531700
references.citation: Cancer Res. 2005 Sep 15;65(18):8455-60
references.pmid: 16166325
references.citation: Mol Cancer Res. 2006 May;4(5):319-30
references.pmid: 16687487
references.citation: Int J Biochem Cell Biol. 2007;39(7-8):1358-66
references.pmid: 17499003
references.citation: Free Radic Res. 2002 Apr;36(4):381-7
references.pmid: 12069101
references.citation: Blood. 1999 Sep 15;94(6):2102-11
references.pmid: 10477740
references.citation: Gynecol Oncol. 2008 Jun;109(3):394-402
references.pmid: 18423823
references.citation: Cell Death Differ. 1999 May;6(5):471-80
references.pmid: 10381639
references.citation: Hepatogastroenterology. 2007 Mar;54(74):489-92
references.pmid: 17523305
references.citation: J Natl Cancer Inst. 2006 Feb 15;98(4):236-44
references.pmid: 16478742
references.citation: Cancer Res. 2003 Jun 15;63(12):3413-7
references.pmid: 12810678
references.citation: Oncol Lett. 2010 Sep;1(5):889-891
references.pmid: 22966401
references.citation: Cancer Res. 2004 Jan 1;64(1):31-4
references.pmid: 14729604
references.citation: J Biol Chem. 2005 Feb 11;280(6):4254-63
references.pmid: 15561720
references.citation: Nat Rev Cancer. 2010 Apr;10(4):267-77
references.pmid: 20300106
references.citation: Prostate. 2008 Aug 1;68(11):1223-31
references.pmid: 18465755
references.citation: Cancer Res. 2007 Apr 1;67(7):3364-70
references.pmid: 17409446
references.citation: Int J Cancer. 2006 Jul 1;119(1):41-8
references.pmid: 16450384
references.citation: Biochem Biophys Res Commun. 2004 Nov 5;324(1):269-75
references.pmid: 15465013
references.citation: J Mol Med (Berl). 2011 Mar;89(3):205-12
references.pmid: 21301795
references.citation: Nat Cell Biol. 2006 Nov;8(11):1213-5
references.pmid: 17077852
references.citation: Mol Pharmacol. 1988 Nov;34(5):695-701
references.pmid: 3193959
references.citation: Mol Oncol. 2008 Jun;2(1):94-101
references.pmid: 19383331
references.citation: Cancer Res. 2007 Apr 15;67(8):3512-7
references.pmid: 17440056
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683
references.citation: Int J Cancer. 2010 Dec 1;127(11):2510-9
references.pmid: 20533281
references.citation: Arch Biochem Biophys. 2000 Mar 1;375(1):21-30
references.pmid: 10683245