title: Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells.
abstract: BACKGROUND
  Bcl-2 plays a major role in the pathobiology and drug resistance of ovarian cancer, and inhibition of bcl-2 was useful for OC therapy. It has previously reported that TW-37, a small-molecule inhibitor of Bcl-2 family proteins, inhibited cell growth and induced apoptosis in many cancer cells. In the present study,we investigate the effect of TW-37 or / and in combination with cisplain on several ovarian cancer (OC) cell lines with high bcl-2 expression.
  
  
  METHODS
  The bcl-2 mRNA and protein expression, and the cisplain (DDP) sensitivity of OC cell lines SKOV3, OVCAR3, OV-90 and 3AO and SKOV3DDP were determined by Quantitative real-time RT-PCR,Western blot, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting (MTT) assays. The effects of TW-37 alone or combined with cisplain on growth and apoptosis in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells was detected by MTT,clonogenic assay, ELISA and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay.
  
  
  RESULTS
  The cell lines SKOV3 and 3AO were sensitive, whereas OVCAR3, OV-90 and SKOV3DDP were resistant to cisplain. Significant positive correlation was observed between basal bcl-2 mRNA and protein and cisplain sensitivity. Cisplain treatment did not activate bcl-2 in vitro. Treatment with TW-37 inhibited bcl-2 expression in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells , and inhibited growth and induced apoptosis ,and increased cisplain killing of the bcl-2 overexpressed cells in a does and time-dependant manner in vitro.
  
  
  CONCLUSIONS
  Bcl-2 level positively correlated with sensitivity to cisplain. Treatment with TW-37 was effective alone and in combination with cisplain in bcl-2 overexpressed OC cell lines in vitro. Thus, TW-37 may be a useful therapeutic agent for OCs.
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiuping
authors.initials: X
authors.lastname: Wei
authors.forename: Ruizhen
authors.initials: R
authors.lastname: Dai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D010051:Ovarian Neoplasms / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019253:Proto-Oncogene Proteins c-bcl-2; D013450:Sulfones; C515128:TW-37 compound; D002945:Cisplatin
references.citation: Br J Cancer. 2000 Jan;82(2):436-40
references.pmid: 10646901
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):2226-35
references.pmid: 17404107
references.citation: J Med Chem. 2006 Oct 19;49(21):6139-42
references.pmid: 17034116
references.citation: Methods Mol Med. 2001;39:687-91
references.pmid: 21340831
references.citation: Int J Gynecol Cancer. 2008 Mar-Apr;18(2):241-8
references.pmid: 18334006
references.citation: Semin Oncol. 2006 Apr;33(2 Suppl 6):S3-11
references.pmid: 16716797
references.citation: Mol Cancer. 2005;4(1):18
references.pmid: 15882455
references.citation: J Clin Oncol. 2008 Feb 20;26(6):995-1005
references.pmid: 18195328
references.citation: Mol Cancer Ther. 2008 Jun;7(6):1708-19
references.pmid: 18566242
references.citation: Am J Surg Pathol. 2005 Feb;29(2):218-24
references.pmid: 15644779
references.citation: Cancer Cell. 2004 Jan;5(1):19-24
references.pmid: 14749123
references.citation: Expert Opin Emerg Drugs. 2005 May;10(2):413-24
references.pmid: 15934876
references.citation: J Surg Oncol. 2005 Dec 15;92(4):337-43
references.pmid: 16299808
references.citation: Clin Cancer Res. 2009 Mar 15;15(6):2048-57
references.pmid: 19276284
references.citation: Toxicol Lett. 2001 Mar 31;120(1-3):51-7
references.pmid: 11323161
references.citation: Cancer Res. 2009 Apr 1;69(7):2757-65
references.pmid: 19318573
references.citation: Curr Cancer Drug Targets. 2004 Mar;4(2):147-63
references.pmid: 15032666
references.citation: Oncogene. 2007 Feb 26;26(9):1324-37
references.pmid: 17322918
references.citation: Obstet Gynecol. 1998 May;91(5 Pt 1):783-92
references.pmid: 9572231
references.citation: Mol Cancer Ther. 2006 Jun;5(6):1387-95
references.pmid: 16818496
references.citation: Mol Cancer Ther. 2009 Apr;8(4):893-903
references.pmid: 19372562