title: Anti-tumor effects of CIK combined with oxaliplatin in human oxaliplatin-resistant gastric cancer cells in vivo and in vitro.
abstract: BACKGROUND
  Drug resistance remains a great challenge in the treatment of gastric cancer. The goal of this study was to explore the anti-tumor effects and mechanism of cytokine-induced killer (CIK) cell combined with oxaliplatin (L-OHP) in human oxaliplatin-resistant gastric cancer cells.
  
  
  METHODS
  After producing oxaliplatin-resistant gastric cancer cells, cell morphology, growth and doubling time were observed, followed by detection of cell cycle distribution and apoptosis, drug sensitivity (e.g., L-OHP) and expression of P-gp and livin. MTT assay, in vivo pharmacodynamics and pathomorphology experiments were used to detect killing activities of CIK combined with L-OHP.
  
  
  RESULTS
  Compared with parental gastric cancer cells, oxaliplatin-resistant gastric cancer cells in S phase were reduced and cell apoptosis rate was increased (P < 0.05), the inhibition rate of 10 chemotherapeutics on oxaliplatin-resistant gastric cancer cells was significantly lower and the expression of P-gp was significantly higher (P < 0.05). However, there was no significant difference in livin expression between parental gastric cancer cells and oxaliplatin-resistant gastric cancer cells (P > 0.05). The in vitro killing activity of CIK combined with L-OHP on parental cells and oxaliplatin-resistant cells were significantly enhanced compared with L-OHP or CIK alone. And it showed greater synergetic effects against oxaliplatin-resistant cells compared with parental cells (P < 0.05). In addition, survival rate, abdominal circumference and pathomorphology results revealed stronger in vivo anti-tumor effects when the two therapies were combined.
  
  
  CONCLUSIONS
  The mechanism of oxaliplatin-resistant cell secondary multidrug resistance was correlated with the variation of cell cycle distribution, extension of doubling time and upregulation of P-gp expression. The synergistic effect of CIK in combination with L-OHP on killing activity against oxaliplatin-resistant cells was shown in vivo and in vitro.
authors.affiliation: Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhao
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Hu
authors.forename: Liqiao
authors.initials: L
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape; D055612:Cytokine-Induced Killer Cells / Q000276:immunology / Q000637:transplantation*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013997:Time Factors; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C419866:BIRC7 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin
references.citation: Cancer Chemother Pharmacol. 1990;25(4):299-303
references.pmid: 2295116
references.citation: Annu Rev Biochem. 1993;62:385-427
references.pmid: 8102521
references.citation: Anticancer Res. 2006 May-Jun;26(3B):2237-42
references.pmid: 16821594
references.citation: Ai Zheng. 2006 Apr;25(4):398-403
references.pmid: 16613669
references.citation: J Exp Med. 1991 Jul 1;174(1):139-49
references.pmid: 1711560
references.citation: EMBO J. 2005 Feb 9;24(3):645-55
references.pmid: 15650747
references.citation: Hepatology. 2005 Sep;42(3):588-97
references.pmid: 16037944
references.citation: Cell Immunol. 1996 Apr 10;169(1):85-90
references.pmid: 8612299
references.citation: Biol Blood Marrow Transplant. 2005 Mar;11(3):181-7
references.pmid: 15744236
references.citation: Br J Cancer. 2007 Aug 6;97(3):334-44
references.pmid: 17609664
references.citation: Eur J Haematol. 1997 Jul;59(1):14-9
references.pmid: 9260576
references.citation: Oncogene. 2005 Jan 20;24(4):573-84
references.pmid: 15580304
references.citation: Zhonghua Wai Ke Za Zhi. 1997 Jun;35(6):325-8
references.pmid: 10374463
references.citation: Crit Rev Oncol Hematol. 2000 Aug;35(2):75-93
references.pmid: 10936465
references.citation: Biochem Pharmacol. 1996 Dec 24;52(12):1855-65
references.pmid: 8951344
references.citation: Chin Med J (Engl). 2004 Sep;117(9):1348-52
references.pmid: 15377427
references.citation: Cancer Res. 1990 Jun 1;50(11):3218-25
references.pmid: 2334917
references.citation: Semin Surg Oncol. 1999 Sep;17(2):139-43
references.pmid: 10449686
references.citation: Chin Med J (Engl). 1996 May;109(5):353-5
references.pmid: 9208490
references.citation: Leukemia. 1997 May;11(5):723-8
references.pmid: 9180298
references.citation: Anticancer Res. 2001 Jan-Feb;21(1B):595-600
references.pmid: 11299811
references.citation: J Immunol. 1994 Aug 15;153(4):1687-96
references.pmid: 7519209
references.citation: Cell Mol Life Sci. 2002 Aug;59(8):1406-12
references.pmid: 12363043
references.citation: Cancer Immunol Immunother. 2000 Aug;49(6):335-45
references.pmid: 10946816
references.citation: Semin Oncol. 1998 Apr;25(2 Suppl 5):4-12
references.pmid: 9609103
references.citation: Br J Cancer. 1998 Jun;77 Suppl 4:8-11
references.pmid: 9647613
references.citation: Arch Pharm Res. 2007 Nov;30(11):1464-70
references.pmid: 18087816
references.citation: Bone Marrow Transplant. 1995 Jan;15(1):33-9
references.pmid: 7538001
references.citation: Clin Cancer Res. 1997 Dec;3(12 Pt 2):2630-2
references.pmid: 10068265
references.citation: Exp Hematol. 1993 Dec;21(13):1673-9
references.pmid: 7694868
references.citation: Anticancer Res. 2008 Nov-Dec;28(6B):3997-4002
references.pmid: 19192663
references.citation: Zhonghua Zhong Liu Za Zhi. 2004 Aug;26(8):465-8
references.pmid: 15555334
references.citation: Mutat Res. 1996 Aug 17;355(1-2):59-70
references.pmid: 8781577
references.citation: Br J Cancer. 1991 Jan;63(1):17-28
references.pmid: 1989661
references.citation: Ann Oncol. 1992 Feb;3(2):155-62
references.pmid: 1606087