Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells

被引:116
作者
Maaser, K
Höpfner, M
Jansen, A
Weisinger, G
Gavish, M
Kozikowski, AP
Weizman, A
Carayon, P
Riecken, EO
Zeitz, M
Scherübl, H [1 ]
机构
[1] Free Univ Berlin, Benjamin Franklin Hosp, Med Clin 1, D-1000 Berlin, Germany
[2] Tel Aviv Univ, Sackler Fac Med, Dept Endocrinol, IL-69978 Tel Aviv, Israel
[3] Technion Israel Inst Technol, Bruce Rappaport Fac Med, Dept Pharmacol, IL-31096 Haifa, Israel
[4] Georgetown Univ, Med Ctr, Drug Discovery Program, Washington, DC 20007 USA
[5] Beilinson Med Ctr, Felsenstein Med Res Ctr, Lab Biol Psychiat, IL-49100 Petah Tiqwa, Israel
[6] Beilinson Med Ctr, Geha Psychiat Hosp, Res Unit, IL-49100 Petah Tiqwa, Israel
[7] Sackler Fac Med, Tel Aviv, Israel
[8] Sanofi Synthelabo Res, Dept Immunol Oncol, F-38184 Montpellier, France
关键词
peripheral benzodiazepine receptor; colorectal cancer; cell proliferation; apoptosis; cell cycle;
D O I
10.1054/bjoc.2001.2181
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The peripheral benzodiazepine receptor (PBR) has been implicated in growth control of various tumour models. Although colorectal cancers were found to overexpress PBR, the functional role of PBR in colorectal cancer growth has not been addressed to date. Using primary cell cultures of human colorectal cancers and the human colorectal carcinoma cell lines HT29, LS174T, and Colo320 DM we studied the involvement of PBR in the growth control and apoptosis of colorectal cancers. Both mRNA and protein expression of PBR were detected by RT-PCR and flow cytometry. Using confocal laser scanning microscopy and immunohistochemistry the PBR was localized in the mitochondria. The specific PBR ligands FGIN-1-27. PK 11195, or Ro5-4864 inhibited cell proliferation dose-dependently. FGIN-1-27 decreased the mitochondrial membrane potential, which indicates an early event in apoptosis. Furthermore, FGIN-1-27, PK 11195 or Ro5-4864 increased caspase-3 activity. In addition to their apoptosis-inducing effects, PBR ligands induced cell cycle arrest in the G(1)/G(0)-phase. Thus, our data demonstrate a functional involvement of PBR in colorectal cancer growth and qualify the PBR as a possible target for innovative therapeutic approaches in colorectal cancer. (C) 2001 Cancer Research Campaign.
引用
收藏
页码:1771 / 1780
页数:10
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