Landau M, Weizman A, Zoref-Shani E, Beery E, Wasseman L, Landau O, Gavish M, Brenner S, Nordenberg J
Laboratory of Biochemistry and Pharmacology of Cancer Cells, Felsenstein Medical Research Center, Petach Tikva, Israel.
Biochem Pharmacol. 1998 Oct 15;56(8):1029-34. doi: 10.1016/s0006-2952(98)00149-x.
In this study, we evaluated the effect of several ligands active at the central-type and peripheral-type benzodiazepine receptor (BzR) (clonazepam, diazepam, PK11195 and Ro5-4864) on the growth and differentiation of B16 melanoma cells. All tested BzR ligands were able to suppress proliferation of the cells at the micromolar range and in a concentration-dependent manner. However, agents selectively active at the peripheral-type BzR (PK11195 and Ro5-4864) exhibited more potent antiproliferative activity. In addition, the BzR ligands were demonstrated to affect the cell cycle by reducing the percent of cells in the S phase and increasing the percent in the G2/M phase. BzR ligands induced cellular phenotypic alterations, which have been previously shown to be associated with melanoma cell differentiation. These alterations included: marked morphological changes, enhancement of melanogenesis, lipid accumulation and increase in the activity of gamma glutamyl transpeptidase. All BzR ligands induced a marked reduction in the concentration of UTP and most of them did the same in GTP and CTP, while ATP levels were not significantly altered. In summary, BzR ligands (clonazepam, diazepam, PK11195 and Ro5-4864) were found to exert antitumor effects in B16 melanoma cells. These findings encourage further studies of a possible therapeutic potential of BzR ligands in treatment of melanoma.
在本研究中，我们评估了几种作用于中枢型和外周型苯二氮䓬受体（BzR）的配体（氯硝西泮、地西泮、PK11195和Ro5-4864）对B16黑色素瘤细胞生长和分化的影响。所有测试的BzR配体都能够在微摩尔范围内以浓度依赖的方式抑制细胞增殖。然而，在外周型BzR上具有选择性活性的药物（PK11195和Ro5-4864）表现出更强的抗增殖活性。此外，BzR配体被证明通过减少S期细胞百分比和增加G2/M期细胞百分比来影响细胞周期。BzR配体诱导细胞表型改变，这些改变先前已被证明与黑色素瘤细胞分化有关。这些改变包括：明显的形态变化、黑素生成增强、脂质积累以及γ-谷氨酰转肽酶活性增加。所有BzR配体均导致UTP浓度显著降低，大多数配体对GTP和CTP也有同样的作用，而ATP水平没有明显改变。总之，发现BzR配体（氯硝西泮、地西泮、PK11195和Ro5-4864）在B16黑色素瘤细胞中发挥抗肿瘤作用。这些发现鼓励进一步研究BzR配体在治疗黑色素瘤方面可能的治疗潜力。
