BMS-275183诱导的头颈癌基因表达模式。

BMS-275183-induced gene expression patterns in head and neck carcinoma.

作者信息

Yoo George H, Tran Vivian R, Lemonnier Lori A, Ezzat Waleed H, Subramanian Geetha, Piechocki Marie P, Ensley John F, Lonardo Fulvio, Kim Harold, Lin Ho-Sheng

机构信息

Department of Otolaryngology--Head and Neck Surgery, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA.

出版信息

Am J Otolaryngol. 2007 Sep-Oct;28(5):309-15. doi: 10.1016/j.amjoto.2006.10.001.

DOI:10.1016/j.amjoto.2006.10.001

PMID:17826531

Abstract

PURPOSE

BMS-275183 is an orally bioavailable taxane that has antitumor activity in preclinical cancer models. However, limited BMS-275183 studies have been performed in head and neck squamous cell carcinoma (HNSCC) cell lines. The purpose of this study is to identify the biological activity of BMS-275183 on HNSCC.

MATERIALS AND METHODS

Head and neck squamous cell carcinoma cell lines, HN6, HN12, and HN30, were exposed to BMS-275183. BMS-275183-induced growth suppression, cell-cycle arrest, and apoptosis were measured. Then, expression of selected proteins that were induced by BMS-275183 was determined by Western blot analysis.

RESULTS

BMS-275183 suppressed proliferation and induced G(2)M arrest and apoptosis in all HNSCC cell lines tested. BMS-275183 altered the expression of cell-cycle regulators, such as cyclin A and cyclin B1. The expression of E2F and p27 was decreased and increased, respectively, in all HNSCC cell lines. Cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) were increased in HN6 and HN12 cells. epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) expression were decreased by BMS-275183 in HN6 and HN30 cell lines, whereas phosphorylated epidermal growth factor receptor (pEGFR) was decreased in only HN6 cells.

CONCLUSIONS

BMS-275183 induced cellular apoptosis, cell-cycle arrest, and altered gene expression in HNSCC via molecular pathways similar to other taxanes. These preclinical experiments suggest that BMS-275183 may be useful in treating HNSCC and that the aforementioned genes can potentially be used as surrogate end-point biomarkers.

摘要

目的

BMS-275183是一种口服生物可利用的紫杉烷类药物，在临床前癌症模型中具有抗肿瘤活性。然而，针对头颈部鳞状细胞癌（HNSCC）细胞系开展的BMS-275183研究有限。本研究的目的是确定BMS-275183对HNSCC的生物学活性。

材料与方法

将头颈部鳞状细胞癌细胞系HN6、HN12和HN30暴露于BMS-275183。检测BMS-275183诱导的生长抑制、细胞周期停滞和细胞凋亡情况。然后，通过蛋白质印迹分析确定BMS-275183诱导的所选蛋白质的表达。

结果

BMS-275183在所有测试的HNSCC细胞系中均抑制增殖并诱导G(2)M期停滞和细胞凋亡。BMS-275183改变了细胞周期调节因子的表达，如细胞周期蛋白A和细胞周期蛋白B1。在所有HNSCC细胞系中，E2F的表达降低，而p27的表达升高。在HN6和HN12细胞中，裂解的半胱天冬酶3和聚（ADP-核糖）聚合酶（PARP）增加。在HN6和HN30细胞系中，BMS-275183降低了表皮生长因子受体（EGFR）和丝裂原活化蛋白激酶（MAPK）的表达，而仅在HN6细胞中磷酸化表皮生长因子受体（pEGFR）降低。