Mihara Mariko, Shintani Satoru, Kiyota Akihisa, Matsumura Tomohiro, Wong David T W
Department of Oral and Maxillofacial Surgery, Ehime University School of Medicine, Ehime 791-0295, Japan.
Int J Oncol. 2002 Jul;21(1):95-101.
Cyclin-dependent kinases (Cdks) play essential roles in the intracellular controls of the cell cycles. Roscovitine, [2-(R)-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine], is a potent and selective inhibitor of the Cdk2 and Cdc2. We investigated whether this compound was effective against head and neck squamous cell carcinoma (HNSCC) cells. Roscovitine was found to inhibit the growth of all 11 HNSCC cell lines in time- and dose-dependent manner and to diminish the Cdk2 and Cdc2 activities. An induction of apoptosis was observed in all cells, as judged by the cell morphology, along with the appearance of cells with sub-G1 DNA contents, DNA fragmentations, and poly(ADP-ribose) polymerase (PARP) cleavage. In four HNSCC cell lines, apoptosis was induced without antecedent marked cell cycle arrest, and in the other seven cell lines, cell cycle arrest preceded cell death. We also found up-regulation of Bcl-xS in the former cell lines, and in the latter cell lines, the expressions of Bcl-2 and Bcl-xL were induced simultaneously. These results suggest that roscovitine exerts antitumor activities in HNSCC and is associated with induction of Bcl-xS. Roscovitine can be considered to provide a new chemopreventive and chemotherapeutic strategy for the clinical management of HNSCC.
细胞周期蛋白依赖性激酶（Cdks）在细胞周期的细胞内调控中发挥着重要作用。罗司维汀，[2-(R)-(1-乙基-2-羟乙基氨基)-6-苄基氨基-9-异丙基嘌呤]，是一种强效且选择性的Cdk2和Cdc2抑制剂。我们研究了该化合物对头颈鳞状细胞癌（HNSCC）细胞是否有效。结果发现，罗司维汀能以时间和剂量依赖性方式抑制所有11种HNSCC细胞系的生长，并降低Cdk2和Cdc2的活性。通过细胞形态学观察，所有细胞均出现凋亡，同时伴有亚G1期DNA含量的细胞、DNA片段化以及聚（ADP-核糖）聚合酶（PARP）裂解的出现。在4种HNSCC细胞系中，凋亡诱导发生时无明显的前期细胞周期阻滞，而在其他7种细胞系中，细胞周期阻滞先于细胞死亡。我们还发现，在前一种细胞系中Bcl-xS上调，而在后一种细胞系中，Bcl-2和Bcl-xL的表达同时被诱导。这些结果表明，罗司维汀在HNSCC中发挥抗肿瘤活性，并与Bcl-xS的诱导有关。罗司维汀可被认为是为HNSCC的临床管理提供了一种新的化学预防和化疗策略。
