Mandal Mahitosh, Younes Maher, Swan Eric A, Jasser Samar A, Doan Dao, Yigitbasi Orhan, McMurphey Andrea, Ludwick James, El-Naggar Adel K, Bucana Cora, Mills Gordon B, Myers Jeffrey N
Department of Head and Neck Surgery, Unit 441, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Oral Oncol. 2006 Apr;42(4):430-9. doi: 10.1016/j.oraloncology.2005.09.011. Epub 2006 Jan 27.
Therapies that target signaling pathways critical to the pathogenesis and progression of squamous cell carcinoma of the head and neck (HNSCC) are needed. One such target, phosphatidylinositol 3-kinase, and its downstream target serine/threonine kinase, Akt, are up-regulated in HNSCC. Targeted therapy could consist of inhibitors of these kinases or, alternatively, of inhibitors of the pathways that they regulate. To explore the effect of Akt inhibition on the growth and survival of HNSCC tumors, we evaluated the effect of a novel Akt inhibitor, KP372-1, on the growth, survival, and sensitivity to anoikis of HNSCC cell lines in culture. Using Western blotting of head and neck cancer cell lines and squamous mucosa and carcinoma specimens, we found that Akt was highly phosphorylated in head and neck cancer cell lines and human head and neck squamous carcinoma specimens. Treatment of HNSCC cell lines with KP372-1 blocked the activation of Akt, inhibited head and neck cancer cell proliferation, and induced apoptosis and anoikis in several HNSCC cell lines. Furthermore, KP372-1 decreased the phosphorylation of the S6 ribosomal (Ser240/244) protein, which is a downstream target of Akt. Taken together, these findings indicate that KP372-1 may be a useful therapeutic agent for HNSCC and should be further evaluated in preclinical models of HNSCC.
需要针对对头颈部鳞状细胞癌（HNSCC）的发病机制和进展至关重要的信号通路的疗法。这样一个靶点是磷脂酰肌醇3激酶及其下游靶点丝氨酸/苏氨酸激酶Akt，它们在HNSCC中上调。靶向治疗可以由这些激酶的抑制剂组成，或者由它们所调节的通路的抑制剂组成。为了探索Akt抑制对HNSCC肿瘤生长和存活的影响，我们评估了一种新型Akt抑制剂KP372-1对培养的HNSCC细胞系的生长、存活和对失巢凋亡敏感性的影响。通过对头颈部癌细胞系以及鳞状黏膜和癌组织标本进行蛋白质免疫印迹分析，我们发现Akt在头颈部癌细胞系和人头部及颈部鳞状癌组织标本中高度磷酸化。用KP372-1处理HNSCC细胞系可阻断Akt的激活，抑制头颈部癌细胞增殖，并在几种HNSCC细胞系中诱导凋亡和失巢凋亡。此外，KP372-1降低了S6核糖体蛋白（Ser240/244）的磷酸化，该蛋白是Akt的下游靶点。综上所述，这些发现表明KP372-1可能是一种对HNSCC有用的治疗剂，应在HNSCC的临床前模型中进一步评估。
