p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma.
p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma.
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DOI：
10.1016/j.oraloncology.2010.10.011
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发表时间：
2011-01
期刊：
影响因子：
4.8
通讯作者：
Koch, Wayne M.
中科院分区：
文献类型：
--
作者：
Roh, Jong-Lyel;Kang, Sung Koo;Minn, Il;Califano, Joseph A.;Sidransky, David;Koch, Wayne M.
我们评估p53再活化（p53 RA）小分子是否诱导p53依赖性细胞凋亡的头颈部鳞状细胞癌（HNSCC），一个问题，以前没有解决的头颈部癌。在TP 53状态不同的四种人HNSCC细胞系中测试PRIMA-1、CP-31398、RITA和nutlin-3。分别用p53 RA小分子或与化疗药物联合治疗后，对细胞生长、活力、细胞周期进程和凋亡进行评估。在用PRIMA-1或CP-31398处理的携带突变型TP 53的肿瘤细胞系中以及用nutlin-3处理的携带野生型TP 53的细胞系中观察到显著的p53再活化。p53 RA小分子诱导的细胞周期阻滞和凋亡与p21和BAX的上调以及caspase-3的裂解有关。Nutlin-3在肿瘤细胞中显示出最大的生长抑制，显示出MDM 2依赖性p53降解。高剂量的p53 RA小分子治疗也诱导细胞系凋亡的p53或MDM 2表达无关。在联合治疗中，p53 RA小分子增强了顺铂、5-氟尿嘧啶、紫杉醇和厄洛替尼对HNSCC细胞的抗肿瘤活性。p53 RA小分子有效地恢复了具有突变型或野生型TP 53的HNSCC中的p53肿瘤抑制功能。p53 RA试剂与化疗药物组合可在临床上用于对抗HNSCC。
We evaluate whether p53-reactivating (p53RA) small molecules induce p53-dependent apoptosis in head and neck squamous cell carcinoma (HNSCC), a question that has not been previously addressed in head and neck cancer. PRIMA-1, CP-31398, RITA, and nutlin-3 were tested in four human HNSCC cell lines differing in TP53 status. Cell growth, viability, cell cycle progression, and apoptosis after treatment with p53RA small molecules individually or in combination with chemotherapeutic agents were assessed. Prominent p53 reactivation was observed in mutant TP53-bearing tumor cell lines treated with PRIMA-1 or CP-31398, and in wild-type TP53-bearing cell lines treated with nutlin-3. Cell-cycle arrest and apoptosis induced by p53RA small molecules were associated with upregulation of p21 and BAX, and cleavage of caspase-3. Nutlin-3 showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. High-dose treatment with p53RA small molecules also induced apoptosis in cell lines independent of p53 or MDM2 expression. In combination therapy, p53RA small molecules enhanced the antitumor activity of cisplatin, 5-fluorouracil, paclitaxel, and erlotinib against HNSCC cells. The p53RA small molecules effectively restored p53 tumor suppressive function in HNSCCs with mutant or wild-type TP53. The p53RA agents may be clinically useful against HNSCC, in combination with chemotherapeutic drugs.
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影响因子：
3.9
作者：
Olivier, M;Eeles, R;Hainaut, P
通讯作者：
Hainaut, P
影响因子：
45.3
作者：
Clayman, GL;El-Naggar, AK;Goepfert, H
通讯作者：
Goepfert, H
影响因子：
158.5
作者：
Poeta, M. Luana;Manola, Judith;Koch, Wayne M.
通讯作者：
Koch, Wayne M.
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
4
作者：
Magrini, R.;Russo, D.;Menichini, P.
通讯作者：
Menichini, P.