ON 01910.Na (rigosertib) inhibits PI3K/Akt pathway and activates oxidative stress signals in head and neck cancer cell lines.
ON 01910.Na (rigosertib) inhibits PI3K/Akt pathway and activates oxidative stress signals in head and neck cancer cell lines.
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DOI：
10.18632/oncotarget.12692
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发表时间：
2016-11-29
期刊：
影响因子：
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通讯作者：
Hoffman BS
中科院分区：
文献类型：
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作者：
Prasad A;Khudaynazar N;Tantravahi RV;Gillum AM;Hoffman BS
头颈部鳞状细胞癌（HNSCC）的特点是发病率和死亡率高。治疗失败、耐药性和放化疗毒性使得有必要开发替代治疗策略。苯乙烯基苄基砜是一种新型小分子抑制剂家族，在多项临床试验中被评估为抗肿瘤药物。这些化合物的活性已经在几项临床前肿瘤研究中得到了很好的表征，但它们的活性尚未在HNSCC中得到充分的研究。我们在HNSCC临床前模型中检测了ON 01910.Na（rigosertib），一种处于后期开发阶段的苯乙烯基苄基砜。Rigosertib以剂量依赖性方式诱导HPV（+）和HPV（−）HNSCC细胞的细胞毒性。潜在分子机制的表征表明，rigosertib诱导PI 3 K/Akt/mTOR通路抑制，诱导氧化应激，导致活性氧（ROS）生成增加，并激活细胞外信号调节激酶（ERK 1/2）和c-Jun NH 2-末端激酶（JNK）。在rigosertib治疗后还观察到ATF-2的磷酸化和细胞质易位增加。细胞信号传导的这些变化使我们考虑将rigosertib与HNSCC标准治疗（如顺铂和放疗）联合使用。我们的研究强调了rigosertib在HNSCC中具有良好的临床前活性，无论HPV状态如何，并为rigosertib与HNSCC标准治疗药物联合治疗提供了分子基础。
Squamous cell carcinoma of the head and neck (HNSCC) is characterized by high morbidity and mortality. Treatment failure, drug resistance and chemoradiation toxicity have necessitated the development of alternative treatment strategies. Styryl benzyl sulfones, a family of novel small molecule inhibitors, are being evaluated as anti-neoplastic agents in multiple clinical trials. The activity of these compounds has been well characterized in several preclinical tumor studies, but their activity has yet to be fully examined in HNSCC. We tested ON 01910.Na (rigosertib), a styryl benzyl sulfone in late-stage development, in HNSCC preclinical models. Rigosertib induced cytotoxicity in both HPV(+) and HPV(−) HNSCC cells in a dose-dependent manner. Characterization of the underlying molecular mechanism indicated that rigosertib induced inhibition of the PI3K/Akt/mTOR pathway, induced oxidative stress resulting in increased generation of reactive oxygen species (ROS), and activated extracellular signal-regulated kinases (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Increased phosphorylation and cytoplasmic translocation of ATF-2 were also observed following rigosertib treatment. These changes in cell signaling led us to consider combining rigosertib with HNSCC standard-of-care therapies, such as cisplatin and radiation. Our study highlights the promising preclinical activity of rigosertib in HNSCC irrespective of HPV status and provides a molecular basis for rigosertib in combination with standard of care agents for HNSCC.