Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas
Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas
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DOI：
10.1007/s00280-008-0747-1
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发表时间：
2009-02-01
影响因子：
3
通讯作者：
Guminski, Alexander
中科院分区：
文献类型：
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作者：
Erlich, Rafael B.;Rickwood, Danny;Guminski, Alexander
在这里，我们调查，如果丙戊酸（VA）可以提高头颈部鳞状细胞癌（HNSCC）的常用疗法的疗效和分子机制，可能与其抗癌effects.Proliferation和生存能力的不同类型的细胞进行VA治疗单独或联合方案分别通过BrdU掺入和LDH释放。与组蛋白去乙酰化酶抑制活性的VA兼容的分子标记物进行了评估，通过蛋白质印迹法测定从培养的细胞和肿瘤活检获得的裂解物中，所有类型的细胞与VA治疗导致组蛋白H3乙酰化和p21表达的剂量依赖性增加，以及剂量依赖性的细胞抑制。相反，对VA的细胞毒性反应是可变的，并且与细胞抑制、组蛋白乙酰化或p21诱导无关。在1周口服VA疗程之前和之后从患者中采集的肿瘤活检样本中也观察到对VA反应的变异性。此外，我们发现，临床可达到的浓度的VA加顺铂的组合引起顺铂的细胞毒性在vitro中增加了三倍至七倍，VA在SCC细胞和正常人角质形成细胞（HK）中作为组蛋白脱乙酰酶抑制剂（HDI），增强顺铂在SCC细胞系中的细胞毒性作用，并降低SCC细胞的活力，而不是HK。总之，这些结果提供了初步证据，表明VA可能是一种有价值的药物，在开发更好的治疗方案HNSCC。
Here we investigate if valproic acid (VA) can enhance the efficacy of commonly used therapies for head and neck squamous cell carcinomas (HNSCC) and the molecular mechanisms that may be related to its anticancer effects.Proliferation and viability of distinct cell types subjected to VA treatment alone or in combination regimens were measured through BrdU incorporation and LDH release, respectively. Molecular markers compatible with histone deacetylase inhibitory activity of VA were assessed through western blots assays in lysates obtained from cultured cells and tumour biopsies.Treatment of all cell types with VA resulted in a dose-dependent increase in histone H3 acetylation and p21 expression, as well as dose-dependent cytostasis. In contrast, the cytotoxic response to VA was variable and did not correlate with cytostasis, histone acetylation or p21 induction. The variability in response to VA was also observed in tumour biopsy samples collected from patients prior to and following a 1 week oral course of VA. In addition, we found that a combination of a clinically achievable concentration of VA plus cisplatin caused a threefold to sevenfold increase in cisplatin cytotoxicity in vitro.VA acts as a histone deacetylase inhibitor (HDI) in SCC cells and normal human keratinocytes (HKs), potentiates the cytotoxic effect of cisplatin in SCC cell lines and decreases the viability of SCC cells as opposed to HKs. Taken together, the results provide initial evidence that VA might be a valuable drug in the development of better therapeutic regimens for HNSCC.