Resveratrol selectively induces DNA Damage, independent of Smad4 expression, in its efficacy against human head and neck squamous cell carcinoma.
Resveratrol selectively induces DNA Damage, independent of Smad4 expression, in its efficacy against human head and neck squamous cell carcinoma.
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DOI：
10.1158/1078-0432.ccr-11-1072
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发表时间：
2011-08-15
期刊：
影响因子：
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通讯作者：
Sclafani RA
中科院分区：
文献类型：
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作者：
Tyagi A;Gu M;Takahata T;Frederick B;Agarwal C;Siriwardana S;Agarwal R;Sclafani RA
Smad4信号的改变和缺失导致基因组不稳定和头颈部鳞状细胞癌(HNSCC)，提示针对Smad4依赖和非依赖途径的药物可以控制HNSCC。白藜芦醇对人鼻咽癌细胞株FADU、CAL27、DET562和CAL27-Smad4细胞的存活率、DNA损伤、细胞周期进程、细胞凋亡、DNA损伤、γH_2AX表达和病灶形成(γH_2AX和BRCA_1)进行了研究。白藜芦醇在裸鼠体内对FaDu异种移植瘤的生长效果也进行了检测。对异种移植的γ、H_2AX和裂解的Caspase-3进行分析。白藜芦醇(5-50μM)可抑制FADU和CAL27细胞的活力和诱导DNA损伤，但对NHEK和HFF细胞无此作用，显示其对HNSCC细胞的选择性，但DET562细胞即使在100μM时仍对白藜芦醇耐药，稳定表达Smad4的DET562细胞表现出与亲本CAL27相似的白藜芦醇作用，表明DET562细胞中白藜芦醇的缺乏与细胞中Smad4状态无关。此外，白藜芦醇还可引起FADU和CAL27细胞的S期阻滞和凋亡死亡，并诱导BRCA1和γ的H_2AX灶。白藜芦醇(50 mg/kgbw)对裸鼠Fas-Du肿瘤生长也有抑制作用，与对照组相比，白藜芦醇处理组移植瘤中γ-H_AX和裂解的caspase-3显著增加。我们的发现首次显示白藜芦醇在体外和体内对HNSCC细胞的抗增殖、DNA损伤和凋亡作用与Smad4状态无关，这表明需要更多的研究来确定白藜芦醇对HNSCC的潜在有效性。
Alterations in Smad4 signaling and its loss causes genomic instability and head and neck squamous cell carcinoma (HNSCC), suggesting that agents which target both Smad4-dependent and -independent pathways could control HNSCC. Resveratrol efficacy was evaluated against HNSCC cells, FaDu, Cal27, Det562, and Cal27-Smad4 for viability, DNA damage, cell cycle progression, and apoptosis, as well as DNA damage, γH2AX expression and foci formation (γH2AX and Brca1). Resveratrol efficacy was also examined in nude mice for FaDu xenograft growth. Xenografts were analyzed for γH2AX and cleaved caspase-3. Resveratrol (5-50 μM) suppressed viability and induced DNA damage in FaDu and Cal27 cells, but not in NHEK and HFF, showing its selectivity towards HNSCC cells; however, Det562 cells were resistant to resveratrol even at 100 μM. Cal27 cells stably transfected with Smad4 showed similar resveratrol effects as parental Cal27 indicating that a lack of resveratrol effect in Det562 cells was independent of Smad4 status in these cells. Furthermore, resveratrol caused S phase arrest and apoptotic death of FaDu and Cal27 cells together with induction of Brca1 and γH2AX foci. Resveratrol (50 mg/kg bw) treatment also inhibited FaDu tumor growth in nude mice, and γH2AX and cleaved caspase-3 were strongly increased in xenografts from resveratrol-treated mice compared to controls. Our findings for the first time showed anti-proliferative, DNA damaging and apoptotic effects of resveratrol in HNSCC cells independent of Smad4 status, both in vitro and in vivo, suggesting that more studies are needed to establish its potential usefulness against HNSCC.