Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Cancer Prev Res (Phila). 2013 Aug;6(8):843-54. doi: 10.1158/1940-6207.CAPR-13-0070. Epub 2013 Jun 26.
Constitutive activation of proinflammatory transcription factors such as STAT3 and NF-κB plays a pivotal role in the proliferation and survival of squamous cell carcinoma of the head and neck (HNSCC). Thus, the agents that can modulate deregulated STAT3 and NF-κB activation have a great potential both for the prevention and treatment of HNSCC. In the present report, we investigated the potential effects of garcinol, an active component of Garcinia indica on various inflammatory mediators involved in HNSCC progression using cell lines and xenograft mouse model. We found that garcinol inhibited constitutively activated STAT3 in HNSCC cells in a time- and dose-dependent manner, which correlated with the suppression of the upstream kinases (c-Src, JAK1, and JAK2) in HNSCC cells. Also, we noticed that the generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol. Furthermore, garcinol exhibited an inhibitory effect on the constitutive NF-κB activation, mediated through the suppression of TGF-β-activated kinase 1 (TAK1) and inhibitor of IκB kinase (IKK) activation in HNSCC cells. Garcinol also downregulated the expression of various gene products involved in proliferation, survival, and angiogenesis that led to the reduction of cell viability and induction of apoptosis in HNSCC cells. When administered intraperitoneally, garcinol inhibited the growth of human HNSCC xenograft tumors in male athymic nu/nu mice. Overall, our results suggest for the first time that garcinol mediates its antitumor effects in HNSCC cells and mouse model through the suppression of multiple proinflammatory cascades.
组成型激活的促炎转录因子，如 STAT3 和 NF-κB，在头颈部鳞状细胞癌（HNSCC）的增殖和存活中起着关键作用。因此，能够调节失调的 STAT3 和 NF-κB 激活的药物在预防和治疗 HNSCC 方面具有很大的潜力。在本报告中，我们使用细胞系和异种移植小鼠模型研究了 Garcinia indica 的一种活性成分 garcinol 对涉及 HNSCC 进展的各种炎症介质的潜在影响。我们发现 garcinol 以时间和剂量依赖的方式抑制 HNSCC 细胞中组成型激活的 STAT3，这与 HNSCC 细胞中上游激酶（c-Src、JAK1 和 JAK2）的抑制相关。此外，我们注意到活性氧的产生参与了 garcinol 对 STAT3 的抑制作用。此外，garcinol 表现出对组成型 NF-κB 激活的抑制作用，这是通过抑制 TGF-β 激活激酶 1（TAK1）和 IκB 激酶（IKK）在 HNSCC 细胞中的激活来介导的。Garcinol 还下调了参与增殖、存活和血管生成的各种基因产物的表达，导致 HNSCC 细胞活力降低和凋亡诱导。当腹腔内给药时，garcinol 抑制了雄性无胸腺 nu/nu 小鼠中人类 HNSCC 异种移植肿瘤的生长。总的来说，我们的研究结果首次表明，garcinol 通过抑制多种促炎级联反应，介导其在 HNSCC 细胞和小鼠模型中的抗肿瘤作用。
