Li Lan, Braiteh Fadi S, Kurzrock Razelle
Division of Cancer Medicine, Phase I Program and Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, 77230, USA.
Cancer. 2005 Sep 15;104(6):1322-31. doi: 10.1002/cncr.21300.
Because a role for nuclear factor-kappaB (NF-kappaB) has been implicated in the pathogenesis of pancreatic carcinoma, this transcription factor is a potential target for the treatment of this devastating disease. Curcumin (diferuloylmethane) is a phytochemical with potent NF-kappaB-inhibitory activity. It is pharmacologically safe, but its bioavailability is poor after oral administration.
The authors encapsulated curcumin in a liposomal delivery system that would allow intravenous administration. They studied the in vitro and in vivo effects of this compound on proliferation, apoptosis, signaling, and angiogenesis using human pancreatic carcinoma cells. NF-kappaB was constitutively active in all human pancreatic carcinoma cell lines evaluated and liposomal curcumin consistently suppressed NF-kappaB binding (electrophoretic mobility gel shift assay) and decreased the expression of NF-kappaB-regulated gene products, including cyclooxygenase-2 (immunoblots) and interleukin-8 (enzyme-linked immunoassay), both of which have been implicated in tumor growth/invasiveness. These in vitro changes were associated with concentration and time-dependent antiproliferative activity (3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay [MTT assay]) and proapoptotic effects (annexin V/propidium iodide staining [fluorescence-activated cell sorting] and polyadenosine-5'-diphosphate-ribose-polymerase cleavage).
The activity of liposomal curcumin was equal to or better than that of free curcumin at equimolar concentrations. In vivo, curcumin suppressed pancreatic carcinoma growth in murine xenograft models and inhibited tumor angiogenesis.
Liposomal curcumin down-regulated the NF-kappaB machinery, suppressed growth, and induced apoptosis of human pancreatic cells in vitro. Antitumor and antiangiogenesis effects were observed in vivo. The experiments in the current study provide a biologic rationale for treatment of patients suffering from pancreatic carcinoma with this nontoxic phytochemical encapsulated in liposomes for systemic delivery.
由于核因子-κB（NF-κB）在胰腺癌发病机制中发挥作用，该转录因子是治疗这种毁灭性疾病的潜在靶点。姜黄素（二阿魏酰甲烷）是一种具有强大NF-κB抑制活性的植物化学物质。它在药理学上是安全的，但口服给药后生物利用度较差。
作者将姜黄素封装在脂质体递送系统中，使其能够静脉给药。他们使用人胰腺癌细胞研究了该化合物对增殖、凋亡、信号传导和血管生成的体外和体内作用。在所有评估的人胰腺癌细胞系中，NF-κB均呈组成性激活，脂质体姜黄素持续抑制NF-κB结合（电泳迁移率凝胶阻滞试验），并降低NF-κB调节的基因产物的表达，包括环氧合酶-2（免疫印迹法）和白细胞介素-8（酶联免疫吸附测定）——这两种物质均与肿瘤生长/侵袭有关。这些体外变化与浓度和时间依赖性抗增殖活性（3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐试验[MTT试验]）和促凋亡作用（膜联蛋白V/碘化丙啶染色[荧光激活细胞分选]和聚腺苷酸-5'-二磷酸-核糖聚合酶裂解）相关。
在等摩尔浓度下，脂质体姜黄素的活性等于或优于游离姜黄素。在体内，姜黄素抑制小鼠异种移植模型中的胰腺癌生长并抑制肿瘤血管生成。
脂质体姜黄素在体外下调了NF-κB机制，抑制了人胰腺细胞的生长并诱导其凋亡。在体内观察到了抗肿瘤和抗血管生成作用。本研究中的实验为用这种封装在脂质体中用于全身递送的无毒植物化学物质治疗胰腺癌患者提供了生物学依据。
