使用中性脂质体体内递送小干扰RNA靶向粘着斑激酶用于卵巢癌治疗
Focal adhesion kinase targeting using in vivo short interfering RNA delivery in neutral liposomes for ovarian carcinoma therapy.
作者信息
Halder Jyotsnabaran, Kamat Aparna A, Landen Charles N, Han Liz Y, Lutgendorf Susan K, Lin Yvonne G, Merritt William M, Jennings Nicholas B, Chavez-Reyes Arturo, Coleman Robert L, Gershenson David M, Schmandt Rosemarie, Cole Steven W, Lopez-Berestein Gabriel, Sood Anil K
机构信息
Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
出版信息
Clin Cancer Res. 2006 Aug 15;12(16):4916-24. doi: 10.1158/1078-0432.CCR-06-0021.
PURPOSE
Focal adhesion kinase (FAK) plays a critical role in ovarian cancer cell survival and in various steps in the metastatic cascade. Based on encouraging in vitro results with FAK silencing, we examined the in vivo therapeutic potential of this approach using short interfering RNA (siRNA) in the neutral liposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC).
EXPERIMENTAL DESIGN
Therapy experiments of FAK siRNA with or without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8MDR in nude mice. Additional experiments with a cisplatin-resistant cell line (A2780-CP20) were also done. Assessments of angiogenesis (CD31), cell proliferation (proliferating cell nuclear antigen), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) were done using immunohistochemical analysis.
RESULTS
A single dose of FAK siRNA-DOPC was highly effective in reducing in vivo FAK expression for up to 4 days as assayed by Western blot and immunohistochemical analysis. Therapy experiments were started 1 week after injection of the ovarian cancer cells. Treatment with FAK siRNA-DOPC (150 mug/kg twice weekly) reduced mean tumor weight by 44% to 72% in the three cell lines compared with the control group (Ps < 0.05 for HeyA8, A2780-CP20, and SKOV3ip1). When FAK siRNA-DOPC was combined with docetaxel, there was even greater reduction in mean tumor weight in all models (all Ps < 0.05). Similar results were observed in combination with cisplatin. Treatment with FAK siRNA-DOPC plus docetaxel resulted in decreased microvessel density, decreased expression of vascular endothelial growth factor and matrix metalloproteinase-9, and increased apoptosis of tumor-associated endothelial cells and tumor cells.
CONCLUSIONS
Taken together, these findings suggest that FAK siRNA-DOPC plus docetaxel or platinum might be a novel therapeutic approach against ovarian cancer.
目的
粘着斑激酶（FAK）在卵巢癌细胞存活及转移级联反应的各个步骤中发挥关键作用。基于FAK沉默在体外实验中令人鼓舞的结果，我们使用中性脂质体1,2 - 二油酰 - sn - 甘油 - 3 - 磷脂酰胆碱（DOPC）包裹的小干扰RNA（siRNA）研究了这种方法在体内的治疗潜力。
实验设计
在裸鼠中使用人卵巢癌细胞系SKOV3ip1、HeyA8和HeyA8MDR进行了FAK siRNA联合或不联合多西他赛的治疗实验。还对顺铂耐药细胞系（A2780 - CP20）进行了额外实验。使用免疫组织化学分析对血管生成（CD31）、细胞增殖（增殖细胞核抗原）和凋亡（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）进行评估。
结果
通过蛋白质印迹和免疫组织化学分析测定，单剂量的FAK siRNA - DOPC在长达4天的时间里能高效降低体内FAK表达。在注射卵巢癌细胞1周后开始治疗实验。与对照组相比，用FAK siRNA - DOPC（150μg/kg，每周两次）治疗使三种细胞系的平均肿瘤重量降低了44%至72%（HeyA8、A2780 - CP20和SKOV3ip1的P值均<0.05）。当FAK siRNA - DOPC与多西他赛联合使用时，所有模型中的平均肿瘤重量降低得更多（所有P值均<0.05）。与顺铂联合使用时也观察到了类似结果。用FAK siRNA - DOPC加用多西他赛治疗导致微血管密度降低、血管内皮生长因子和基质金属蛋白酶 - 9的表达减少，以及肿瘤相关内皮细胞和肿瘤细胞的凋亡增加。
结论
综上所述，这些发现表明FAK siRNA - DOPC加用多西他赛或铂类可能是一种针对卵巢癌的新型治疗方法。
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