Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts
Combinational antitumor effect of siRNA against midkine and paclitaxel on growth of human prostate cancer xenografts
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DOI：
10.1002/cncr.22068
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发表时间：
2006-08-15
期刊：
影响因子：
6.2
通讯作者：
Muramatsu, Takashi
中科院分区：
文献类型：
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作者：
Takei, Yoshifumi;Kadomatsu, Kenji;Muramatsu, Takashi
背景中期因子（MK）是一种肝素结合生长因子，可促进各种细胞的生长、迁移和存活。它的过度表达已被观察到在许多人类恶性肿瘤，使其成为一个有吸引力的治疗靶点。我们建立了一个涉及RNA干扰的人中期因子阻断系统。针对人中期因子的合成小干扰RNA（siRNA）几乎完全抑制人前列腺癌细胞系PC-3的中期因子分泌，从而抑制转染细胞的增殖和锚定非依赖性生长。中期因子siRNA与去端胶原一起显著抑制了皮下异种移植的PC-3肿瘤的生长。中期因子siRNA的这些抑制作用通过与化疗剂紫杉醇（PTX）在体外和体内的组合治疗而增强。用于联合治疗的PTX剂量（12 mg/kg）未引起白细胞减少症或肝损伤，这通常被报告为PTX的严重不良反应。该组合对肿瘤生长的作用与表现出严重不良反应的较高剂量的单独PTX相当。中期因子siRNA主要抑制细胞增殖和轻微的血管生成，而PTX促进凋亡和轻微抑制血管生成。联合治疗对抑制血管生成特别有效;因此，它对所有方面（增殖、凋亡和血管生成）都有显著影响。我们建立了一种新的和安全的癌症治疗策略，涉及中期因子siRNA联合PTX，副作用少。
BACKGROUND. Midkine (MK) is a heparin-binding growth factor that promotes the growth, migration, and survival of various cells. Its overexpression has been observed in many human malignancies, making it an attractive therapeutic target.METHODS. We established a human midkine blockade system involving RNA interference.RESULTS. The synthetic small interfering RNA (siRNA) targeting human midkine almost completely inhibited the secretion of midkine by a human prostate cancer cell line, PC-3, and consequently suppressed the proliferation and anchorage-independent growth of the transfected cells. The midkine siRNA, together with atelocollagen, significantly suppressed the growth of PC-3 tumors, which had been subcutaneously xenografted. These inhibitory effects of midkine siRNA were augmented by combinational treatment with a chemotherapeutic, paclitaxel (PTX), both in vitro and in vivo. The dose of PTX (12 mg/kg) used for the combinational treatment did not cause leukopenia or liver damage, which are often reported as serious adverse effects of PTX. The effect of the combination on tumor growth was comparable with that of PTX alone at higher doses that have exhibited severe adverse effects. Midkine siRNA suppressed mainly cell proliferation and slightly angiogenesis, whereas PTX enhanced apoptosis and slightly suppressed angiogenesis. The combination treatment was particularly effective for suppression of angiogenesis; consequently, it had striking effects on all aspects (proliferation, apoptosis, and angiogenesis).CONCLUSIONS. We established a novel and safe cancer therapy strategy involving midkine siRNA combined with PTX, with less adverse effects.