Inhibition of ovarian cancer cell proliferation by a cell cycle inhibitory peptide fused to a thermally responsive polypeptide carrier.
Inhibition of ovarian cancer cell proliferation by a cell cycle inhibitory peptide fused to a thermally responsive polypeptide carrier.
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DOI：
10.1002/ijc.24725
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发表时间：
2010-01-15
影响因子：
6.4
通讯作者：
Raucher, Drazen
中科院分区：
文献类型：
--
作者：
Massodi, Iqbal;Moktan, Shama;Rawat, Aruna;Bidwell, Gene L., III;Raucher, Drazen
目前实体瘤的治疗受到正常组织耐受性的限制，导致治疗指数狭窄。为了提高药物的特异性和有效性，并减少在正常组织中的毒性，我们已经开发了一种用于细胞周期抑制肽的多肽载体，其具有热靶向肿瘤部位的潜力。这种多肽的设计是基于弹性蛋白样多肽（ELP）。通过在N-末端添加细胞穿透肽Bac-7和在C-末端添加衍生自p21的23个氨基酸的肽（Bac-ELP 1-p21）来修饰ELP的编码序列。Bac-ELP 1-p21在低于生理温度（37°C）的水溶液中可溶，但当温度升高到39°C以上时聚集，使其成为有希望的热响应治疗载体，其可以通过应用聚焦热疗主动靶向实体肿瘤。虽然Bac-ELP 1-p21在37°C下对SKOV-3细胞增殖没有任何影响，但与热无响应的对照多肽相比，使用热疗增加了Bac-ELP 1-p21的抗增殖作用。共聚焦显微镜显示Bac-ELP 1-p21在SKOV-3细胞中既存在于胞质中又存在于胞核中，且在加热的细胞中富含核定位的多肽。使用蛋白质印迹，我们表明Bac-ELP 1-p21导致42°C处理的细胞中Rb磷酸化水平降低。该多肽还诱导caspase活化、PARP裂解以及S期和G2/M期的细胞周期停滞。这些研究表明，ELP是一种很有前途的大分子载体，用于向实体肿瘤递送细胞周期抑制肽。
Current treatment of solid tumors is limited by normal tissue tolerance, resulting in a narrow therapeutic index. To increase drug specificity and efficacy and to reduce toxicity in normal tissues, we have developed a polypeptide carrier for a cell cycle inhibitory peptide, which has the potential to be thermally targeted to the tumor site. The design of this polypeptide is based on elastin-like polypeptide (ELP). The coding sequence of ELP was modified by the addition of the cell penetrating peptide Bac-7 at the N-terminus and a 23 amino acid peptide derived from p21 at the C-terminus (Bac-ELP1-p21). Bac-ELP1-p21 is soluble in aqueous solutions below physiological temperature (37°C) but aggregates when the temperature is raised above 39°C, making it a promising thermally responsive therapeutic carrier that may be actively targeted to solid tumors by application of focused hyperthermia. While Bac-ELP1-p21 at 37°C did not have any effect on SKOV-3 cell proliferation, the use of hyperthermia increased the antiproliferative effect of Bac-ELP1-p21 compared with a thermally unresponsive control polypeptide. Bac-ELP1-p21 displayed both a cytoplasmic and nuclear distribution in the SKOV-3 cells, with nuclear-localized polypeptide enriched in the heated cells, as revealed by confocal microscopy. Using Western blotting, we show that Bac-ELP1-p21 caused a decrease in Rb phosphorylation levels in cells treated at 42°C. The polypeptide also induced caspase activation, PARP cleavage, and cell cycle arrest in S-phase and G2/M-phase. These studies indicate that ELP is a promising macromolecular carrier for the delivery of cell cycle inhibitory peptides to solid tumors.
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影响因子：
64.8
作者：
LUO, Y;HURWITZ, J;MASSAGUE, J
通讯作者：
MASSAGUE, J
影响因子：
5.8
作者：
Bidwell, GL;Raucher, D
通讯作者：
Raucher, D
影响因子：
5.8
作者：
Bidwell, Gene L., III;Fokt, Izabela;Raucher, Drazen
通讯作者：
Raucher, Drazen
影响因子：
10.8
作者：
Massodi, I;Bidwell, GL;Raucher, D
通讯作者：
Raucher, D
影响因子：
3.4
作者：
Bidwell, Gene L., III;Davis, Aisha N.;Raucher, Drazen
通讯作者：
Raucher, Drazen