Thermally targeted p21 peptide enhances bortezomib cytotoxicity in androgen-independent prostate cancer cell lines.
Thermally targeted p21 peptide enhances bortezomib cytotoxicity in androgen-independent prostate cancer cell lines.
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DOI：
10.1097/cad.0000000000000036
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发表时间：
2014-02
影响因子：
2.3
通讯作者：
Raucher D
中科院分区：
文献类型：
--
作者：
Mikecin AM;Walker LR;Kuna M;Raucher D
前列腺癌仍然是男性最常见的恶性肿瘤之一。除了手术切除，前列腺癌的治疗包括激素治疗、化疗和放射治疗。前列腺癌进展到雄激素非依赖性状态限制了常规治疗方法的潜力。硼替佐米是FDA批准的用于治疗髓性白血病的蛋白酶体抑制剂，已显示对抑制前列腺癌生长具有积极作用。不幸的是，硼替佐米的治疗窗口非常窄，可能导致严重的副作用。弹性蛋白样多肽（Elastin-like polypeptide，ELP）是一种基因工程的热响应性大分子载体，由于其在正常生理条件下的可溶性，其能够靶向递送结合的分子。此外，ELP聚集在轻度高温反应。使用ELP作为载体，可以改善治疗药物的药理学性质以及降低在正常组织中的毒性。在这项工作中，我们研究了联合治疗雄激素非依赖性前列腺癌细胞与硼替佐米和结合到ELP载体的p21 Cip 1/Waf 1蛋白的C-末端部分。我们已经发现，硼替佐米和ELP结合的p21 Cip 1/Waf 1蛋白的联合治疗导致细胞周期停滞以及细胞凋亡相对于单一治疗增加。我们相信这种方法代表了雄激素非依赖性前列腺癌治疗的一个有前途的方向。
Prostate cancer remains one of the most common malignancies in men. Besides surgical resection, treatments for prostate cancer include hormone therapy, chemotherapy and radiation therapy. Advancement of prostate cancer to androgen-independent state limits the potential of conventional therapeutic approaches. Bortezomib, an FDA approved proteosomal inhibitor for the treatment of myeloid leukemia, has been shown to have a positive effect on the inhibition of prostate cancer growth. Unfortunately, bortezomib has a very narrow therapeutic window which can lead to severe side effects. Elastin-like polypeptide (ELP) is a genetically engineered, thermally responsive macromolecular carrier that enables a targeted delivery of the bound molecule due to its soluble property under normal physiologic conditions. Additionally, ELP aggregates in response to mild hyperthermia. Using ELP as a carrier, it is possible to improve pharmacological properties of the therapeutic drug as well as reduce toxicity in normal tissues. In this work, we have investigated the combination treatment of androgen-independent prostate cancer cells with bortezomib and C-terminal part of the p21Cip1/Waf1 protein bound to the ELP carrier. We have found that combination treatment with bortezomib and ELP-bound p21Cip1/Waf1 protein leads to increased cell cycle arrest as well as apoptosis with regards to single treatments. We believe that this approach represents a promising direction for the treatment of androgen-independent prostate cancer.