A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy.
A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy.
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DOI：
10.1158/1940-6207.capr-08-0184
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Lee HY
中科院分区：
文献类型：
--
作者：
Kim WY;Chang DJ;Hennessy B;Kang HJ;Yoo J;Han SH;Kim YS;Park HJ;Seo SY;Mills G;Kim KW;Hong WK;Suh YG;Lee HY
天然化合物鱼藤素通过直接与热休克蛋白90（Hsp 90）结合并抑制其功能，对多种癌症具有有希望的预防和治疗活性。然而，鱼藤素超过一定剂量的潜在副作用可能是其临床应用的实质性障碍。为了开发具有降低的潜在副作用的鱼藤素衍生物，我们合成了五种鱼藤素类似物（SH-02、SH-03、SH-09、SH-14和SH-15），并将它们与母体化合物以及彼此的结构和生物化学特征、溶解度和对正常人的抗增殖作用进行比较，癌前和恶性人支气管上皮（HBE）和非小细胞肺癌（NSCLC）细胞系。四种衍生物与鱼藤素一样有效地破坏缺氧诱导因子-1 α的稳定性。在H460 NSCLC细胞中的反相蛋白质阵列（RPPA）分析显示鱼藤素及其衍生物抑制许多蛋白质的表达，包括Hsp 90客户端和参与磷酸肌醇3激酶（PI 3 K）/Akt途径的蛋白质。其中一个衍生物SH-14显示了几个潜在的临床用途：具有最高的凋亡活性，对Src/信号转导和转录激活因子（STAT）信号转导没有可检测的影响，而Src/STAT信号转导可促进癌症进展，与帕金森病的发病机制密切相关（鱼藤素、SH-02和SH-03强烈激活该信号传导）;更好的水溶性;在大多数癌前和恶性HBE和NSCLC细胞系中诱导凋亡活性的剂量（1 μM）下，对永生化HBE细胞的细胞毒性较小（与鱼藤素相比）。这些集体结果表明，新衍生物SH-14具有癌症化学预防和治疗的强大潜力，具有等效的功效和较小的毒性（与鱼藤素相比）。
The natural compound deguelin has promising preventive and therapeutic activity against diverse cancers by directly binding to heat-shock protein 90 (Hsp90) and thus suppressing its function. Potential side effects of deguelin over a certain dose, however, could be a substantial obstacle to its clinical use. To develop a derivative(s) of deguelin with reduced potential side effects, we synthesized five deguelin analogues (SH-02, SH-03, SH-09, SH-14 and SH-15) and compared them with the parent compound and each other for structural and biochemical features, solubility, and antiproliferative effects on normal, premalignant and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines. Four derivatives destabilized hypoxia-inducible factor-1α as potently as did deguelin. Reverse-phase protein array (RPPA) analysis in H460 NSCLC cells revealed that deguelin and the derivatives suppressed expression of a number of proteins including Hsp90 clients and proteins involved in the phosphoinositide 3 kinase (PI3K)/Akt pathway. One derivative, SH-14, showed several features of potential superiority for clinical use: the highest apoptotic activity; no detectable influence on Src/signal transducer and activator of transcription (STAT) signaling, which can promote cancer progression and is closely related to pathogenesis of Parkinson’s disease (deguelin, SH-02 and SH-03 strongly activated this signaling); better aqueous solubility; and less cytotoxicity to immortalized HBE cells (versus deguelin) at a dose (1 μM) that induced apoptotic activity in most premalignant and malignant HBE and NSCLC cell lines. These collective results suggest that the novel derivative SH-14 has strong potential for cancer chemoprevention and therapy, with equivalent efficacy and lesser toxicity (versus deguelin).