Department of Cancer Biology, University of Massachusetts Medical School, Worcester, USA.
Clin Cancer Res. 2010 Oct 1;16(19):4779-88. doi: 10.1158/1078-0432.CCR-10-1818. Epub 2010 Sep 28.
This study aimed to characterize the preclinical activity of the first class of combinatorial, mitochondria-targeted, small molecule heat shock protein-90 (Hsp90) inhibitors, gamitrinibs, in models of hormone-refractory, drug-resistant, localized, and bone metastatic prostate cancer in vivo.
Mitochondrial permeability transition, apoptosis, and changes in metabolic activity were examined by time-lapse videomicroscopy, multiparametric flow cytometry, MTT, and analysis of isolated mitochondria. Drug-resistant prostate cancer cells were generated by chronic exposure of hormone-refractory PC3 cells to the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG). The effect of gamitrinibs on s.c. or intratibial prostate cancer growth was studied in xenograft models. Bone metastatic tumor growth and bone parameters were quantified by micro-computed tomography imaging.
In the NCI 60-cell line screening, gamitrinibs were active against all tumor cell types tested, and efficiently killed metastatic, hormone-refractory, and multidrug-resistant prostate cancer cells characterized by overexpression of the ATP binding cassette transporter P-glycoprotein. Mechanistically, gamitrinibs, but not 17-AAG, induced acute mitochondrial dysfunction in prostate cancer cells with loss of organelle membrane potential, release of cytochrome c, and caspase activity, independently of proapoptotic Bcl-2 proteins Bax and Bak. Systemic administration of gamitrinibs to mice was well tolerated, and inhibited s.c. or bone metastatic prostate cancer growth in vivo.
Gamitrinibs have preclinical activity and favorable safety in models of drug-resistant and bone metastatic prostate cancer in vivo.
本研究旨在描述第一代组合型、靶向线粒体的小分子热休克蛋白 90（Hsp90）抑制剂——加米替尼在激素难治性、耐药性、局限性和骨转移性前列腺癌的体内模型中的临床前活性。
通过时差视频显微镜、多参数流式细胞术、MTT 和分离线粒体分析，检测线粒体通透性转换、细胞凋亡和代谢活性的变化。通过对激素难治性 PC3 细胞进行慢性暴露于 Hsp90 抑制剂 17-烯丙基氨基格尔德霉素（17-AAG）来产生耐药性前列腺癌细胞。在异种移植模型中研究加米替尼对皮下或胫骨内前列腺癌生长的影响。通过微计算机断层扫描成像定量分析骨转移肿瘤生长和骨参数。
在 NCI 60 细胞系筛选中，加米替尼对所有测试的肿瘤细胞类型均具有活性，并且有效地杀死了转移性、激素难治性和多药耐药性前列腺癌细胞，这些细胞特征是过度表达三磷酸腺苷结合盒转运蛋白 P-糖蛋白。从机制上讲，加米替尼而不是 17-AAG 可诱导前列腺癌细胞急性线粒体功能障碍，导致细胞器膜电位丧失、细胞色素 c 释放和 caspase 活性，与促凋亡 Bcl-2 蛋白 Bax 和 Bak 无关。加米替尼在小鼠中的全身给药耐受性良好，并抑制体内皮下或骨转移前列腺癌的生长。
加米替尼在耐药性和骨转移性前列腺癌的体内模型中具有临床前活性和良好的安全性。
