State Key Laboratory of Oncology in South China, Guangzhou, China.
Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, China.
Invest New Drugs. 2017 Oct;35(5):566-575. doi: 10.1007/s10637-017-0477-5. Epub 2017 Jun 20.
The availability of effective medication for the treatment of refractory or recurrent neuroblastoma remains limited. This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab-paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained positive for DCN, SPARC and stabilin-1 respectively and correlated to age, stage and N-MYC status in 96 children and adolescents with neuroblastoma. Transfected neuroblastoma cells stably expressed DCN, with in vivo and in vitro studies demonstrating rAAV-DCN sensitized the anticancer effect of nab-paclitaxel. Systemic rAAV-DCN in neuroblastoma-grafted nude mice inhibited stabilin-1, up-regulated SPARC, and increased the intratumoral uptake of paclitaxel. Macrophage depletion or anti-stabilin-1 monoclonal antibody increased the intratumoral uptake of nab-paclitaxel and its anticancer effects to a degree comparable to that achieved by systemic rAAV-DCN. The systemic administration of rAAV-DCN up-regulates DCN in neuroblastoma and accelerates the intratumoral uptake of nab-paclitaxel by inhibiting stabilin-1 mediated SPARC degradation.
有效药物治疗难治性或复发性神经母细胞瘤的供应仍然有限。本研究旨在探讨增加decorin（DCN）表达对nab-紫杉醇瘤内摄取的影响，作为一种治疗神经母细胞瘤的新方法。评估神经母细胞瘤的临床特征与 DCN、分泌型酸性富含半胱氨酸蛋白（SPARC）和稳定素-1 的表达之间的相关性。评估重组腺相关病毒-DCN（rAAV-DCN）在体内和体外的抗癌作用。并研究 rAAV-DCN 对神经母细胞瘤荷瘤裸鼠紫杉醇瘤内摄取的影响。总体而言，96 例神经母细胞瘤患儿和青少年中，有 12.5%、17.7%和 71.9%的肿瘤分别对 DCN、SPARC 和稳定素-1 呈阳性染色，与年龄、分期和 N-MYC 状态相关。转染的神经母细胞瘤细胞稳定表达 DCN，体内和体外研究表明 rAAV-DCN 增敏 nab-紫杉醇的抗癌作用。神经母细胞瘤荷瘤裸鼠系统给予 rAAV-DCN 抑制稳定素-1，上调 SPARC，并增加紫杉醇的瘤内摄取。巨噬细胞耗竭或抗稳定素-1 单克隆抗体增加 nab-紫杉醇的瘤内摄取及其抗癌作用，程度与系统给予 rAAV-DCN 相当。rAAV-DCN 的系统给药可上调神经母细胞瘤中的 DCN，并通过抑制稳定素-1 介导的 SPARC 降解加速 nab-紫杉醇的瘤内摄取。
