Li Senlin, Chen Siyu, Dong Zhihui, Song Xingdong, Li Xiuling, Huang Ziqi, Li Huiru, Huang Linzhuo, Zhuang Ganyuan, Lan Ran, Guo Mingyan, Li Wende, Saw Phei Er, Zhang Lei
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Acta Pharm Sin B. 2023 Mar;13(3):967-981. doi: 10.1016/j.apsb.2022.03.003. Epub 2022 Mar 12.
Platinum-based chemotherapy resistance is a key factor of poor prognosis and recurrence in hepatocellular carcinoma (HCC). Herein, RNAseq analysis revealed that elevated tubulin folding cofactor E () expression is associated with platinum-based chemotherapy resistance. High expression of TBCE contributes to worse prognoses and earlier recurrence among liver cancer patients. Mechanistically, TBCE silencing significantly affects cytoskeleton rearrangement, which in turn increases cisplatin-induced cycle arrest and apoptosis. To develop these findings into potential therapeutic drugs, endosomal pH-responsive nanoparticles (NPs) were developed to simultaneously encapsulate TBCE siRNA and cisplatin (DDP) to reverse this phenomena. NPs (siTBCE + DDP) concurrently silenced TBCE expression, increased cell sensitivity to platinum treatment, and subsequently resulted in superior anti-tumor effects both and in orthotopic and patient-derived xenograft (PDX) models. Taken together, NP-mediated delivery and the co-treatment of siTBCE + DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.
铂类化疗耐药是肝细胞癌（HCC）预后不良和复发的关键因素。在此，RNA测序分析显示，微管蛋白折叠辅助因子E（TBCE）表达升高与铂类化疗耐药相关。TBCE的高表达导致肝癌患者预后更差、复发更早。从机制上讲，TBCE沉默显著影响细胞骨架重排，进而增加顺铂诱导的细胞周期停滞和凋亡。为了将这些发现转化为潜在的治疗药物，开发了内体pH响应纳米颗粒（NPs），以同时封装TBCE小干扰RNA（siRNA）和顺铂（DDP）来逆转这种现象。纳米颗粒（siTBCE + DDP）同时沉默TBCE表达，增加细胞对铂治疗的敏感性，并随后在原位和患者来源的异种移植（PDX）模型中均产生了优异的抗肿瘤效果。综上所述，NP介导的递送以及siTBCE + DDP联合治疗在多种肿瘤模型中均被证明可有效逆转DDP的化疗耐药性。
