Concurrent silencing of TBCE and drug delivery to overcome platinum-based resistance in liver cancer

  • Acta Pharm Sin B. 2023 Mar;13(3):967-981. doi: 10.1016/j.apsb.2022.03.003.
Senlin Li  1  2 ,  Siyu Chen  3 ,  Zhihui Dong  1 ,  Xingdong Song  2 ,  Xiuling Li  1 ,  Ziqi Huang  2 ,  Huiru Li  2 ,  Linzhuo Huang  1 ,  Ganyuan Zhuang  1 ,  Ran Lan  2 ,  Mingyan Guo  4 ,  Wende Li  3 ,  Phei Er Saw  1 ,  Lei Zhang  2
Affiliations
  • 1. 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.
  • 2. Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
  • 3. Guangdong Laboratory Animals Monitoring Institute, Guangdong Key Laboratory of Laboratory Animals, Guangzhou, 510663, China.
  • 4. Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
PMID: 36970197 DOI: 10.1016/j.apsb.2022.03.003
Abstract

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 (TBCE) 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 in vitro and in vivo 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.

Keywords
Chemoresistance; Combination therapy; Hepatocellular carcinoma; Nanomedicine; Nanoparticle; RNA interference; Tubulin folding cofactor E; siRNA delivery.
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