1.Concurrent silencing of TBCE and drug delivery to overcome platinum-based resistance in liver cancer.
Senlin LI ; Siyu CHEN ; Zhihui DONG ; Xingdong SONG ; Xiuling LI ; Ziqi HUANG ; Huiru LI ; Linzhuo HUANG ; Ganyuan ZHUANG ; Ran LAN ; Mingyan GUO ; Wende LI ; Phei Er SAW ; Lei ZHANG
Acta Pharmaceutica Sinica B 2023;13(3):967-981
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.
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