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

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. Mechanisti-cally, 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 siR-NA 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 thorn DDP proved to be effective in reversing chemotherapy resistance of DDP in multiple tumor models.(c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Platinum-based chemotherapy resistance is associated with elevated tubulin folding cofactor E (TBCE) expression, which contributes to poor prognosis and early recurrence in liver cancer patients. Mechanistically, TBCE silencing affects cytoskeleton rearrangement, leading to increased cisplatin-induced cell cycle arrest and apoptosis. The use of endosomal pH-responsive nanoparticles (NPs) to deliver TBCE siRNA and cisplatin simultaneously reverses chemotherapy resistance and shows superior anti-tumor effects in vitro and in vivo. Summary: NP-mediated delivery of siTBCE and cisplatin effectively reverses platinum-based chemotherapy resistance.