Bovine milk-derived exosomes mediated delivery of resibufogenin and its effect on platinum-resistant ovarian carcinoma.

Abstract

e17065 Background: Platinum-resistant ovarian carcinoma presents poor prognosis owing to its chemotherapeutic resistance. Resibufogenin is a kind of traditional Chinese medicine with potential anti-cancer ability. Exosomes are naturally occurring membrane particles that mediate intercellular communication by delivering molecular information between cells. The purpose of the current study was to evaluate the effect of bovine-milk-derived exosomes as carriers of resibufogenin to Platinum-resistant ovarian carcinoma and investigate the mechanism. Methods: Exosomes were isolated from bovine-milk using differential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and western blot. Drug screening among 172 traditional Chinese medicines to find out resibufogenin. The exosomes were loaded with resibufogenin and the effectiveness of exosome-mediated drug was assessed with viability assay, transwell assay and flow cytometry assay. The distribution of exosome-delivered resibufogenin in cells was inspected by confocal microscopy. Xenograft mouse models were constructed to clarify the treatment response in vivo. mRNA sequencing assay, qPCR assay, immunohistochemistry assay and western blotting assay were used to detect and verify the targeted pathways. Results: Our main finding that resibufogenin inhibits the proliferation, migration and invasion in platinum-resistant ovarian carcinoma. Bovine-milk-derived exosomes delivered resibufogenin into platinum-resistant ovarian carcinoma and enhanced the cytotoxicity of resibufogenin. In vivo experiment demonstrated that resibufogenin suppressed the growth of xenograft tumors, with lower ki-67 expression and higher tunel expression. The mRNA sequencing assay, qPCR assay, immunohistochemistry assay and western blotting assay showed that the PI3K/AKT and Regulation of actin cytoskeleton signaling pathways account for the results above. Conclusions: Bovine-milk-derived exosomes can be used as effective carriers of resibufogenin to platinum-resistant ovarian carcinoma. Bovine-milk-derived exosomes-loading resibufogenin inhibits platinum-resistant ovarian carcinoma growth and migration in vitro and in vivo through PI3K/AKT and Regulation of actin cytoskeleton signaling pathway.