1. Bufalin: A promising therapeutic drug against the cisplatin-resistance of ovarian cancer by targeting the USP36/c-Myc axis.
- Author
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Li B, Tan S, Yu X, and Wang Y
- Subjects
- Female, Humans, Cell Line, Tumor, Animals, Mice, Nude, Apoptosis drug effects, Mice, Cell Proliferation drug effects, Mice, Inbred BALB C, Signal Transduction drug effects, Cisplatin pharmacology, Cisplatin therapeutic use, Drug Resistance, Neoplasm drug effects, Ovarian Neoplasms drug therapy, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms genetics, Bufanolides pharmacology, Bufanolides therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Ubiquitin Thiolesterase metabolism, Ubiquitin Thiolesterase genetics, Ubiquitin Thiolesterase antagonists & inhibitors, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins c-myc genetics
- Abstract
Cisplatin (DPP) resistance is a severe obstacle to ovarian cancer (OC) treatment. Our research aims to uncover the therapeutic effect and the underlying mechanism of Bufalin against DDP resistance. The cell viability, proliferation capacity, γH2AX expression, and apoptosis ratio were quantified via CCK8 assay, colony formation assay, immunofluorescence, and flow cytometry analysis respectively. Xenografting experiment was performed to detect the tumor growth. Molecular docking was applied to mimic the combination of Bufalin and USP36 protein, and Western blotting was conducted to measure the Bax, Bcl-2, γH2AX, USP36, and c-Myc expression. The c-Myc ubiquitination and half-life were detected via ubiquitination assay and cycloheximide chasing assay. Bufalin treatment notably suppressed the cell viability and colony numbers, and increased the apoptosis ratio and γH2AX level in the DDP treatment group. Bufalin therapy also notably inhibited tumor growth, Bax, Bcl-2, and γH2AX expression in vivo. Moreover, the Bufalin application remarkedly reduced the c-Myc expression and half-life and increased the c-Myc ubiquitination via interaction and subsequent down-regulation of USP36. Knockdown of USP36 reversed the antiproliferative effect and proapoptotic capacity of Bufalin therapy in the DDP treatment group. In conclusion, Bufalin can overcome the DDP resistance in vitro and in vivo via the USP36/c-Myc axis, which innovatively suggests the therapeutic potential of Bufalin against DDP resistance ovarian cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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