Drug library screening identifies histone deacetylase inhibition as a novel therapeutic strategy for choriocarcinoma

• Published in: Cancer medicine (Malden, MA) MA), 2023-02, Vol.12 (4), p.4543-4556
• Main Authors: Watanabe, Eri, Yokoi, Akira, Yoshida, Kosuke, Sugiyama, Mai, Kitagawa, Masami, Nishino, Kimihiro, Yamamoto, Eiko, Niimi, Kaoru, Yamamoto, Yusuke, Kajiyama, Hiroaki
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Camptothecin; Cell growth; Cell Line, Tumor; Chemoresistance; Chemotherapy; Choriocarcinoma; Choriocarcinoma - drug therapy; Digoxin; drug repositioning; Drug screening; Drugs; FDA approval; Female; Ferroptosis; Genes; Histone deacetylase; histone deacetylase inhibitors; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - pharmacology; Lymphocytes T; Malignancy; Mice; NF-E2-Related Factor 2; Proteins; T-cell lymphoma; Topotecan; Tumors; vorinostat; Vorinostat - pharmacology
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.5243

Background Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy. Methods Three choriocarcinoma cell lines (JAR, JEG‐3, and BeWo) and a human extravillous trophoblast cell line (HTR‐8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA‐approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor‐bearing mice. Functional analyses of drug effects were performed based on RNA sequencing. Results Muti‐step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti‐cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis‐related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell‐bearing mice model. Conclusion Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T‐cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis‐related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma. We evaluated the growth inhibitory effect of 1271 FDA‐approved compounds by MTS assay and identified vorinostat, a histone deacetylase inhibitor, as one of the therapeutic candidates. Vorinostat showed a remarkable anti‐cancer effect both in vitro and in vivo by inducing ferroptosis.