A high-content screen for C/EBPα expression identifies novel therapeutic agents in dedifferentiated liposarcoma Journal Article
| Authors: | Angeles, C. V.; Velez, A.; Rios, J.; Laxa, B.; Shum, D.; Ruiz, P. D.; Shen, Y.; Ostrovnaya, I.; Gularte-Mérida, R.; Nacev, B. A.; Dickson, M. A.; Djaballah, H.; Okada, T.; Singer, S. |
| Article Title: | A high-content screen for C/EBPα expression identifies novel therapeutic agents in dedifferentiated liposarcoma |
| Abstract: | Purpose: Dedifferentiated liposarcoma (DDLS), one of the most common and aggressive sarcomas, infrequently responds to chemotherapy. DDLS survival and growth depend on underexpression of C/EBPα, a tumor suppressor and transcriptional regulator controlling adipogenesis. We sought to screen and prioritize candidate drugs that increase C/EBPα expression and may therefore serve as differentiation-based therapies for DDLS. Experimental Design: We screened known bioactive compounds for the ability to restore C/EBPα expression and inhibit proliferation selectively in two DDLS cell lines but not in normal adipose-derived stem cells (ASC). Selected hits’ activity was validated, and the mechanism of the most potent, SN-38, was investigated. The in vivo efficacy of irinotecan, the prodrug of SN-38, was evaluated in DDLS xenograft models. Results: Of 3,119 compounds, screen criteria were met by 19. Validation experiments confirmed the DDLS selectivity of deguelin, emetine, and SN-38 and showed that they induce apoptosis in DDLS cells. SN-38 had the lowest IC50 (approximately 10 nmol/L), and its pro-apoptotic effects were countered by knockdown of CEBPA but not of TP53. Irinotecan significantly inhibited tumor growth at well-tolerated doses, induced nuclear expression of C/EBPα, and inhibited HIF1α expression in DDLS patient-derived and cancer cell line xenograft models. In contrast, doxorubicin, the most common treatment for nonresectable DDLS, reduced tumor growth by 30% to 50% at a dose that caused weight loss. Conclusions: This high-content screen revealed potential treatments for DDLS. These include irinotecan, which induces apoptosis of DDLS cells in a C/EBPα-dependent, p53-independent manner, and should be clinically evaluated in patients with advanced DDLS. © 2021 American Association for Cancer Research. |
| Keywords: | controlled study; human tissue; protein expression; unclassified drug; human cell; doxorubicin; nonhuman; cytarabine; antineoplastic agent; mouse; animal tissue; apoptosis; etoposide; animal experiment; animal model; antineoplastic activity; drug screening; drug selectivity; protein p53; irinotecan; cancer inhibition; bleomycin; chlorhexidine; hypoxia inducible factor 1alpha; teniposide; nocodazole; cetrimide; parthenolide; cebpa gene; dedifferentiated liposarcoma; ccaat enhancer binding protein alpha; tp53 gene; ancitabine; emetine; gene knockdown; human; female; article; ic50; firtecan; fenbendazole; acrisorcin; anthothecol; cetylpyridinium salt; deguelin; koparin 2' methyl ether; pararosaniline pamoate; strophanthidin; high content screening; liposarcoma cell line |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 1 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-01-01 |
| Start Page: | 175 |
| End Page: | 186 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-19-2486 |
| PUBMED: | 34667024 |
| PROVIDER: | scopus |
| PMCID: | PMC9265140 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2022 -- Source: Scopus |
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