{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wang Y"],"funding":["BLRD VA","National Cancer Center","National Cancer Institute","NCI NIH HHS","U.S. Department of Veterans Affairs"],"pagination":["1175-1188"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10947827"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["30(6)"],"pubmed_abstract":["<h4>Purpose</h4>DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development.<h4>Experimental design</h4>The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy.<h4>Results</h4>Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1-3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301-induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301-treated xenografts.<h4>Conclusions</h4>NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death."],"journal":["Clinical cancer research : an official journal of the American Association for Cancer Research"],"pubmed_title":["Preclinical Evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer."],"pmcid":["PMC10947827"],"funding_grant_id":["R01 CA224275","CA224275","I01 BX000792","P30 CA060553","I01 BX006012","CA060553","IO1BX000792"],"pubmed_authors":["Wei JJ","Matei D","Cardenas H","Keathley R","Siu E","Alhunayan SA","Tan Y","Cheng JX","Prabhu Dessai CV","Wang Y","Tanner E","Situ X"],"additional_accession":[]},"is_claimable":false,"name":"Preclinical Evaluation of NTX-301, a Novel DNA Hypomethylating Agent in Ovarian Cancer.","description":"<h4>Purpose</h4>DNA methylation causes silencing of tumor-suppressor and differentiation-associated genes, being linked to chemoresistance. Previous studies demonstrated that hypomethylating agents (HMA) resensitize ovarian cancer to chemotherapy. NTX-301 is a highly potent and orally bioavailable HMA, in early clinical development.<h4>Experimental design</h4>The antitumor effects of NTX-301 were studied in ovarian cancer models by using cell viability, stemness and ferroptosis assays, RNA sequencing, lipidomic analyses, and stimulated Raman spectroscopy.<h4>Results</h4>Ovarian cancer cells (SKOV3, IC50 = 5.08 nmol/L; OVCAR5 IC50 = 3.66 nmol/L) were highly sensitive to NTX-301 compared with fallopian tube epithelial cells. NTX-301 downregulated expression of DNA methyltransferases 1-3 and induced transcriptomic reprogramming with 15,000 differentially expressed genes (DEG, P < 0.05). Among them, Gene Ontology enrichment analysis identified regulation of fatty acid biosynthesis and molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase, known features of cancer stem cells. Low-dose NTX-301 reduced the ALDH(+) cell population and expression of stemness-associated transcription factors. Stearoyl-coenzyme A desaturase 1 (SCD), which regulates production of unsaturated fatty acids (UFA), was among the top DEG downregulated by NTX-301. NTX-301 treatment decreased levels of UFA and increased oxidized lipids, and this was blunted by deferoxamine, indicating cell death via ferroptosis. NTX-301-induced ferroptosis was rescued by oleic acid. In vivo, monotherapy with NTX-301 significantly inhibited ovarian cancer and patient-derived xenograft growth (P < 0.05). Decreased SCD levels and increased oxidized lipids were detected in NTX-301-treated xenografts.<h4>Conclusions</h4>NTX-301 is active in ovarian cancer models. Our findings point to a new mechanism by which epigenetic blockade disrupts lipid homeostasis and promotes cancer cell death.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-05-27T03:08:43.322Z","creation":"2025-04-04T02:04:54.309Z"},"accession":"S-EPMC10947827","cross_references":{"pubmed":["38231483"],"doi":["10.1158/1078-0432.CCR-23-2368","10.1158/1078-0432.ccr-23-2368"]}}