title: Identification of 5-nitrofuran-2-amide derivatives that induce apoptosis in triple negative breast cancer cells by activating C/EBP-homologous protein expression.
abstract: The transcription factor C/EBP-homologous protein (CHOP) is a key component of the terminal unfolded protein response (UPR) that mediates unresolvable endoplasmic reticulum stress-induced apoptosis. CHOP induction is known to cause cancer cell death. Chemicals that induce CHOP expression would thus be valuable as potential cancer therapeutics and as research tools. Here, we identified 5-nitrofuran-2-amide derivatives as small molecule activators of CHOP expression that induced apoptosis in triple negative breast cancer (TNBC) cells. Our preliminary structure-activity relationship studies indicated that compounds with an N-phenyl-5-nitrofuran-2-carboxamide skeleton were particularly potent inducers of TNBC cell apoptosis. The compounds activate CHOP expression via the PERK-eIF2α-ATF4 branch of the UPR. These results indicate that small molecule activators of CHOP expression may have therapeutic potential for TNBC.
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, OK, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Duan
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, OK, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, OK, USA.
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, OK, USA. Electronic address: weidong-wang@omrf.org.
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000577:Amides / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D009581:Nitrofurans / Q000737:chemistry* / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D000577:Amides; D022762:CCAAT-Enhancer-Binding Proteins; D009581:Nitrofurans
keywords: Antitumor agents; CHOP activator; Cancer; Triple negative breast cancer; Unfolded protein response