4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells.
Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor for the tumor necrosis factor-related apoptosis-inducing ligand TRAIL and in drug resistance in human malignancies. c-FLIP is an antagonist of caspases-8 and -10, which inhibits apoptosis and is expressed as long (c-FLIP(L)) and short (c-FLIP(S)) splice forms. c-FLIP is often overexpressed in various human cancers, including breast cancer. Several studies have shown that silencing c-FLIP by specific siRNAs sensitizes cancer cells to TRAIL and anticancer agents. However, systemic use of siRNA as a therapeutic agent is not practical at present. In order to reduce or inhibit c-FLIP expression, small molecules are needed to allow targeting c-FLIP without inhibiting caspases-8 and -10. We used a small molecule inhibitor of c-FLIP, 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH), and show that CMH, but not its inactive analog, downregulated c-FLIP(L) and c-FLIP(S) mRNA and protein levels, caused poly(ADP-ribose) polymerase (PARP) degradation, reduced cell survival, and induced apoptosis in MCF-7 breast cancer cells. These results revealed that c-FLIP is a critical apoptosis regulator that can serve as a target for small molecule inhibitors that downregulate its expression and serve as effective targeted therapeutics against breast cancer cells.
Bijangi-Vishehsaraei
Khadijeh
K
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA.
Huang
Su
S
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA.
Safa
Ahmad R
AR
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA.
Saadatzadeh
Mohammad Reza
MR
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Murphy
Michael P
MP
Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
C554680:4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D006877:Hydroxamic Acids; D012333:RNA, Messenger
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