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

Khadijeh Bijangi-Vishehsaraei, Mohammad Reza Saadatzadeh, Su Huang, Michael P. Murphy, Ahmad R. Safa

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Cellular FLICE (FADD-like IL-1β-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-FLIPL) and short (c-FLIPS) 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-FLIPL and c-FLIPS 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.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalMolecular and Cellular Biochemistry
Volume342
Issue number1-2
DOIs
StatePublished - Sep 2010

Keywords

  • 4-(4-Chloro-2-methylphenoxy)-N- hydroxybutanamide (CMH)
  • Apoptosis
  • Breast cancer
  • c-FLIP
  • Caspases
  • Death receptors

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Molecular Biology
  • Cell Biology

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