title: Breast cancer cells can evade apoptosis-mediated selective killing by a novel small molecule inhibitor of Bcl-2.
abstract: Proteins of the Bcl-2 family are key regulators of caspase activation and apoptosis. Some members of this family, notably Bcl-2 and Bcl-x(L), are overexpressed in cancer cells, which have been associated with chemoresistance. We have designed and synthesized a small molecule inhibitor of Bcl-2, named YC137, and studied its role in cancer cells. In vitro studies showed that YC137 inhibits the binding of the Bid BH3 peptide to Bcl-2, thus disrupting an interaction essential for the antiapoptotic activity of Bcl-2. This inhibitor induces apoptosis of hematopoietic progenitors overexpressing Bcl-2 but not Bcl-x(L) and breast cancer cells that express high levels of Bcl-2. On the contrary, a variety of normal primary cells, including CD34(+) progenitors, myoblasts, and peripheral blood mononuclear cells, do not respond to the inhibitor. A breast cancer cell line resistant to YC137 was generated. Analysis of resistant cells revealed a reduced expression of Bcl-2, which correlated with low activation of signal transducer and activator of transcription-3 (Stat3) and reduced expression of the human epidermal growth factor receptor-2 (HER2). Of note, YC137-resistant cells were more sensitive to apoptosis induced by chemotherapy. Because HER2 has not been linked previously to the Stat3-Bcl-2 transcriptional pathway, we additionally confirmed that specific blockade of HER2 in breast cancer cells resulted in down-regulation of Stat3 activity and reduced levels of Bcl-2. Consistently, HER2 blockade led to YC137 resistance. These data provide evidence for the selective killing of tumor cells by YC137 and represent the first example of in vitro selection of cancer cells refractory to a Bcl-2 inhibitor.
authors.affiliation: Unidad de Genetica Molecular and Servicio de Oncologia Medica, Hospital Universitario Marques de Valdecilla, Servicio Cantabro de Salud, Santander, Spain.
authors.forename: Pedro Jose
authors.initials: PJ
authors.lastname: Real
authors.forename: Yeyu
authors.initials: Y
authors.lastname: Cao
authors.forename: Renxiao
authors.initials: R
authors.lastname: Wang
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.forename: Jaime
authors.initials: J
authors.lastname: Sanz-Ortiz
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Fernandez-Luna
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D050796:STAT3 Transcription Factor; D013844:Thiazoles / Q000494:pharmacology*; D015534:Trans-Activators / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D013844:Thiazoles; D015534:Trans-Activators; C494086:STAT3 protein, human; C493272:YC137