RESUMO
Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist.
Assuntos
Anticorpos Monoclonais/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/agonistas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vimentina/metabolismo , Anticorpos Monoclonais Humanizados , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Receptor Tirosina Quinase AxlRESUMO
We investigated the composition of extracts derived from Guaiacum spp. (Zygophyllaceae), a group of neotropical tree species with varied uses in Central and South American traditional medicine. Activity-guided fractionation of Guaiacum heartwood extracts led to the identification of four new spirocyclic lignans, named ramonanins A-D (1-4). The ramonanins exhibit cytotoxic activity against human breast cancer cell lines with an IC50 value of 18 µM and induce cell death via apoptotic mechanisms. The ramonanins are derived from four units of coniferyl alcohol and feature an unusual spirocyclic ring system.