RESUMO
The nuclear factor (NF)-kappaB system is a promising anticancer target due to its role in oncogenesis and chemoresistance in preclinical models. To provide evidence in a clinical setting on the role of NF-kappaB in breast cancer, we aimed to study the value of basal NF-kappaB/p65 in predicting resistance to neoadjuvant chemotherapy, and to characterise the pharmacodynamic changes in NF-kappaB/p65 expression following chemotherapy in patients with locally advanced breast cancer. Pre- and post-chemotherapy tumour specimens from 51 breast cancer patients treated with anthracycline- and/or taxane-containing neoadjuvant chemotherapy were assayed by immunohistochemistry for NF-kappaB/p65 subcellular expression. We studied NF-kappaB/p65, a well-characterised member of the NF-kappaB family that undergoes nuclear translocation when NF-kappaB is activated. Activation of NF-kappaB (i.e. nuclear NF-kappaB/p65 staining in pre-therapy specimens) was linked to chemoresistance. Patients with NF-kappaB/p65 nuclear staining in pre-treatment samples had a 20% clinical response rate, while patients with undetected nuclear staining had a 91% response rate to chemotherapy (P = 0.002). Notably, four patients achieved a complete histological response and none of them had pre-treatment NF-kappaB/p65 nuclear staining. Moreover, the number of patients with NF-kappaB/p65 activation increased after chemotherapy exposure. It is concluded that NF-kappaB/p65 activation assayed by immunohistochemistry is a predictive factor of resistance to neoadjuvant chemotherapy in breast cancer patients. Moreover, NF-kappaB activation was inducible following chemotherapy in a proportion of breast cancer patients. These novel clinical findings strengthen the rationale for the use of NF-kappaB inhibitors to prevent or overcome chemoresistance in breast cancer.
Assuntos
Neoplasias da Mama/terapia , Resistencia a Medicamentos Antineoplásicos , Terapia Neoadjuvante , Fator de Transcrição RelA/metabolismo , Adulto , Idoso , Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Citoplasma/química , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , NF-kappa B/análise , NF-kappa B/metabolismo , Prognóstico , Fator de Transcrição RelA/análise , Regulação para CimaAssuntos
Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos B/imunologia , Linfoma de Célula do Manto/imunologia , Linfoma/patologia , Ribonucleosídeos/farmacologia , Neoplasias Esplênicas/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Humanos , Técnicas In Vitro , Linfoma/sangue , Linfoma de Célula do Manto/sangue , Linfoma de Célula do Manto/patologia , Neoplasias Esplênicas/sangueRESUMO
We have previously reported that prodigiosin (2-methyl-3-pentyl-6-methoxyprodigiosene) induces apoptosis in human hematopoietic cancer cell lines with no marked toxicity in nonmalignant cell lines. In this study, we demonstrate that prodigiosin induces apoptosis of B-cell chronic lymphocytic leukemia (B-CLL) cells (n=32 patients). The dose-response for the cytotoxic effect of prodigiosin was analyzed in cells from 12 patients showing an IC(50) of 116+/-25 nM. Prodigiosin induced apoptosis of B-CLL cells through caspase activation. We also analyzed the cytotoxic effect of prodigiosin in T cells from B-CLL samples and no differences were observed with respect to leukemia cells. This is the first report showing that prodigiosin induces apoptosis in human primary cancer cells.
