RESUMO
Nab-paclitaxel is an albumin-bound 130-nm particle form of paclitaxel that has shown an improved efficacy in experimental tumor models and clinical studies compared with solvent-based paclitaxel. Anti-vascular endothelial growth factor A (VEGF-A) antibody bevacizumab is known to enhance antitumor activity of cytotoxic drugs. This study evaluated the effects of combined nab-paclitaxel and bevacizumab therapy on growth and metastatic spread of orthotopic breast tumors. Cytotoxic and clonogenic assays measured VEGF-A-dependent modulation of nabpaclitaxel toxicity on cultured tumor cells. Antitumor effects were assessed in mice with luciferase-tagged, well-established MDA-MB-231 tumors (250-310 mm3) treated with one, two, or three cycles of nab-paclitaxel (10 mg/kg, daily for five consecutive days), bevacizumab (2-8 mg/kg, twice a week), or with combination of both drugs. VEGF-A protected MDA-MB-231 cells against nab-paclitaxel cytotoxicity, whereas bevacizumab sensitized cells to the effect of the drug. Combined bevacizumab and nab-paclitaxel treatment synergistically inhibited tumor growth and metastasis resulting in up to 40% of complete regressions of well-established tumors. This therapy also decreased the incidence of lymphatic and pulmonary metastases by 60% and 100%, respectively. The significant increase in the cure of tumor-bearing mice in the nab-paclitaxel/bevacizumab combined group compared with mice treated with single drugs strongly advocates for implementing such strategy in clinics.
Assuntos
Albuminas/farmacologia , Neoplasias da Mama/metabolismo , Paclitaxel/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Bevacizumab , Linhagem Celular Tumoral , Humanos , Luciferases/metabolismo , Camundongos , Modelos Biológicos , Metástase Neoplásica , Transplante de Neoplasias , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The Notch signaling plays a key role in cell differentiation, survival, and proliferation through diverse mechanisms. Thus, alterations of the Notch signaling can lead to a variety of disorders including human malignancies. In this review, we will focus on recent advancements in identification of aberrant Notch signaling in cancer, and the possible underlying mechanisms in breast cancer. We will also highlight the therapeutic potential of targeting Notch for cancer treatment.
