ABSTRACT
Endocrine therapy is currently the main therapeutic approach for estrogen receptor-positive (ER+) breast cancer, the most frequent subtype of breast cancer in women worldwide. For this subtype of tumors, the current clinical treatment includes aromatase inhibitors (AIs) and anti-estrogenic compounds, such as Tamoxifen and Fulvestrant, being AIs the first-line treatment option for post-menopausal women. Moreover, the recent guidelines also suggest the use of these compounds by pre-menopausal women after suppressing ovaries function. However, besides its therapeutic efficacy, the prolonged use of this type of therapies may lead to the development of several adverse effects, as well as, endocrine resistance, limiting the effectiveness of such treatments. In order to surpass this issues and clinical concerns, during the last years, several studies have been suggesting alternative therapeutic approaches, considering the function of aromatase, ERα and ERß. Here, we review the structural and functional features of these three targets and their importance in ER+ breast cancer treatment, as well as, the current treatment strategies used in clinic, emphasizing the importance of the development of multi-target compounds able to simultaneously modulate these key targets, as a novel and promising therapeutic strategy for this type of cancer.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Aromatase Inhibitors/therapeutic use , Aromatase/genetics , Breast Neoplasms/drug therapy , Estrogen Receptor alpha/genetics , Androstadienes/therapeutic use , Aromatase/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Estrogen Receptor alpha/antagonists & inhibitors , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/antagonists & inhibitors , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , Fadrozole/therapeutic use , Female , Fulvestrant/therapeutic use , Gene Expression , Humans , Molecular Targeted Therapy , Tamoxifen/therapeutic useABSTRACT
Nuclear factor-kappa B (NF-kappaB) is an important transcription factor, involved in many immune and inflammatory responses. It is critical in HIV gene expression as it has kappa B binding sites in the HIV-1 long-terminal repeat. Hence, targeting NF-kappaB to prevent its DNA binding holds a significant therapeutic potential. In this context, we report Evans Blue as a novel inhibitor of NF-kappaB-DNA binding. Evans Blue was found to be inhibiting DNA binding of NF-kappaB at a low concentration of 100 microM. Further, molecular modeling studies using docking and generation of electrostatic potential maps predicted a possible binding mode of EB to the DNA binding region of NF-kappaB, consistent with the experimental activity.
