ABSTRACT
Because of the high prevalence and association of somatic symptoms in depression, a holistic treatment plan that also targets the associated somatic symptoms can be the cornerstone for such patients. In this paper, we present the case of a 53-year-old male physician with depression associated with the somatic symptoms of dysphagia. The initial failure in treating his swallowing defect led to the deterioration in his condition. Moreover, his unique history, complicated by multifactorial life stressors, also raises the attention that there are a variety of presentations of depression.
ABSTRACT
We report in vitro and in vivo evaluation of a newly designed trifunctional theranostic agent for targeting solid tumors. This agent combines a dendritic wedge with high boron content for boron neutron capture therapy or boron MRI, a monomethine cyanine dye for visible-light fluorescent imaging, and an integrin ligand for efficient tumor targeting. We report photophysical properties of the new agent, its cellular uptake and in vitro targeting properties. Using live animal imaging and intravital microscopy (IVM) techniques, we observed a rapid accumulation of the agent and its retention for a prolonged period of time (up to 7 days) in fully established animal models of human melanoma and murine mammary adenocarcinoma. This macromolecular theranostic agent can be used for targeted delivery of high boron load into solid tumors for future applications in boron neutron capture therapy.
Subject(s)
Dendrimers/therapeutic use , Neoplasms/diagnosis , Neoplasms/therapy , Animals , Biological Transport , Cell Line, Tumor , Cell Survival , Dendrimers/metabolism , Dendrimers/pharmacokinetics , Humans , Integrins/metabolism , Ligands , Mice , Neoplasms/pathology , Tissue DistributionABSTRACT
Hypoxia is a hallmark of solid tumors, is associated with local invasion, metastatic spread, resistance to chemo- and radiotherapy, and is an independent, negative prognostic factor for a diverse range of malignant neoplasms. The cellular response to hypoxia is primarily mediated by a family of transcription factors, among which hypoxia-inducible factor 1 (HIF1) plays a major role. Under normoxia, the oxygen-sensitive α subunit of HIF1 is rapidly and constitutively degraded but is stabilized and accumulates under hypoxia. Upon nuclear translocation, HIF1 controls the expression of over 100 genes involved in angiogenesis, altered energy metabolism, antiapoptotic, and pro-proliferative mechanisms that promote tumor growth. A designed transcriptional antagonist, dimeric epidithiodiketopiperazine (ETP 2), selectively disrupts the interaction of HIF1α with p300/CBP coactivators and downregulates the expression of hypoxia-inducible genes. ETP 2 was synthesized via a novel homo-oxidative coupling of the aliphatic primary carbons of the dithioacetal precursor. It effectively inhibits HIF1-induced activation of VEGFA, LOX, Glut1, and c-Met genes in a panel of cell lines representing breast and lung cancers. We observed an outstanding antitumor efficacy of both (±)-ETP 2 and meso-ETP 2 in a fully established breast carcinoma model by intravital microscopy. Treatment with either form of ETP 2 (1 mg/kg) resulted in a rapid regression of tumor growth that lasted for up to 14 days. These results suggest that inhibition of HIF1 transcriptional activity by designed dimeric ETPs could offer an innovative approach to cancer therapy with the potential to overcome hypoxia-induced tumor growth and resistance.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lung Neoplasms/drug therapy , Lung/drug effects , Piperazines/therapeutic use , p300-CBP Transcription Factors/metabolism , Animals , Antineoplastic Agents/chemistry , Breast/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Dimerization , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Nude , Models, Molecular , Piperazines/chemistry , Protein Interaction Maps/drug effects , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Recent evidence supports the existence of a plasma membrane ER. In many cells, E2 activates signal transduction and cell proliferation, but the steroid inhibits signaling and growth in other cells. These effects may be related to interactions of ER with signal-modulating proteins in the membrane. It is also unclear how ER moves to the membrane. Here, we demonstrate ER in purified vesicles from endothelial cell plasma membranes and colocalization of ERalpha with the caveolae structural coat protein, caveolin-1. In human vascular smooth muscle or MCF-7 (human breast cancer) cell membranes, coimmunoprecipitation shows that ER associates with caveolin-1 and -2. Importantly, E2 rapidly and differentially stimulates ER-caveolin association in vascular smooth muscle cells but inhibits association in MCF-7 cells. E2 also stimulates caveolin-1 and -2 protein synthesis and activates a caveolin-1 promoter/luciferase reporter in smooth muscle cells. However, the steroid inhibits caveolin synthesis in MCF-7 cells. To determine a function for caveolin-ER interaction, we expressed caveolin-1 in MCF-7 cells. This stimulated ER translocation to the plasma membrane and also inhibited E2-induced ERK (MAPK) activation. Both functions required the caveolin-1 scaffolding domain. Depending upon the target cell, membrane ERs differentially associate with caveolin, and E2 differentially modulates the synthesis of this signaling-inhibitory scaffold protein. This may explain the discordant signaling and actions of E2 in various cell types. In addition, caveolin-1 is capable of facilitating ER translocation to the membrane.
