Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis.

The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic.

Identification and Characterization of a Small Molecule Bcl-2 Functional Converter.

Unlabelled: Cancer cells exploit the expression of anti-apoptotic protein Bcl-2 to evade apoptosis and develop resistance to therapeutics. High levels of Bcl-2 leads to sequestration of pro-apoptotic proteins causing the apoptotic machinery to halt. In this study, we report discovery of a small molecule, BFC1108 (5-chloro-N-(2-ethoxyphenyl)-2-[(4-methoxybenzyol)amino]benzamide), which targets Bcl-2 and converts it into a pro-apoptotic protein.

Suppression of Ah Receptor (AhR) increases the aggressiveness of TNBC cells and 11-Cl-BBQ-activated AhR inhibits their growth.

Triple-negative breast cancer (TNBC) represents around 15% of the 2.26 million breast cancers diagnosed worldwide annually and has the worst outcome. Despite recent therapeutic advances, there remains a lack of targeted therapies for this breast cancer subtype.

Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline.

Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses.

Tumor-Suppressive Functions of the Aryl Hydrocarbon Receptor (AhR) and AhR as a Therapeutic Target in Cancer.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in regulating a wide range of biological responses. A diverse array of xenobiotics and endogenous small molecules bind to the receptor and drive unique phenotypic responses. Due in part to its role in mediating toxic responses to environmental pollutants, AhR activation has not been traditionally viewed as a viable therapeutic approach.

11-Cl-BBQ, a select modulator of AhR-regulated transcription, suppresses lung cancer cell growth via activation of p53 and p27.

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and functions as a tumour suppressor in different cancer models. In the present study, we report detailed characterization of 11-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (11-Cl-BBQ) as a select modulator of AhR-regulated transcription (SMAhRT) with anti-cancer actions. Treatment of lung cancer cells with 11-Cl-BBQ induced potent and sustained AhR-dependent anti-proliferative effects by promoting G1 phase cell cycle arrest.

Loss of the aryl hydrocarbon receptor increases tumorigenesis in p53-deficient mice.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates cell fate via activation of a diverse set of genes. There are conflicting reports describing the role of AhR in cancer. AhR-knockout mice do not develop tumors spontaneously, yet the AhR can act as a tumor suppressor in certain contexts.

The cyclin-dependent kinase inhibitor p27 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity.

p27 functions to coordinate cell cycle progression through the inhibition of cyclin-dependent kinase (CDK) complexes. p27 also exerts distinct activities beyond CDK-inhibition, including functioning as a transcriptional regulator. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with diverse biological roles.

Molecular Analysis of in Non-Small-Cell Lung Cancer.

Our previous study found that zinc finger protein 71 (ZNF71) mRNA expression was associated with chemosensitivity and its protein expression was prognostic of non-small-cell lung cancer (NSCLC). The Krüppel associated box (KRAB) transcriptional repression domain is commonly present in human zinc finger proteins, which are linked to imprinting, silencing of repetitive elements, proliferation, apoptosis, and cancer. This study revealed that had a significantly higher expression than the -less isoform in NSCLC tumors ( = 197) and cell lines ( = 117).

Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of proteins. The AhR was cloned and characterized for its role in mediating the toxicity of dioxins. Subsequent research has identified the role of AhR in suppression of cancer cell growth.

The Zebrafish Xenograft Models for Investigating Cancer and Cancer Therapeutics.

In order to develop new cancer therapeutics, rapid, reliable, and relevant biological models are required to screen and validate drug candidates for both efficacy and safety. In recent years, the zebrafish () has emerged as an excellent model organism suited for these goals. Larval fish or immunocompromised adult fish are used to engraft human cancer cells and serve as a platform for screening potential drug candidates.

The chemistry and toxicology of vaping.

Vaping is the process of inhaling and exhaling an aerosol produced by an e-cigarette, vape pen, or personal aerosolizer. When the device contains nicotine, the Food and Drug Administration (FDA) lists the product as an electronic nicotine delivery system or ENDS device. Similar electronic devices can be used to vape cannabis extracts.

Dietary Indole-3-Carbinol Activates AhR in the Gut, Alters Th17-Microbe Interactions, and Exacerbates Insulitis in NOD Mice.

The diet represents one environmental risk factor controlling the progression of type 1 diabetes (T1D) in genetically susceptible individuals. Consequently, understanding which specific nutritional components promote or prevent the development of disease could be used to make dietary recommendations in prediabetic individuals. In the current study, we hypothesized that the immunoregulatory phytochemcial, indole-3-carbinol (I3C) which is found in cruciferous vegetables, will regulate the progression of T1D in nonobese diabetic (NOD) mice.

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities.

Osteosarcoma (OS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. The proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined.

Small RNA Biosensor Design Strategy To Mitigate Off-Analyte Response.

Several bottlenecks in the design of current sensor technologies for small noncoding RNA must be addressed. The small size of the sensors and the large number of other nucleotides that may have sequence similarity makes selectivity a real concern. Many of the current sensors have one strand with an exposed region called a toehold.

Improved in vivo targeting of BCL-2 phenotypic conversion through hollow gold nanoshell delivery.

Although new cancer therapeutics are discovered at a rapid pace, lack of effective means of delivery and cancer chemoresistance thwart many of the promising therapeutics. We demonstrate a method that confronts both of these issues with the light-activated delivery of a Bcl-2 functional converting peptide, NuBCP-9, using hollow gold nanoshells. This approach has shown not only to increase the efficacy of the peptide 30-fold in vitro but also has shown to reduce paclitaxel resistant H460 lung xenograft tumor growth by 56.

Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells.

Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance.

Identification of a Raloxifene Analog That Promotes AhR-Mediated Apoptosis in Cancer Cells.

We previously reported that raloxifene, an estrogen receptor modulator, is also a ligand for the aryl hydrocarbon receptor (AhR). Raloxifene induces apoptosis in estrogen receptor-negative human cancer cells through the AhR. We performed structure-activity studies with seven raloxifene analogs to better understand the structural requirements of raloxifene for induction of AhR-mediated transcriptional activity and apoptosis.

TCDD, FICZ, and Other High Affinity AhR Ligands Dose-Dependently Determine the Fate of CD4+ T Cell Differentiation.

FICZ and TCDD, two high-affinity AhR ligands, are reported to have opposite effects on T cell differentiation with TCDD inducing regulatory T cells and FICZ inducing Th17 cells. This dichotomy has been attributed to ligand-intrinsic differences in AhR activation, although differences in sensitivity to metabolism complicate the issue. TCDD is resistant to AhR-induced metabolism and produces sustained AhR activation following a single dose in the μg/kg range, whereas FICZ is rapidly metabolized and AhR activation is transient.

AhR activation increases IL-2 production by alloreactive CD4 T cells initiating the differentiation of mucosal-homing Tim3 Lag3 Tr1 cells.

Activation of the aryl hydrocarbon receptor (AhR) by immunosuppressive ligands promotes the development of regulatory T (Treg) cells. Although AhR-induced Foxp3 Treg cells have been well studied, much less is known about the development and fate of AhR-induced Type 1 Treg (AhR-Tr1) cells. In the current study, we identified the unique transcriptional and functional changes in murine CD4 T cells that accompany the differentiation of AhR-Tr1 cells during the CD4 T-cell-dependent phase of an allospecific cytotoxic T lymphocyte (allo-CTL) response.

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target.

The aryl hydrocarbon receptor (AhR) was initially identified as the receptor that binds and mediates the toxic effects induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related halogenated aromatics. Other toxic compounds including some polynuclear aromatic hydrocarbons act through the AhR; however, during the last 25 years, it has become apparent that the AhR plays an essential role in maintaining cellular homeostasis. Moreover, the scope of ligands that bind the AhR includes endogenous compounds such as multiple tryptophan metabolites, other endogenous biochemicals, pharmaceuticals and health-promoting phytochemicals including flavonoids, indole-3-carbinol and its metabolites.