Dichloroacetate and Quercetin Prevent Cell Proliferation, Induce Cell Death and Slow Tumor Growth in a Mouse Model of HPV-Positive Head and Neck Cancer.

Elevated glucose uptake and production of lactate are common features of cancer cells. Among many tumor-promoting effects, lactate inhibits immune responses and is positively correlated with radioresistance. Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase that decreases lactate production.

Ability of metformin to deplete NAD+ contributes to cancer cell susceptibility to metformin cytotoxicity and is dependent on NAMPT expression.

Background: Nicotinamide adenine dinucleotide (NAD+) is vital for not only energy metabolism but also signaling pathways. A major source of NAD+ depletion is the activation of poly (ADP-ribose) polymerase (PARP) in response to DNA damage. We have previously demonstrated that metformin can cause both caspase-dependent cell death and PARP-dependent cell death in the MCF7 breast cancer cells but not in the MDA-MB-231 (231) breast cancer cells while in high-glucose media.

Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer (TNBC).

This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration.

Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma.

Chemoradiotherapy (CRT) for locally-advanced head and neck squamous cell carcinoma (LA-HSNCC) yields 5-year survival rates near 50% despite causing significant toxicity. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously. The safety of adding this agent to CRT is unknown.

Lactate induces PD-L1 in HRAS-positive oropharyngeal squamous cell carcinoma.

Intratumoral lactate production negatively correlates with survival and tumor clearance in the setting of human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC). Robust anti-tumor immune activity is required for tumor clearance in human patients and animal models of this disease, and intratumoral lactate interferes with this process. While lactate is known to directly inhibit T cell activity, recent evidence has demonstrated that lactate can affect gene expression in multiple cell types.

Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid.

Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression analyses of human ATRTs and normal brain samples indicate that ATRTs have aberrant expression of epigenetic markers including class I histone deacetylases (HDAC's) and lysine demethylase (LSD1).

Use of Antimetastatic SOD3-Mimetic Albumin as a Primer in Triple Negative Breast Cancer.

Of the deaths attributed to cancer, 90% are due to metastasis. Treatments that prevent or cure metastasis remain elusive. Low expression of extracellular superoxide dismutase (EcSOD or SOD3) has been associated with poor outcomes and increased metastatic potential in multiple types of cancer.

Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC.

Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor's ability to compensate by using other metabolic pathways to meet energy and growth demands.

β-Adrenergic receptor modulates mitochondrial metabolism and disease progression in recurrent/metastatic HPV(+) HNSCC.

The incidence of human papillomavirus-associated head and neck squamous cell carcinoma (HPV[ + ] HNSCC) is rapidly increasing. Although clinical management of primary HPV( + ) HNSCC is relatively successful, disease progression, including recurrence and metastasis, is often fatal. Moreover, patients with progressive disease face limited treatment options and significant treatment-associated morbidity.

mTOR inhibition as an adjuvant therapy in a metastatic model of HPV+ HNSCC.

Effective treatments for recurrent/metastatic human papillomavirus-positive (HPV+) head and neck squamous cell cancer (HNSCC) are limited. To aid treatment development, we characterized a novel murine model of recurrent/metastatic HPV+ HNSCC. Further analysis of the parental tumor cell line and its four recurrent/metastatic derivatives led to preclinical testing of an effective treatment option for this otherwise fatal disease.

Deregulation of Internal Ribosome Entry Site-Mediated p53 Translation in Cancer Cells with Defective p53 Response to DNA Damage.

Synthesis of the p53 tumor suppressor and its subsequent activation following DNA damage are critical for its protection against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) at the 5' untranslated region of the p53 mRNA. However, the connection between IRES-mediated p53 translation and p53's tumor suppressive function is unknown.

Translational Control Protein 80 Stimulates IRES-Mediated Translation of p53 mRNA in Response to DNA Damage.

Synthesis of the p53 tumor suppressor increases following DNA damage. This increase and subsequent activation of p53 are essential for the protection of normal cells against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) that is located at the 5'-untranslated region (UTR) of p53 mRNA and found that the IRES activity increases following DNA damage.

Mechanisms by which low glucose enhances the cytotoxicity of metformin to cancer cells both in vitro and in vivo.

Different cancer cells exhibit altered sensitivity to metformin treatment. Recent studies suggest these findings may be due in part to the common cell culture practice of utilizing high glucose, and when glucose is lowered, metformin becomes increasingly cytotoxic to cancer cells. In low glucose conditions ranging from 0 to 5 mM, metformin was cytotoxic to breast cancer cell lines MCF7, MDAMB231 and SKBR3, and ovarian cancer cell lines OVCAR3, and PA-1.

Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells.

The unique metabolism of breast cancer cells provides interest in exploiting this phenomenon therapeutically. Metformin, a promising breast cancer therapeutic, targets complex I of the electron transport chain leading to an accumulation of reactive oxygen species (ROS) that eventually lead to cell death. Inhibition of complex I leads to lactate production, a metabolic byproduct already highly produced by reprogrammed cancer cells and associated with a poor prognosis.

Improved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibition.

Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) incidence is increasing at a near epidemic rate. We investigated whether the mammalian (or mechanistic) target of rapamycin (mTOR) inhibitor, rapamycin, can be used as a concurrent agent to standard-of-care cisplatin/radiation therapy (CRT) to attenuate tumor lactate production, thus enhancing CRT-induced immune-mediated clearance of this antigenic tumor type. A C57Bl/6-derived mouse oropharyngeal epithelial cell line retrovirally transduced with HPV type 16 E6/E7 and human squamous cell carcinoma cell lines were evaluated for their response to rapamycin in vitro with proliferation assays, Western blots, and lactate assays.

Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures.

Background: High mortality rates in ovarian cancer are largely a result of resistance to currently used chemotherapies. Expanding therapies with a variety of drugs has the potential to reduce this high mortality rate. Metformin and phenethyl isothiocyanate (PEITC) are both potentially useful in ovarian cancer, and they are particularly attractive because of their safety.

Far upstream element binding protein 1 activates translation of p27Kip1 mRNA through its internal ribosomal entry site.

The cyclin dependent kinase inhibitor p27 plays an important role in controlling the eukaryotic cell cycle by regulating progression through G1 and entry into S phase. It is often elevated during differentiation and under conditions of cellular stress. In contrast, it is commonly downregulated in cancer cells and its levels are generally inversely correlated with favorable prognosis.

CUG-binding protein represses translation of p27Kip1 mRNA through its internal ribosomal entry site.

The cyclin dependent kinase inhibitor p27 (Kip1) plays an important role in controlling the eukaryotic cell cycle. The 5'-untranslated region of the p27 mRNA harbors an internal ribosome entry site (IRES) which may facilitate synthesis of p27 in certain conditions. In this study, the RNA-associated protein CUGBP1 was shown to interact with the human p27 5'-untranslated region.

Metformin induces both caspase-dependent and poly(ADP-ribose) polymerase-dependent cell death in breast cancer cells.

There is substantial evidence that metformin, a drug used to treat type 2 diabetics, is potentially useful as a therapeutic agent for cancer. However, a better understanding of the molecular mechanisms through which metformin promotes cell-cycle arrest and cell death of cancer cells is necessary. It will also be important to understand how the response of tumor cells differs from normal cells and why some tumor cells are resistant to the effects of metformin.

Phosphorylation at serine 482 affects stability of NF90 and its functional role in mitosis.

Objectives: NF90 is a multifunctional double-strand RNA binding protein with documented roles in transcription, mRNA stability, translation, RNA processing and transport, and mitosis. It is a phosphoprotein that interacts with, and is a substrate for, several protein kinases. The study described here was initiated to gain better understanding of specific NF90 phosphorylation sites and their relationship to mechanisms by which NF90 performs its various functions.

Structure and activity of the internal ribosome entry site within the human p27 Kip1 5'-untranslated region.

The cyclin dependent kinase inhibitor p27(Kip1) is a key cell cycle regulatory protein that is often downregulated in cancer cells. The cellular levels of p27(Kip1) are regulated, in part, through translational control mechanisms. The 5'-UTR of the p27(Kip1) mRNA is known to harbor an IRES that may facilitate expression of p27(Kip1) under conditions of stress such as loss of cell adhesion or growth factor and nutrient deprivation.

Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1.

Background: The antihyperglycemic drug metformin may have beneficial effects on the prevention and treatment of cancer. Metformin is known to activate AMP-activated protein kinase (AMPK). It has also been shown to inhibit cyclin D1 expression and proliferation of some cultured cancer cells.