Molecular mechanisms of resistance to kinase inhibitors and redifferentiation in thyroid cancers.

Protein kinases play critical roles in cell survival, proliferation, and motility. Their dysregulation is therefore a common feature in the pathogenesis of a number of solid tumors, including thyroid cancers. Inhibiting activated protein kinases has revolutionized thyroid cancer therapy, offering a promising strategy in treating tumors refractory to radioactive iodine treatment or cytotoxic chemotherapies.

Hidden in plain sight: The effects of BCG vaccination in the COVID-19 pandemic.

To investigate the relationship between Bacille Calmette-Guérin (BCG) vaccination and SARS-CoV-2 by a bioinformatics approach, two datasets for the SARS-CoV-2 infection group and BCG-vaccinated group were downloaded. Differentially Expressed Genes were identified. Gene ontology and pathways were functionally enriched, and networking was constructed in NetworkAnalyst.

A novel gene panel for prediction of lymph-node metastasis and recurrence in patients with thyroid cancer.

Background: Although well-differentiated papillary thyroid cancer may remain indolent, lymph node metastases and the recurrence rates are approximately 50% and 20%, respectively. No current biomarkers are able to predict metastatic lymphadenopathy and recurrence in early stage papillary thyroid cancer. Hence, identifying prognostic biomarkers predicting cervical lymph-node metastases would prove very helpful in determining treatment.

Xanthohumol increases death receptor 5 expression and enhances apoptosis with the TNF-related apoptosis-inducing ligand in neuroblastoma cell lines.

High-risk neuroblastoma (NB) is lethal childhood cancer. Published data including ours have reported the anti-proliferative effect of Xanthohumol (XN), a prenylated chalcone, in various cancer types suggesting that XN could be a useful small molecule compound against cancer. The TNF-Related Apoptosis-Inducing Ligand (TRAIL) is an endogenous ligand that is expressed in various immune cells.

Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro.

Background: Neuroblastoma (NB) is a devastating disease. Despite recent advances in the treatment of NB, about 60% of high-risk NB will have relapse and therefore long-term event free survival is very minimal. We have reported that targeting glycogen synthase kinase-3 (GSK-3) may be a potential strategy to treat NB.

Antiproliferative and apoptotic effects of xanthohumol in cholangiocarcinoma.

Cholangiocarcinoma remains the second most prevalent hepatic neoplasm in the United States with a 5-year survival rate of less than 10%. Currently, no systemic therapy has demonstrated efficacy. Therefore, an urgent need for the identification of molecularly targeted compound(s) remains.

Suberoylanilide hydroxamic Acid, a histone deacetylase inhibitor, alters multiple signaling pathways in hepatocellular carcinoma cell lines.

Introduction: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has preclinical efficacy in hepatocellular carcinoma (HCC), despite an unclear molecular mechanism. We sought to further investigate the effects of SAHA on HCC. We hypothesize SAHA will inhibit HCC cellular proliferation through apoptosis and aid in further profiling SAHA's effect on HCC oncogenic pathways.

Role of Akt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy.

Background: We have shown that an Akt inhibitor, MK2206, reduces hepatocellular carcinoma (HCC) proliferation. To further delineate MK2206, we sought to investigate the Notch1 pathway and hypothesize that MK2206 treatment will result in Notch1 inhibition with either subsequent or parallel Akt suppression.

Methods: HCC cell lines were treated with various concentrations of MK2206.

Potential Molecular Targeted Therapeutics: Role of PI3-K/Akt/mTOR Inhibition in Cancer.

Primary liver cancer is one of the most commonly occurring cancers worldwide. Hepatocellular carcinoma (HCC) represents the majority of primary liver cancer and is the 3rd most common cause of cancer-related deaths globally. Survival rates of patients with HCC are dependent upon early detection as concomitant liver dysfunction and advanced disease limits traditional therapeutic options such as resection or ablation.

Glycogen synthase kinase-3 inhibitor AR-A014418 suppresses pancreatic cancer cell growth via inhibition of GSK-3-mediated Notch1 expression.

Background: Glycogen synthase kinase-3 (GSK-3) can act as either a tumour promoter or suppressor by its inactivation depending on the cell type. There are conflicting reports on the roles of GSK-3 isoforms and their interaction with Notch1 in pancreatic cancer. It was hypothesized that GSK-3α stabilized Notch1 in pancreatic cancer cells thereby promoting cellular proliferation.

Xanthohumol inhibits Notch signaling and induces apoptosis in hepatocellular carcinoma.

Despite improvement in therapeutic strategies, median survival in advanced hepatocellular carcinoma (HCC) remains less than one year. Therefore, molecularly targeted compounds with less toxic profiles are needed. Xanthohumol (XN), a prenylated chalcone has been shown to have anti-proliferative effects in various cancers types in vitro.

Curcumin-mediated regulation of Notch1/hairy and enhancer of split-1/survivin: molecular targeting in cholangiocarcinoma.

Background: Cholangiocarcinoma (CCA) is highly malignant and characterized by poor prognosis with chemotherapeutic resistance. Therefore, continued development of novel, effective approaches are needed. Notch expression is markedly upregulated in CCA, but the utility of Notch1 inhibition is not defined.

Xanthohumol-Mediated Suppression of Notch1 Signaling Is Associated with Antitumor Activity in Human Pancreatic Cancer Cells.

Pancreatic cancer remains a lethal disease with limited treatment options. At the time of diagnosis, approximately 80% of these patients present with unresectable tumors caused by either locally advanced lesions or progressive metastatic growth. Therefore, development of novel treatment strategies and new therapeutics is needed.

Inhibition of the AKT pathway in cholangiocarcinoma by MK2206 reduces cellular viability via induction of apoptosis.

Introduction: Cholangiocarcinoma (CCA) is an aggressive disease with limited effective treatment options. The PI3K/Akt/mTOR pathway represents an attractive therapeutic target due to its frequent dysregulation in CCA. MK2206, an allosteric Akt inhibitor, has been shown to reduce cellular proliferation in other cancers.

Specific glycogen synthase kinase-3 inhibition reduces neuroendocrine markers and suppresses neuroblastoma cell growth.

Objective: Neuroblastoma is a common neuroendocrine (NE) tumor that presents in early childhood, with a high incidence of malignancy and recurrence. The glycogen synthase kinase-3 (GSK-3) pathway is a potential therapeutic target, as this pathway has been shown to be crucial in the management of other NE tumors. However, it is not known which isoform is necessary for growth inhibition.

MK-2206 causes growth suppression and reduces neuroendocrine tumor marker production in medullary thyroid cancer through Akt inhibition.

Background: Development of targeted therapies for medullary thyroid cancer (MTC) has focused on inhibition of the rearranged during transfection (RET) proto-oncogene. Akt has been demonstrated to be a downstream target of RET via the key mediator phosphoinositide-3-kinase. MK-2206 is an orally administered allosteric Akt inhibitor that has exhibited minimal toxicity in phase I trials.

Mitochondria-targeted antioxidant and glycolysis inhibition: synergistic therapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Mito-carboxy proxyl (Mito-CP), a lipophilic cationic nitroxide, accumulates in the mitochondria because of the large negative transmembrane potential. Studies have shown that these agents act by disrupting the energy-producing mechanism, inducing mitochondrial-mediated apoptosis, and also enhancing the action of other chemotherapeutic agents in cancer cells.

Leflunomide suppresses growth in human medullary thyroid cancer cells.

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the calcitonin-secreting parafollicular cells of the thyroid gland. Leflunomide (LFN) is a disease-modifying antirheumatic drug approved for the treatment of rheumatoid arthritis, and its active metabolite teriflunomide has been identified as a potential anticancer drug. In this study we investigated the ability of LFN to similarly act as an anticancer drug by examining the effects of LFN treatment on MTC cells.

Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth.

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive malignancy with undifferentiated features, for which conventional treatments, including radioactive iodine ablation, are usually not effective. Recent evidence suggests that the Notch1 pathway is important in the regulation of thyroid cancer cell growth and expression of thyrocyte differentiation markers. However, drug development targeting Notch1 signaling in ATC remains largely underexplored.

Neuroendocrine phenotype alteration and growth suppression through apoptosis by MK-2206, an allosteric inhibitor of AKT, in carcinoid cell lines in vitro.

Carcinoids are neuroendocrine malignancies characterized by their overproduction of various bioactive hormones that lead to the carcinoid syndrome. We have shown previously that AKT serves as a key regulator of growth and phenotypic expression of tumor markers in carcinoids by the genetic depletion of AKT expression. However, no small-molecule inhibitor of AKT kinase activity has been developed until recently.

Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy.

A multifunctional gold (Au) nanorod (NR)-based nanocarrier capable of co-delivering small interfering RNA (siRNA) against achaete-scute complex-like 1 (ASCL1) and an anticancer drug (doxorubicin (DOX)) specifically to neuroendocrine (NE) cancer cells was developed and characterized for combined chemotherapy and siRNA-mediated gene silencing. The Au NR was conjugated with (1) DOX, an anticancer drug, via a pH-labile hydrazone linkage to enable pH-controlled drug release, (2) polyarginine, a cationic polymer for complexing siRNA, and (3) octreotide (OCT), a tumor-targeting ligand, to specifically target NE cancer cells with overexpressed somatostatin receptors. The Au NR-based nanocarriers exhibited a uniform size distribution as well as pH-sensitive drug release.

Synergistic effect of pasireotide and teriflunomide in carcinoids in vitro.

Background/aim: Somatostatin (SST) analogs are mainstay for controlling tumor proliferation and hormone secretion in carcinoid patients. Recent data suggest that extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation may potentiate the anti-tumor effects of SST analogs in carcinoids. Additionally, ERK1/2 phosphorylating agents have been shown to suppress biomarker expression in carcinoids.

The Phosphatidylinositol 3-kinase/Akt Signaling Pathway in Neuroendocrine Tumors.

The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is often aberrantly activated in neuroendocrine-derived cancers. Therefore, selectively targeting this pathway using small-molecule inhibitors may reduce neuroendocrine tumor burden, potentiate adjunct therapies, and achieve symptomatic control for patients with hormonally active and inoperable disease. Here, we discuss the role of the PI3K-Akt pathway in the malignant transformation of neuroendocrine tumors, specifically carcinoids and small cell lung cancers.

Antiproliferative effect of chrysin on anaplastic thyroid cancer.

Background: Anaplastic thyroid cancer (ATC) is an undifferentiated, aggressive malignancy, for which there are no effective therapies. Though ATCs only make up less than 2% of all thyroid cancer cases, they represent over half of the thyroid cancer-related deaths. Chrysin, a natural flavonoid, has recently been reported as a potential anti-cancer agent.

Expression of the active Notch1 decreases MTC tumor growth in vivo.

Background: Human medullary thyroid cancer (MTC) is a neuroendocrine (NE) tumor, derived from thyroid C-cells. Besides surgery, there are no curative therapies for MTC. This emphasizes the need for the development of new therapies.