ABSTRACT
Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11.
ABSTRACT
BACKGROUND: Extensive resection of the tumor has been associated with better survival of anaplastic thyroid carcinoma (ATC) patients. However, surgery is not the rule for ATC patients with distant metastases at the time of diagnosis (stage IV-C), regardless of tumor resectability. The aim of this work was to explore the potential role of surgery in ATC patients, including those in stage IV-C. METHODS: We considered all the consecutive ATC patients referred to our institution from June 1999 to July 2012. Patients with stage IV-A incidentally discovered ATC were excluded because of their better prognosis. All patients eligible for surgery at the time of diagnosis were first operated with the intent to obtain a macroscopically complete resection (R0, R1), or a R2 resection with minimal macroscopical residual tumor. These operations were defined as "maximal debulking," whereas operations that did not achieve this goal were defined as "partial debulking." After surgery, almost all patients received adjuvant chemotherapy, associated to radiotherapy in more than 50% of patients. RESULTS: There were 55 eligible patients (34 women; median age 73.15 years). Thirty-one patients had distant metastases (stage IV-C). The median overall survival was 5.55 months [CI 4.94-6.60], with no difference according to stage. "Maximal debulking" was obtained in 70.73% of operated patients as a first modality and resulted associated with better survival than "partial debulking" (6.57 months [CI 5.52-12.09] vs. 3.25 months [CI 0.66-4.80]), without any difference between stage IV-B and IV-C patients. Furthermore, 21% of patients submitted to "maximal debulking" died secondary to local progression of the tumor, whereas this was the case for 69% of patients treated with "partial debulking" or not operated at all. CONCLUSIONS: Early "maximal debulking," followed by adjuvant therapy, can improve the survival and ameliorate the quality of residual life preventing the risk of suffocation. This effect is also observed in patients with distant metastasis at diagnosis and treated with this approach: they have an outcome similar to that observed in stage IV-B patients. We thus suggest that surgery may be considered in the management of all ATC patients, and should not be restricted a priori to stages IV-A and IV-B.
Subject(s)
Thyroid Carcinoma, Anaplastic/surgery , Thyroid Neoplasms/surgery , Thyroidectomy , Adult , Aged , Aged, 80 and over , Chemotherapy, Adjuvant , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Prognosis , Radiotherapy, Adjuvant , Retrospective Studies , Survival Rate , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/mortality , Thyroid Carcinoma, Anaplastic/radiotherapy , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/mortality , Thyroid Neoplasms/radiotherapy , Treatment OutcomeABSTRACT
Triple-negative breast cancer (TNBC) is a very aggressive type of tumour and its aggressiveness is linked to E-cadherin downregulation. In estrogen-sensitive breast cancer, high levels of E-cadherin fit with high levels of ERα and MTA3 (a component of the transcription Mi-2/NuRD complex with intrinsic DAC activity). In TNBC the E-cadherin downregulation could be due to epigenetic silencing of the CDH1 gene as well as to the lack of a fully functioning ERα-activated pathway. We report that the pan-histone deacetylase inhibitor LBH589, a potent anti-proliferative agent, induced E-cadherin expression on cell membranes of MDA-MB-231 cells (TNBC), determining a reduction of cell invasion and migration. Even though E-cadherin expression in breast cancer is also regulated by estradiol and the ERα/MTA3/Snail/Slug pathway, LBH589 is able to increase E-cadherin without affecting the estrogen pathway. In fact, no expression of ERα, PR and FoxA1 was observed in MDA-MB-231 cells before and after LBH589 treatment; furthermore, the drug caused an increase in Snail and Slug expression with a concomitant reduction of MTA3 levels. Taking into consideration its anti-proliferative and anti-invasive properties, we suggest the use of LBH589 in aggressive breast cancer refractory to hormonal therapy.
Subject(s)
Breast Neoplasms/drug therapy , Epigenesis, Genetic , Hydroxamic Acids/administration & dosage , Indoles/administration & dosage , Neoplasm Invasiveness/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cadherins/biosynthesis , Cell Line, Tumor , Estradiol , Estrogen Receptor alpha/biosynthesis , Female , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/administration & dosage , Humans , PanobinostatABSTRACT
Clinical studies have linked the increased consumption of fructose to the development of obesity, dyslipidemia, and impaired glucose tolerance, and a role in hepatosteatosis development is presumed. Fructose can undergo a nonenzymatic reaction from which advanced glycation end products (AGEs) are derived, leading to the formation of dysfunctional, fructosylated proteins; however, the in vivo formation of AGEs from fructose is still less known than that from glucose. In the present study C57Bl/6J mice received 15% (wt/vol) fructose (FRT) or 15% (wt/vol) glucose (GLC) in water to drink for 30 wk, resembling human habit to consume sugary drinks. At the end of the protocol both FRT- and GLC-drinking mice had increased fasting glycemia, glucose intolerance, altered plasma lipid profile, and marked hepatosteatosis. FRT mice had higher hepatic triglycerides deposition than GLC, paralleled by a greater increased expression and activity of the sterol regulatory element-binding protein 1 (SREBP1), the transcription factor responsible for the de novo lipogenesis, and of its activating protein SCAP. LC-MS analysis showed a different pattern of AGE production in liver tissue between FRT and GLC mice, with larger amount of carboxymethyl lysine (CML) generated by fructose. Double immunofluorescence and coimmunoprecipitation analysis revealed an interaction between CML and SCAP that could lead to prolonged activation of SREBP1. Overall, the high levels of CML and activation of SCAP/SREBP pathway associated to high fructose exposure here reported may suggest a key role of this signaling pathway in mediating fructose-induced lipogenesis.
Subject(s)
Fatty Liver/chemically induced , Fructose/pharmacology , Glycation End Products, Advanced/toxicity , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Sterol Regulatory Element Binding Protein 1/metabolism , Animals , Drinking , Fatty Liver/metabolism , Fructose/metabolism , Glucose/metabolism , Glucose/pharmacology , Glucose Intolerance/chemically induced , Glucose Intolerance/metabolism , Glycation End Products, Advanced/metabolism , Hypoglycemia/chemically induced , Hypoglycemia/metabolism , Lipids/blood , Liver/metabolism , Lysine/analogs & derivatives , Lysine/metabolism , Male , Mice , Mice, Inbred C57BL , Signal Transduction , Sterol Regulatory Element Binding Protein 1/genetics , Triglycerides/metabolismABSTRACT
BACKGROUND: Anaplastic thyroid cancers (ATCs) represent only 1%-2% of all thyroid tumors, but they account for up to 50% of the mortality. Treatment of differentiated thyroid carcinomas is well standardized and the use of radioiodine represents an essential step; in contrast, there is no standardized therapeutic approach for anaplastic tumors and their prognosis is poor. The resistance of ATC to radioiodine treatment is principally due to the absence of expression of the sodium iodide symporter (NIS), mainly due to epigenetic silencing. The acetylation status of histones is involved in the epigenetic control of gene expression and is usually disrupted in advanced thyroid cancer. Histone deacetylase inhibitors have been demonstrated as potent anticancer drugs with several different effects on cell viability and differentiation. METHODS: Stabilized ATC cell lines (BHT-101 and CAL-62) and primary cultures from patients who underwent thyroidectomy for ATC were treated with the histone deacetylase inhibitor LBH589. After treatment, we evaluated the expression and function of NIS. Gene expression was evaluated by real-time polymerase chain reaction (RT-PCR), NIS promoter activity was determined with a luciferase reporter assay, and protein expression was assessed through immunofluorescence. We tested the protein function by (125)I uptake and efflux experiments; finally the cytotoxic effect of (131)I was determined with a clonogenic assay. RESULTS: Our results demonstrate that treatment with LBH589 leads to NIS RNA expression as shown by RT-PCR and luciferase assay, and to protein expression as determined by immunofluorescence in vitro and by immunohistochemistry in xenograft tumors. Moreover, (125)I uptake and efflux experiments show the correct protein function and iodine retention, which translate into cytotoxicity effects, as demonstrated by a clonogenic assay with (131)I. CONCLUSIONS: This study supplies a new potential strategy for the treatment of ATC by modifying gene expression with the aim of inducing responsiveness towards radioiodine therapy.
Subject(s)
Histone Deacetylase Inhibitors/pharmacology , Iodine Radioisotopes/therapeutic use , Symporters/biosynthesis , Thyroid Neoplasms/radiotherapy , Aged , Aged, 80 and over , Animals , Cell Line, Tumor , Female , Heterografts , Humans , Hydroxamic Acids/pharmacology , Indoles/pharmacology , Iodine Radioisotopes/metabolism , Male , Mice , Middle Aged , Neoplasm Transplantation , Panobinostat , Thyroid Carcinoma, AnaplasticABSTRACT
At present no successful treatment is available for advanced thyroid cancer, which comprises poorly differentiated, anaplastic, and metastatic or recurrent differentiated thyroid cancer not responding to radioiodine. In the last few years, biologically targeted therapies for advanced thyroid carcinomas have been proposed on the basis of the recognition of key oncogenic mutations. Although the results of several phase II trials look promising, none of the patients treated had a complete response, and only a minority of them had a partial response, suggesting that the treatment is, at best, effective in stabilizing patients with progressive disease. "Epigenetic" refers to the study of heritable changes in gene expression that occur without any alteration in the primary DNA sequence. The epigenetic processes establish and maintain the global and local chromatin states that determine gene expression. Epigenetic abnormalities are present in almost all cancers and, together with genetic changes, drive tumor progression. Various genes involved in the control of cell proliferation and invasion (p16INK4A, RASSF1A, PTEN, Rap1GAP, TIMP3, DAPK, RARß2, E-cadherin, and CITED1) as well as genes specific of thyroid differentiation (Na+/I- symport, TSH receptor, pendrin, SL5A8, and TTF-1) present aberrant methylation in thyroid cancer. This review deals with the most frequent epigenetic alterations in thyroid cancer and focuses on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumor cells and potentially restore normal cell functions. Experimental data and clinical trials, especially using deacetylase inhibitors and demethylating agents, are discussed.
ABSTRACT
CONTEXT: Anaplastic thyroid cancer cells are characterized by a mesenchymal phenotype, as revealed by spindle-shaped cells and absent or reduced levels of E-cadherin. Epigenetic silencing is considered one of the leading mechanisms of E-cadherin impairment, which causes the acquisition of the invasive and metastatic phenotype of anaplastic thyroid cancer. OBJECTIVES: In this study we investigated the effects of histone deacetylase inhibition on E-cadherin expression, cell motility, and invasion in anaplastic thyroid cancer cell cultures. DESIGN: Three stabilized cell lines and primary cultures of anaplastic thyroid cancer were treated with various histone deacetylase inhibitors. After treatment, we evaluated histone acetylation by Western blotting and E-cadherin expression by RT-real time PCR. The proper localization of E-cadherin/ß-catenin complex was assessed by immunofluorescence and Western blot. Transcription activity of ß-catenin was measured by luciferase reporter gene and cyclin D1 expression. The effect on cell motility and invasion was studied both in vitro using scratch-wound and transwell invasion assays and in anaplastic thyroid carcinomas tumor xenografts in mice in vivo. RESULTS: Histone deacetylase inhibition induced the E-cadherin expression and the proper membrane localization of the E-cadherin/ß-catenin complex, leading to reduced cancer cell migration and invasion. CONCLUSIONS: We here demonstrate an additional molecular mechanism for the anticancer effect of histone deacetylase inhibition. The antiinvasive effect in addition to the cytotoxic activity of histone deacetylase inhibitors opens up therapeutic perspectives for the anaplastic thyroid tumor that does not respond to conventional therapy.
Subject(s)
Cadherins/genetics , Cell Movement/drug effects , Histone Deacetylase Inhibitors/pharmacology , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzamides/administration & dosage , Benzamides/pharmacology , Cadherins/metabolism , Down-Regulation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/pharmacology , Indoles , Mice , Mice, SCID , Neoplasm Invasiveness , Panobinostat , Protein Transport/drug effects , Pyridines/administration & dosage , Pyridines/pharmacology , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays , beta Catenin/metabolismABSTRACT
Although the pathogenesis of sporadic Alzheimer disease (AD) is not clearly understood, it is likely dependent on several age-related factors. Diabetes is a risk factor for AD, and multiple mechanisms connecting the 2 diseases have been proposed. Hyperglycemia enhances the formation of advanced glycation end products (AGEs) that result from the auto-oxidation of glucose and fructose. The interaction of AGEs with their receptor, named RAGE, elicits the formation of reactive oxygen species that are also believed to be an early event in AD pathology. To investigate a functional link between the disorders diabetes and AD, the effect of 2 AGEs, pentosidine and glyceraldehydes-derived pyridinium (GLAP), was studied on BACE1 expression both in vivo, in streptozotocin treated rats, and in vitro in differentiated neuroblastoma cells. We showed that pentosidine and GLAP were able to upregulate BACE1 expression through their binding with RAGE and the consequent activation of NF-κB. In addition, both pentosidine and GLAP were found to be increased in the brain in sporadic AD patients. Our findings demonstrate that activation of the AGEs/RAGE axis, by upregulating the key enzyme for amyloid-ß production, provides a pathologic link between diabetes mellitus and AD.
Subject(s)
Amyloid Precursor Protein Secretases/physiology , Aspartic Acid Endopeptidases/physiology , Glycation End Products, Advanced/physiology , NF-kappa B/physiology , Receptors, Immunologic/physiology , Signal Transduction/genetics , Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Animals , Diabetes Mellitus, Experimental , Male , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Receptor for Advanced Glycation End Products , Risk Factors , Signal Transduction/physiology , Up-RegulationABSTRACT
Anaplastic thyroid carcinoma (ATC) has a rapidly fatal clinical course, being resistant to multimodal treatments. Microtubules, α/ß tubulin heterodimers, are crucial in cell signaling, division and mitosis and are among the most successful targets for anticancer therapy. Panobinostat (LBH589) is a potent deacetylase inhibitor acting both on histones and nonhistonic proteins, including α-tubulin. In vitro LBH589, evaluated in three ATC cell lines (BHT-101, CAL-62 and 8305C), resulted in impairment of cell viability, inhibition of colony formation, cell cycle arrest and apoptosis induction. Mechanistically, we showed that LBH589 not only affected the expression of p21 and cyclin D1, but markedly determined microtubule stabilization as evidenced by tubulin acetylation and increased tubulin polymerization. In a SCID xenograft model implanted with CAL-62 cells, the cytotoxic properties of LBH589 were confirmed. The drug at the dose of 20 mg/kg significantly impaired tumor growth (final tumor volume 2.5-fold smaller than in untreated animals); at this dose, no relevant side effects were observed. In tumors of treated animals, a significant reduction of Ki67, which was negatively correlated with tubulin acetylation, was observed. Moreover, acetyl-tubulin levels negatively correlated with tumor volume at sacrifice, reinforcing the opinion that tubulin acetylation has a role in the inhibition of tumor growth. In conclusion, LBH589, acting on both histones and nonhistonic proteins in anaplastic thyroid cancer, appears to be a promising therapeutic agent for the treatment of this kind of cancer which is known not to respond to conventional therapy.
Subject(s)
Antineoplastic Agents/toxicity , Histone Deacetylase Inhibitors/toxicity , Hydroxamic Acids/toxicity , Thyroid Neoplasms/metabolism , Acetylation/drug effects , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/drug effects , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/therapeutic use , Histones/metabolism , Humans , Hydroxamic Acids/pharmacology , Hydroxamic Acids/therapeutic use , Indoles , Mice , Mice, Nude , Panobinostat , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/genetics , Tubulin/metabolism , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
ß-Amyloid hyperproduction has been observed in response to alterations in neuronal intracellular cholesterol storage, efflux, and synthesis, induced in rats by a high-fat diet. It has been suggested that cholesterol homeostasis is altered in Alzheimer's disease resulting in higher ß- and γ-secretase activity. In the current study the neuronal activation status of sterol regulatory element binding protein 2 (SREBP2) as well as its involvement in ß-secretase BACE1 activity was investigated in high-fat fed rats (26% fat and 4% cholesterol for 20 weeks), and in SK-N-BE neuroblastoma cells exposed to 20 µM cholesterol. This work demonstrates that in the brain a hyperlipidic diet is able to induce a hyper-expression of BACE1 and determine an unbalance in cerebral cholesterol homeostasis so that SREBP2 is activated. In addition, we show for the first time the involvement of SREBP2 on expression of BACE1 in SK-N-BE cells exposed to high cholesterol. Although the enhanced risk of Alzheimer's disease in metabolic syndrome is related to several factors, our results suggest that SREBP2, which can be modulated by the impairment of cerebral cholesterol homeostasis, has a direct role on BACE1 expression and may be involved in Alzheimer's disease progression.
Subject(s)
Amyloid Precursor Protein Secretases/biosynthesis , Aspartic Acid Endopeptidases/biosynthesis , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Sterol Regulatory Element Binding Proteins/genetics , Sterol Regulatory Element Binding Proteins/physiology , Animals , Blotting, Western , Body Weight/drug effects , Body Weight/genetics , Brain/drug effects , Brain/enzymology , Cell Line, Tumor , Cell Nucleus/metabolism , Cholesterol, Dietary/pharmacology , Chromatin Immunoprecipitation , Chromatography, Gas , Chromatography, High Pressure Liquid , Cytosol/metabolism , Diet , Glucose Tolerance Test , Hydroxycholesterols/metabolism , Insulin/blood , Lipids/blood , Male , Neurons/enzymology , Neurons/physiology , RNA Interference , Rats , Reverse Transcriptase Polymerase Chain Reaction , Tissue Extracts/metabolismABSTRACT
PURPOSE: To evaluate the effects of total body irradiation (TBI) on the endocrine system in adults treated with hematopoietic cell transplantation (HCT) during childhood. METHODS: We studied 40 patients who underwent HCT between 1988 and 2004, mainly for childhood cancer. In 23 patients, the conditioning regimen consisted of high-dose chemotherapy and TBI (TBI+). In the other 17 patients, who did not receive TBI (TBI-), HCT was performed after high-dose chemotherapy alone. RESULTS: Overall, 34% of patients in the TBI+ group showed growth hormone deficiency, compared with none of the patients in the TBI- group (P < 0.05). Leydig cell failure was found in 23% of patients in the TBI+ group and in 0% of the patients in the TBI- group. Elevated FSH levels, suggesting spermatogenesis damage, were found in all the patients receiving TBI and in 36% of the patients in the TBI- group (P < 0.001). Also, primary hypothyroidism was more common in TBI+ (34%) than in TBI- (5.8%) patients (P < 0.05). CONCLUSIONS: Our data indicate that endocrine late effects after HCT are more frequent in patients who received TBI, an observation that should be considered, even if the choice of the conditioning regimen is determined by the underlying condition in most cases.
Subject(s)
Endocrine System Diseases/epidemiology , Hematopoietic Stem Cell Transplantation , Neoplasms/therapy , Radiation Injuries/epidemiology , Whole-Body Irradiation/adverse effects , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Diagnostic Techniques, Endocrine , Endocrine System/radiation effects , Endocrine System Diseases/blood , Endocrine System Diseases/diagnosis , Endocrine System Diseases/etiology , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Retrospective Studies , Transplantation Conditioning/adverse effects , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Nutrient overload leads to obesity and insulin resistance. Pioglitazone, a selective peroxisome proliferator-activated receptor (PPAR)gamma agonist, is currently used to manage insulin resistance, but the specific molecular mechanisms activated by PPARgamma are not yet fully understood. Recent studies suggest the involvement of suppressor of cytokine signalling (SOCS)-3 in the pathogenesis of insulin resistance. This study aimed to investigate the hepatic signalling pathway activated by PPARgamma activation in a non-genetic insulin-resistant animal model. EXPERIMENTAL APPROACH: Male Wistar rats were maintained on a high-cholesterol fructose (HCF) diet for 15 weeks. Pioglitazone (3 mg x kg(-1)) was administered orally for the last 4 weeks of this diet. At the end of the treatment, serum was collected for biochemical analysis. Levels of PPARgamma, SOCS-3, pro-inflammatory markers, insulin receptor substrate-2 and Akt/glycogen synthase kinase-3beta phosphorylation were assessed in rat liver. KEY RESULTS: Rats fed the HCF diet exhibited hyperlipidemia, hyperinsulinemia, impaired glucose tolerance and insulin resistance. Pioglitazone administration evoked a significant improvement in lipid metabolism and insulin responsiveness. This was accompanied by reduced hepatic expression of SOCS-3, interleukin-6, tumour necrosis factor-alpha and markers of neutrophil infiltration. Diet-induced PPARgamma expression was unaffected by the pioglitazone treatment. CONCLUSION AND IMPLICATIONS: Chronic pioglitazone administration reduced hepatic inflammatory responses in rats fed a HCF diet. These effects were associated with changes in hepatic expression of SOCS-3, which may be a crucial link between the reduced local inflammation and the improved insulin signalling.
Subject(s)
Hepatitis/drug therapy , Hypoglycemic Agents/pharmacology , Insulin Resistance , Insulin/blood , Lipids/blood , Liver/drug effects , Overweight/drug therapy , PPAR gamma/agonists , Thiazolidinediones/pharmacology , Administration, Oral , Animals , Cholesterol, Dietary , Dietary Carbohydrates , Disease Models, Animal , Fructose , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Hepatitis/blood , Hepatitis/etiology , Hepatitis/physiopathology , Hypoglycemic Agents/administration & dosage , Inflammation Mediators/metabolism , Insulin Receptor Substrate Proteins/metabolism , Interleukin-6/metabolism , Liver/metabolism , Liver/physiopathology , Male , Neutrophil Infiltration/drug effects , Overweight/blood , Overweight/etiology , Overweight/physiopathology , PPAR gamma/metabolism , Phosphorylation , Pioglitazone , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Wistar , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/metabolism , Thiazolidinediones/administration & dosage , Time Factors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Advanced thyroid cancer refers to thyroid tumors which are resistant to conventional therapies and do not respond to radioiodine and comprises metastatic or recurrent differentiated cancers, poorly differentiated and anaplastic tumors. Progress in the knowledge of genetic/epigenetic alterations in thyroid cancer cells is rapidly offering several opportunities to develop new drugs directed to specific targets. Drugs currently proposed for molecular therapy include: (a) monoclonal antibodies; (b) kinase inhibitors; (c) anti-angiogenetic drugs; (d) proteasome inhibitors; (e) retinoic acid and PPAR-gamma ligands; (f) radionuclide therapy; (g) epigenetic drugs (deacetylase inhibitors and demethylating agents). The results of several phase II trials using molecular drugs look promising. None of the treated patients, however, had a complete response, and only a minority of them had a partial response. The review will focus especially on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumor cells and potentially restore normal cell functions. Deacetylases inhibitors modulate both epigenetic and multiple non-epigenetic mechanisms; they are, thus, viewed as a promising class of anticancer drugs. Experimental data show that deacetylase inhibitors are effective against advanced thyroid cancer. However, since multiple pathways need to be inhibited in order to substantially affect thyroid cancer growth, it is likely that a significant increase in the response rate to treatment of advanced thyroid cancer will be achieved through combinatorial drug therapies. Actually, many pre-clinical and clinical studies evaluate the combination of either two epigenetic drugs or a non-epigenetic chemotherapeutic and an epigenetic drug, in the effort to increase response rates.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Delivery Systems/methods , Thyroid Neoplasms/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Epigenesis, Genetic , Humans , Thyroid Neoplasms/geneticsABSTRACT
This study concentrated on the initial events triggering the development of nonalcoholic fatty liver disease induced by a high-fat plus fructose (HF-F) diet and on the possibility of delaying nonalcoholic fatty liver disease progression by adding dehydroepiandrosterone (DHEA) to the diet. Sterol regulatory element binding protein-1c (SREBP-1c) activation plays a crucial role in the progression of nonalcoholic fatty liver disease induced by an HF-F diet. This study investigated the protective effects of DHEA, a compound of physiological origin with multitargeted antioxidant properties, against the induction of SREBP-1c and on liver insulin resistance in rats fed an HF-F diet, which mimics a typical unhealthy Western diet. An HF-F diet, fortified or not with DHEA (0.01%, w/w), was administered for 15 weeks to male Wistar rats. After HF-F the liver showed unbalanced oxidative status, fatty infiltration, hepatic insulin resistance, and inflammation. The addition of DHEA to the diet reduced both activation of oxidative-stress-dependent pathways and expression of SREBP-1c and partially restored the expression of liver X-activated receptor-alpha and insulin receptor substrate-2 genes. DHEA supplementation of the HF-F diet reduced de novo lipogenesis and delayed progression of nonalcoholic fatty liver disease, demonstrating a relationship between oxidative stress and nonalcoholic fatty liver disease via SREBP-1c.
Subject(s)
Dietary Fats/pharmacology , Fatty Liver/metabolism , Fructose/pharmacology , Sterol Regulatory Element Binding Protein 1/metabolism , Animals , Cell Death , Dehydroepiandrosterone/pharmacology , Dietary Fats/adverse effects , Fatty Liver/pathology , Hyperlipidemias/pathology , Insulin Resistance , Male , Oxidative Stress , Rats , Rats, WistarABSTRACT
New therapeutic approaches are mandatory for anaplastic thyroid cancer. We investigated the ability of a new combined treatment using valproic acid (VPA), the only clinically available histone deacetylase inhibitor, and the tyrosine-kinase inhibitor imatinib mesylate to control the cell growth of anaplastic thyroid cancer cell lines. We showed that treatment with imatinib alone is unable to affect the cell growth of anaplastic thyroid cancer cells, whereas in ARO cells, the combined treatment resulted in a cytostatic effect, with clinically achievable doses of imatinib and VPA. The effect is mediated by G1 growth arrest, acting through p21 expression and the impairment of AKT phosphorylation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Proliferation/drug effects , Enzyme Inhibitors/administration & dosage , Thyroid Neoplasms/drug therapy , Apoptosis/drug effects , Benzamides , Blotting, Western , Cell Cycle/drug effects , Cell Line, Tumor , Gene Expression/drug effects , Histone Deacetylase Inhibitors , Humans , Imatinib Mesylate , Piperazines/administration & dosage , Pyrimidines/administration & dosage , Reverse Transcriptase Polymerase Chain Reaction , Valproic Acid/administration & dosageABSTRACT
OBJECTIVE: There is evidence that insulin reduces brain injury evoked by ischemia/reperfusion (I/R). However, the molecular mechanisms underlying the protective effects of insulin remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3beta (GSK-3beta). Here, we investigate the role of GSK-3beta inhibition on I/R-induced cerebral injury in a rat model of insulinopenic diabetes. RESEARCH DESIGN AND METHODS: Rats with streptozotocin-induced diabetes were subjected to 30-min occlusion of common carotid arteries followed by 1 or 24 h of reperfusion. Insulin (2-12 IU/kg i.v.) or the selective GSK-3beta inhibitor TDZD-8 (0.2-3 mg/kg i.v.) was administered during reperfusion. RESULTS: Insulin or TDZD-8 dramatically reduced infarct volume and levels of S100B protein, a marker of cerebral injury. Both drugs induced phosphorylation of the Ser9 residue, thereby inactivating GSK-3beta in the rat hippocampus. Insulin, but not TDZD-8, lowered blood glucose. The hippocampi of the drug-treated animals displayed reduced oxidative stress at 1 h of reperfusion as shown by the decreased generation of reactive oxygen species and lipid peroxidation. I/R-induced activation of nuclear factor-kappaB was attenuated by both drug treatments. At 24 h of reperfusion, TDZD-8 and insulin significantly reduced plasma levels of tumor necrosis factor-alpha; neutrophil infiltration, measured as myeloperoxidase activity and intercellular-adhesion-molecule-1 expression; and cyclooxygenase-2 and inducible-NO-synthase expression. CONCLUSIONS: Acute administration of insulin or TDZD-8 reduced cerebral I/R injury in diabetic rats. We propose that the inhibitory effect on the activity of GSK-3beta contributes to the protective effect of insulin independently of any effects on blood glucose.
Subject(s)
Brain Ischemia/complications , Diabetes Mellitus, Experimental/physiopathology , Glycogen Synthase Kinase 3/metabolism , Hippocampus/drug effects , Insulin/pharmacology , Reperfusion Injury/prevention & control , Animals , Blood Glucose/metabolism , Blotting, Western , Body Weight/drug effects , Diabetes Mellitus, Experimental/blood , Enzyme-Linked Immunosorbent Assay , Gene Expression/drug effects , Glycogen Synthase Kinase 3/genetics , Hippocampus/metabolism , Hormones/metabolism , Hypoglycemic Agents/pharmacology , Lipid Peroxidation/drug effects , Male , NF-kappa B/metabolism , Oxidative Stress/drug effects , Phosphorylation/drug effects , Rats , Rats, Wistar , Reperfusion Injury/etiology , Reperfusion Injury/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Thiadiazoles/pharmacology , Tumor Necrosis Factor-alpha/bloodABSTRACT
Sex Hormone-Binding Globulin, the specific carrier for sex steroids, regulates hormone bioavailable fraction and estrogen signaling system in breast cancer cells. A common single nucleotide polymorphism in the human SHBG gene results in an amino acid substitution (Asp327Asn), which introduces an additional N-glycosylation site, and is associated with reduced breast cancer risk in postmenopausal women. The frequency of this polymorphism was evaluated in a group of patients that developed breast cancer while taking hormonal replacement therapy (HRT) for menopause, an interesting model of estrogen exposure. The polymorphism frequency was significantly higher in women taking HRT that didn't develop any breast cancer than in breast cancer patients (P<0.05). To get insight into the underlying mechanisms, we compared the ability of recombinant wild type and variant (D327N) SHBG to influence estradiol effects in MCF-7 breast cancer cells. D327N SHBG was more effective than wild type protein in inhibiting estradiol-induced cell proliferation and anti-apoptosis. This depended on the fact that D327N SHBG binding to MCF-7 cells was significantly higher than that of wild type protein. As a consequence, D327N caused a larger induction of the second messenger cAMP and a deeper inhibition of the estradiol-induced Erk (1/2) phosphorylation. Our observations, demonstrating the increased efficiency of D327N SHBG in counteracting estradiol action and a significantly higher frequency of Asp327Asn polymorphism in women not developing breast cancer after estrogen exposure, first provide evidence for the mechanism of D327N SHBG protective action.
Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Estrogens/metabolism , Polymorphism, Single Nucleotide , Sex Hormone-Binding Globulin/genetics , Sex Hormone-Binding Globulin/physiology , Animals , Apoptosis , Breast Neoplasms/etiology , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Hormone Replacement Therapy , Humans , Sex Hormone-Binding Globulin/biosynthesis , Signal TransductionABSTRACT
CONTEXT: Childhood cancer survivors need regular monitoring into young adulthood and beyond, because they are at risk for developing late-onset complications of cancer therapy, including second malignancies. OBJECTIVE: This study focuses on the use of thyroid ultrasound to screen for thyroid carcinoma in a population of childhood cancer survivors. PATIENTS: A total of 129 subjects who had received radiotherapy to the head, neck, or upper thorax for a pediatric cancer were studied in the setting of a long-term follow-up unit. DESIGN: Thyroid ultrasound usually began 5 yr after radiotherapy and was repeated every third year, if negative. Median follow-up time since childhood cancer diagnosis was 15.8 yr (range 6.1-34.8 yr). Solid thyroid nodules were found in 35 patients. Fine-needle aspiration was performed in 19 patients, of which 14 had nodules above 1 cm. MAIN OUTCOME MEASURE: The main outcome measure was the finding of not palpable thyroid cancers. RESULTS: Cytological examination of specimens diagnosed papillary carcinoma in five patients who underwent surgery. The cytological diagnosis of papillary thyroid carcinoma was confirmed in all cases by histological examination. Notably, only two of these patients had palpable nodules; the other three were smaller than 1 cm and were detected only by ultrasound. However, histological examination showed nodal metastases in two of these. CONCLUSIONS: Although ultrasound screening for thyroid cancer in the general population is not cost effective and could lead to unnecessary surgery, due to false positives, we believe that in childhood cancer survivors who received radiotherapy involving the head, neck, or upper thorax, it would be worthwhile.
Subject(s)
Neoplasms/complications , Survivors , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/diagnosis , Adolescent , Adult , Age of Onset , Biopsy, Fine-Needle , Carcinoma, Papillary, Follicular/diagnosis , Carcinoma, Papillary, Follicular/diagnostic imaging , Carcinoma, Papillary, Follicular/pathology , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Long-Term Care , Male , Neoplasm Metastasis/pathology , Neoplasms/radiotherapy , Thyroid Function Tests , Thyroid Neoplasms/pathology , Thyroid Nodule/diagnostic imaging , Thyroidectomy , Ultrasonography , Young AdultABSTRACT
Treatment efficacy of breast cancer can be impaired by cell resistance. The aim of the study was to investigate the anti-tumour effects of valproic acid (VPA), the only clinically available histone deacetylase inhibitor, on both estrogen-sensitive and -insensitive breast cancer cells. VPA, at a concentration lacking severe adverse effects in human, reduces cell viability in estrogen-sensitive cell lines, inducing p21 expression and impairing cell cycle. In ZR-75-1, cell cycle is selectively arrested in G1, whereas MCF-7 cells massively accumulated in sub-G1. Actually, in MCF-7 cells, VPA induces apoptosis, down-regulates Bcl-2 and up-regulates Bak expression. In conclusion, VPA is a powerful antiproliferative agent in estrogen-sensitive breast cancer cells, making this drug of clinical interest as a new approach to treat breast cancer.