A5056981317- Hedgehog Signaling Pathway Studies
- Epigenetics and DNA Methylation
- Circadian rhythm and melatonin
- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- Glioma Diagnosis and Treatment
- Ubiquitin and proteasome pathways
- Chromatin Remodeling and Cancer
- Free Radicals and Antioxidants
- Genomics and Chromatin Dynamics
- Circular RNAs in diseases
- Protein Degradation and Inhibitors
- Tumors and Oncological Cases
- Cancer, Hypoxia, and Metabolism
- Autophagy in Disease and Therapy
- Cancer-related gene regulation
- Digestive system and related health
- Natural Compounds in Disease Treatment
- Histone Deacetylase Inhibitors Research
- Parkinson's Disease Mechanisms and Treatments
- Mitochondrial Function and Pathology
- Cell death mechanisms and regulation
- Bladder and Urothelial Cancer Treatments
- Endoplasmic Reticulum Stress and Disease
- Genetic and Kidney Cyst Diseases
MUSC Hollings Cancer Center
2020-2025
Medical University of South Carolina
2020-2025
University of Miami
2011-2020
Molecular Oncology (United States)
2012-2020
Universidad de Oviedo
2004-2013
Sylvester Comprehensive Cancer Center
2011-2012
Heinrich Heine University Düsseldorf
2012
University of Arizona
2012
Dartmouth–Hitchcock Medical Center
2011
Jackson Memorial Hospital
2011
Epigenetic enzymes modulate signal transduction pathways in different biological contexts. We reasoned that epigenetic regulators might the Hedgehog (HH) signaling pathway, a main driver of cell proliferation various cancers including medulloblastoma. To test this hypothesis, we performed an unbiased small-molecule screen utilizing HH-dependent reporter line (Light2 cells). incubated Light2 cells with small molecules targeting modulators and identified four histone deacetylase inhibitors...
Abstract Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is one deadliest forms cancer with limited therapy options. Overexpression heat shock protein 70 (HSP70) a hallmark that strongly associated aggressive disease and worse clinical outcomes. However, underlying mechanisms by which HSP70 allows tumor cells to thrive under conditions continuous stress have not been fully described. Here, we report PDAC has highest expression relative normal tissue...
Abstract Melatonin is an indolamine mostly produced in the pineal gland, soluble water, and highly lipophilic, which allows it to readily cross blood-brain barrier. possesses antioxidant properties its long-term administration rodents has not been found cause noteworthy side effects. In present work, we that millimolar concentrations of this reduced cell growth C6 glioma cells by 70% after 72 hours treatment, inhibiting progression from G1 S phase cycle. Intraperitoneal 15 mg/kg body weight...
Abstract: Ewing sarcoma, the second most frequent bone cancer type, affects mainly adolescents, who have a survival of 50% 5 yr after diagnosis. Current treatments include combination surgery, radiotherapy and chemotherapy, which present potential serious side effects. Melatonin, natural molecule without relevant effects, has been previously shown to induce cytotoxicity in SK‐N‐MC cells, sarcoma cell line. Here, we found that there is synergy antitumor effect when melatonin (50 μ m –1 )...
The Hedgehog (HH) signaling pathway represents an important class of emerging developmental pathways that play critical roles in the genesis a large number human cancers. pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), key effector HH regulates levels and activity Gli family transcription factors. Although one these compounds, vismodegib, now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations Smo can result...
Low concentrations (nanomolar) of melatonin had been previously shown to inhibit cell proliferation in several cancer lines as well experimental animal models. Additionally, growth inhibition and differentiation prostate by high (micromolar millimolar) have recently reported. In the present paper, we show induction apoptosis doses human neuroblastoma line SK-N-MC. We found accumulation cells G2/M cycle phase cellular death, measured lactate dehydrogenase (LDH) released into culture medium,...
Melatonin is an endogenous indolamine, classically known as a light/dark regulator. Besides classical functions, melatonin has also showed to have wide range of antitumoral effects in numerous cancer experimental models. However, no definite mechanism been described explain the whole antineoplasic effects. Here we describe dual effect on intracellular redox state relation its antiproliferative vs cytotoxic actions cells. Thus, inhibition proliferation correlates with decrease reactive oxygen...
Abstract The pineal hormone melatonin has neuroprotective effects in a large number of models neurodegeneration. Melatonin crosses the blood–brain barrier, shows decrease its nocturnal peaks blood with age that been associated development neurodegenerative disorders, and shown to be harmless at high concentrations. These properties make potential therapeutic agent against disorders but pathways involved such remain unknown. In present report we study intracellular implicated complete...
Oxidative stress has been shown to mediate neuron damage in Parkinson's disease (PD). In the present report, we intend clarify intracellular pathways mediating dopaminergic death after oxidative production using post-mitotic PC12 cells treated with neurotoxin 6-hydroxydopamine (6-OHDA). The use of is crucial, because one suggested implicated relates re-entry neurons (post-mitotic cells) cell cycle. We find that 6-OHDA sequentially increases oxidants, functional and caspase-3 activation,...
The role of Hedgehog (HH) signaling in bladder cancer remains controversial. gene encoding the HH receptor and negative regulator PATCHED1 (PTCH1) resides on a region chromosome 9q, one copy which is frequently lost cancer. Inconsistent with PTCH1 functioning as classic tumor suppressor gene, loss-of-function mutations remaining are not commonly found. Here, we provide direct evidence for critical carcinogenesis. We show that transformed human urothelial cells many carcinoma cell lines...
A small-molecule CK1α activator inhibits the growth of WNT-driven intestinal tumors without toxicity to normal epithelium.
Abstract Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being most common type. Genomic-based classification has stratified MB into four molecular subgroups: Wingless/Int-1 (WNT), Sonic Hedgehog (SHH), Group 3, and 4. This significantly improved our understanding facilitated development better treatments. However, despite these advancements, approximately 30% children experience relapse. Recurrent is often metastatic, nearly all...
Abstract: Incorporation of new therapeutic agents remains as a major challenge for treatment patients with malignant haematological disorders. Melatonin is an indolamine without relevant side effects. It has been shown previously to exhibit synergism several chemotherapeutic drugs in Ewing sarcoma cells by potentiating the extrinsic pathway apoptosis. also sensitizes human glioma against TRAIL increasing DR5 expression. Here, we report induction cell death melatonin lines through activation...
A number of Smoothened (SMO) pathway antagonists are currently undergoing clinical trials as anticancer agents. These drugs proposed to attenuate tumor growth solely through inhibition Hedgehog (HH), which is produced in cells but acts on stromal cells. The pivotal argument underlying this model that the growth-inhibitory properties SMO HH-producing cancer due their off-target effects. Here, we show tumorigenic such lung depend intrinsic level HH activity. Notably, reducing signaling these...
Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy tolerable toxicity, this compound not been evaluated MB. Utilizing bioinformatic dataset integrates...
Despite recent advances in cancer therapy, the 5-year survival rate for Ewing's sarcoma is still very low, and new therapeutic approaches are necessary. It was found previously that melatonin induces cell death line, SK-N-MC, by activating extrinsic apoptotic pathway. Melatonin actions were analysed metabolic viability/survival assays, flow cytometry, quantitative PCR mRNA expression, western blot protein activation/expression electrophoretic mobility shift assay transcription factor...
Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction this process underlies many neurological diseases including ataxia most common pediatric brain tumor, medulloblastoma. To better define pathways controlling abundant cells in mammalian cerebellum, cerebellar granule (GCPs), we performed RNA-sequencing GCPs cycle. Time-series modeling GCP exit identified downregulation activity epigenetic...
Abstract Parkinson's disease has been widely related to both apoptosis and oxidative stress. Many publications relate the loss of mitochondrial potential an apoptosis‐mediated cell death in different vivo vitro models this pathology. The present study used dopaminegic specific neurotoxin 1‐methyl‐4‐phenylpyridinium (MPP + ) on neuron‐like PC12 cells, which is a well‐accepted model disease. Results showed early increase oxidants, drives modulation c‐Jun N‐terminal kinase (JNK) AKT/mammalian...
Abstract Purpose: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup driven by TRP53 mutations is essentially lethal. Casein kinase 1α (CK1α) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors SHH signaling. We therefore tested a second-generation CK1α activator against TRP53-mutant, MYCN-amplified medulloblastoma. Experimental Design: The ability this to block signaling was determined in vitro...