A5039810760- Polyamine Metabolism and Applications
- Neuroblastoma Research and Treatments
- Ubiquitin and proteasome pathways
- Amino Acid Enzymes and Metabolism
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Glycosylation and Glycoproteins Research
- Cellular transport and secretion
- Cannabis and Cannabinoid Research
- Peptidase Inhibition and Analysis
- Toxin Mechanisms and Immunotoxins
- Hippo pathway signaling and YAP/TAZ
- Protein Degradation and Inhibitors
- Pancreatic function and diabetes
- Microtubule and mitosis dynamics
- Signaling Pathways in Disease
- Plant Pathogenic Bacteria Studies
- Legume Nitrogen Fixing Symbiosis
- Respiratory viral infections research
- Neurobiology and Insect Physiology Research
- Plant-Microbe Interactions and Immunity
- Developmental Biology and Gene Regulation
- Cell death mechanisms and regulation
- Metabolism and Genetic Disorders
- Sepsis Diagnosis and Treatment
Grand Rapids Community College
2014-2025
Michigan State University
2015-2025
Cancer Research Center
2003-2023
University of Hawaiʻi at Mānoa
2008-2023
Cancer Center of Hawaii
2004-2023
Helen DeVos Children's Hospital
2018
Michigan United
2015-2017
University of Hawaii at Hilo
2011-2016
University of Hawaii System
1997-2011
University of Hawaii Cancer Center
2011
Neuroblastoma (NB) is the most common cancer in infancy and frequent cause of death from extracranial solid tumors children. Ornithine decarboxylase (ODC) expression an independent indicator poor prognosis NB patients. This study investigated safety, response, pharmacokinetics, genetic metabolic factors associated with ODC a clinical trial inhibitor difluoromethylornithine (DFMO) ± etoposide for patients relapsed or refractory NB.
Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These variations critically influence inhibitory potency subsite selectivity. Here, we describe total synthesis A B, which together with enzyme kinetic studies, allowed us elucidate determinants underlying proteasomal selectivity...
Neuroblastoma (NB) is associated with MYCN oncogene amplification occurring in approximately 30% of NBs and poor prognosis. linked to a number genes including ornithine decarboxylase (ODC), the rate-limiting enzyme polyamine biosynthesis. ODC expression elevated many forms cancer NB. Alpha-difluoromethylornithine (DFMO), an inhibitor, currently being used Phase I clinical trial for treatment However, cells treated DFMO may overcome their depletion by uptake polyamines from extracellular...
We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than α-difluoromethylornithine (DFMO), a U.S. Food Drug Administration (FDA) approved drug. report two X-ray structures ODC complexed with new inhibitors, computational docking, molecular dynamics, binding free energy calculations to validate experimental models. The reveal covalent adducts pyridoxal phosphate (PLP) are formed...
Rare diseases impact approximately 1 in 10 people worldwide, and yet, less than 5% of all rare currently have an approved treatment option available. This is due to many challenges unique diseases, including small, diverse patient populations, the cost drug development that not proportionate number patients who could potentially benefit from treatment, difficulty with clinical trial design validate new therapeutics. As a result, repurposing has become increasingly promising for finding...
Abstract High polyamine (PA) levels and ornithine decarboxylase (ODC) overexpression are well‐known phenomena in many aggressive cancer types. We analyzed the expression of ODC ODC‐activity regulating genes antizymes 1‐3 ( OAZ1‐3 ) antizyme inhibitors 1‐2 (AZ‐IN1‐2 human neuroblastoma (NB) tumors correlated these with genetic clinical features NB. Since is a known target gene MYCN, correlation between MYCN was special interest. Data were obtained from Affymetrix micro‐array analysis 88 NB...
Abstract Ornithine decarboxylase (ODC) is a key enzyme in mammalian polyamine biosynthesis that up-regulated various types of cancer. We previously showed treating human neuroblastoma (NB) cells with the ODC inhibitor α-difluoromethylornithine (DFMO) depleted pools and induced G1 cell cycle arrest without causing apoptosis. However, precise mechanism by which DFMO provokes these changes NB remained unknown. Therefore, we further examined effects DFMO, alone combination phosphatidylinositol...
Abstract The natural product syringolin A (SylA) is a potent proteasome inhibitor with promising anticancer activities. To further investigate its potential as lead structure, selectivity profiling cell lysates was performed. At therapeutic concentrations, rhodamine‐tagged SylA derivative selectively bound to the 20 S active sites without detectable off‐target labelling. Additional of wild‐type and bortezomib‐adapted leukaemic lines demonstrated retention this target subsite well potency...
Neuroblastoma (NB) is the most common extracranial pediatric tumor. NB patients over 18 months of age at time diagnosis are often in later stages disease, present with widespread dissemination, and possess MYCN tumor gene amplification. a transcription factor that regulates expression number genes including ornithine decarboxylase (ODC), rate-limiting enzyme biosynthesis polyamines. Inhibiting ODC cells produces many deleterious effects G1 cell cycle arrest, inhibition proliferation,...
The ornithine decarboxylase 1 ( ODC1 ) gene plays an important role in physiological and cell developmental processes including embryogenesis, organogenesis, neoplastic growth. Here, we report 32‐month‐old Caucasian female with a heterozygous de novo nonsense mutation the that leads to premature abrogation of 14‐aa residues at ODC protein c‐terminus. This is first human case confirming similar symptoms observed transgenic mouse model described over 20 years ago. Phenotypic manifestations...
The eukaryotic initiation factor 5A (eIF5A), which contributes to several crucial processes during protein translation, is the only that requires activation by a unique post-translational hypusine modification. eIF5A hypusination controls cell proliferation and has been linked cancer. enzymes deoxyhypusine synthase (DHPS) hydroxylase uniquely depends on polyamine (PA) spermidine as sole substrate. Ornithine decarboxylase (ODC) rate-limiting enzyme in PA biosynthesis. Both ODC PAs control are...
Neuroblastoma (NB) is an early childhood malignancy that arises from the developing sympathetic nervous system. Harmine a tricyclic β-carboline alkaloid isolated harmal plant exhibits both cytostatic and cytotoxic effects. capable of blocking activities dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family proteins mitogen-activated protein kinase. These kinases promote proliferation inhibit apoptosis. Four human NB cell lines were used to study effects harmine treatment:...
Stardust (Sdt) and Discs-Large (Dlg) are membrane-associated guanylate kinases (MAGUKs) involved in the organization of supramolecular protein complexes at distinct epithelial membrane compartments Drosophila. Loss either Sdt or Dlg affects development with severe effects on apico-basal polarity. Moreover, is required for structural functional integrity synaptic junctions. Recent biochemical cell culture studies have revealed that various mammalian MAGUKs can interact mLin-7/Veli/MALS, a...
Abstract A convergent synthesis of SylA was developed and consists the a fully functionalized macrocycle, which is subsequently coupled with urea moiety. For cyclization, ring‐closing metathesis conformationally preorganized precursor employed. The established synthetic route then applied to derivatives by using various peptidic side chains for decoration macrocycle. resulting collection analogues tested proteasome inhibition, revealing PEGylated as most potent inhibitors.
The preparation of a Syringolin A/Glidobactin A hybrid (SylA-GlbA) consisting SylA macrocycle connected to the GlbA side chain and its potent proteasome targeting all three proteasomal subsites is reported. influence syrbactin moiety on subsite selectivity demonstrated.
Signal transducer and activator of transcription 3 (STAT3) is an oncogenic factor that has been implicated in many human cancers emerged as ideal target for cancer therapy. Withaferin A (WFA) a natural product with promising antiproliferative properties through its association number molecular targets including STAT3. However, the effect WFA pediatric neuroblastoma (NB) interaction STAT3 have not reported. In this study, we found effectively induces dose-dependent cell death high-risk...