A5041029342- Polyamine Metabolism and Applications
- Amino Acid Enzymes and Metabolism
- Cancer Research and Treatments
- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Biochemical and Molecular Research
- Immune Cell Function and Interaction
- Pancreatic function and diabetes
- Chemical Synthesis and Analysis
- Neonatal Health and Biochemistry
- Pneumocystis jirovecii pneumonia detection and treatment
- Immune Response and Inflammation
- Antimicrobial Peptides and Activities
- RNA Interference and Gene Delivery
- HIV/AIDS drug development and treatment
- Antimicrobial agents and applications
- Synthesis and Biological Evaluation
- Carbon and Quantum Dots Applications
- Protein Degradation and Inhibitors
- Cannabis and Cannabinoid Research
- Synthesis and Characterization of Pyrroles
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Environmental Chemistry and Analysis
- thermodynamics and calorimetric analyses
Aminex Therapeutics (United States)
2013-2025
Peter MacCallum Cancer Centre
2021
University of Rochester
2015
Lankenau Institute for Medical Research
2009-2013
Thomas Jefferson University
2013
Neoleukin Therapeutics (United States)
2002-2011
University of Kansas
2005-2007
North Seattle College
2002
Rice University
1996-1998
Purdue University West Lafayette
1997
We determined the effect on exercise tolerance and physiological responses of rigorous rehabilitative training in chronic obstructive pulmonary disease (COPD). Fifteen men 10 women (mean age, 68 +/- 6 yr; FEV1, 0.93 0.27 L) participated a rehabilitation program with an component three per week 45-min sessions cycle ergometer for wk intensity kept near maximal targets. Before after rehabilitation, patients performed incremental test constant work rate (CWR) at 80% peak preprogram test....
Abstract Correcting T-cell immunosuppression may unleash powerful antitumor responses; however, knowledge about the mechanisms and modifiers that be targeted to improve therapy remains incomplete. Here, we report polyamine elevation in cancer, a common metabolic aberration aggressive lesions, contributes significantly tumor depletion strategy can exert effects also promote immunity. A polyamine-blocking (PBT) combines well-characterized ornithine decarboxylase (ODC) inhibitor...
MYCN regulates polyamines in neuroblastoma, and combined inhibition of polyamine synthesis transport has therapeutic effects mouse models.
Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that essential for DNA replication, translation cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, irreversibly inhibited by difluoromethylornithine (DFMO). Herein we show synthesis upregulated DIPG, leading to sensitivity DFMO. DIPG cells...
Glioma-associated myeloid cells generate polyamines to survive and function within the acidic tumor microenvironment.
Activation of glutamine phosphoribosylpyrophosphate (PRPP) amidotransferase (GPATase) by binding a PRPP substrate analog results in the formation 20 Å channel connecting active site for hydrolysis one domain with second domain. This solvent-inaccessible permits transfer NH3 intermediate between two sites. Tunneling may be common mechanism amidotransferase-catalyzed nitrogen and coordination catalysis at distinct sites complex enzymes. The 2.4 crystal structure conformer GPATase also provides...
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...
Polyamine homeostasis determines T cell function.
Cancer cells can overcome the ability of polyamine biosynthesis inhibitors to completely deplete their internal polyamines by importation from external sources. This paper discusses development a group lipophilic analogues that potently inhibit cellular uptake system and greatly increase effectiveness depletion when used in combination with DFMO, well-studied inhibitor. The attachment length-optimized C16 substituent ε-nitrogen atom an earlier lead compound, d-Lys−Spm (5), has produced...
Abstract Cancer cells are addicted to polyamines, polycations essential for cellular function. While dual targeting of polyamine biosynthesis and uptake is under clinical investigation in solid cancers, preclinical studies into its potential haematological malignancies lacking. Here we investigated the efficacy depletion acute leukaemia. The inhibitor difluoromethylornithine (DFMO) inhibited growth a molecularly diverse panel leukaemia cell lines, while non‐malignant were unaffected....
The family of 70-kDa heat-shock proteins (HSP-70) is evolutionarily highly conserved and has been shown to enhance cell survival from thermal injury. This study characterized HSP-72 induction in human epidermoid A-431 cells exposed 45 degrees C for 10 min determined the relationship between HSP-72, intracellular pH (pHi), adenosine 3',5'-cyclic monophosphate (cAMP), G proteins, cytosolic free Ca2+ concentration ([Ca2+]i). Heat shock induced production, which was dependent on both temperature...
Abstract High-risk neuroblastomas, often associated with MYCN oncogene amplification, are addicted to polyamines, small polycations vital for cellular functioning. We have shown that neuroblastoma cells increase polyamine uptake when exposed the biosynthesis inhibitor DFMO, currently in clinical trial, and this mechanism limits efficacy of drug. While finding resulted development transport inhibitors including AMXT 1501, presently under investigation combination mechanisms transporters...
The levels of polyamines are elevated in neoplastic lesions as compared with normal tissues, and cancer cells tend to manifest a robust dependence on these compounds for proliferation survival. We have recently demonstrated that novel approach polyamine depletion suppresses tumor growth T cell-dependent manner, highlighting poorly appreciated role strong modulators antitumor immune responses.
In this paper we describe the synthesis and characterization of a series simple spermine/amino acid conjugates, some which potently inhibit uptake spermidine into MDA-MB-231 breast cancer cells. The presence an amide in functionalized polyamine appeared to add affinity for transporter. extensive biological especially potent analogue from series, Lys-Spm conjugate (31), showed molecule will be extremely useful tool use research. It was shown that 31 combination with DFMO led cytostatic growth...
Abstract Using a recently developed autochthonous mouse model of squamous cell carcinoma (SCC), combination therapy targeting polyamine metabolism was evaluated. The combined 2‐difluoromethylornithine (DFMO), an inhibitor ornithine decarboxylase (ODC), and MQT 1426, transport inhibitor. In 1 trial lasting 4 weeks, with 0.5% DFMO (orally, in the drinking water) 1426 (50 mg/kg i.p., bid) significantly more effective than either single agent alone when complete tumor response endpoint. group,...
Lipopolysaccharides (LPS), also called "endotoxins", are outer-membrane constituents of Gram-negative bacteria. play a key role in the pathogenesis "septic shock", major cause mortality critically ill patient. We had earlier shown that small molecules bind and neutralize LPS if they contain (i) two protonatable cationic groups separated by distance ∼14 Å to facilitate interactions with phosphate moieties on lipid A component (ii) long-chain aliphatic hydrocarbon promote hydrophobic...
Lipopolysaccharides (LPS) play a key role in the pathogenesis of septic shock, major cause mortality critically ill patient. We had previously shown that monoacylated polyamine compounds specifically bind to and neutralize activity LPS with high vitro potency afford complete protection murine model endotoxic shock. Fatty acid amides polyamines may be rapidly cleared from systemic circulation due their susceptibility nonspecific serum amidases and, thus, would predicted have short duration...
We have recently confirmed that lipoteichoic acid (LTA), a major constituent of the gram-positive bacterial surface, is endotoxin bacteria induces proinflammatory molecules in Toll-like receptor 2 (TLR2)-dependent manner. LTA an anionic amphipath whose physicochemical properties are similar to those lipopolysaccharide (LPS), which found on outer leaflet membranes gram-negative organisms. Hypothesizing compounds sequester LPS could also bind and inhibit LTA-induced cellular activation, we...
Polyamines are essential for cell proliferation. Their production is dysregulated in many cancers and polyamine depletion leads to tumour regression mouse models of squamous carcinoma (SCC). The purpose this study was determine the maximally tolerated dose transport inhibitor, MQT 1426, when combined with ornithine decarboxylase (ODC) DFMO, whether therapy results reduction levels. Thirteen cats oral SCC received both drugs orally serial biopsies were obtained measurement. Cats monitored...