A5009284177- Renal cell carcinoma treatment
- Hormonal Regulation and Hypertension
- Protein Kinase Regulation and GTPase Signaling
- Amino Acid Enzymes and Metabolism
- Ubiquitin and proteasome pathways
- Mechanisms of cancer metastasis
- Renal and related cancers
- Metal complexes synthesis and properties
- Steroid Chemistry and Biochemistry
- Cancer-related Molecular Pathways
- Microtubule and mitosis dynamics
- Cancer, Lipids, and Metabolism
- bioluminescence and chemiluminescence research
- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- Endoplasmic Reticulum Stress and Disease
- Computational Drug Discovery Methods
- Cell Adhesion Molecules Research
- CRISPR and Genetic Engineering
- Metalloenzymes and iron-sulfur proteins
- Criminal Justice and Penology
- PI3K/AKT/mTOR signaling in cancer
- Cancer therapeutics and mechanisms
- Blood Pressure and Hypertension Studies
National Cancer Institute
2024
University of Puerto Rico System
2018-2023
University of Puerto Rico, Medical Sciences Campus
2020-2023
University of Alabama at Birmingham
2022
<p>NAD<sup>+</sup> and NADH analysis of UOK365 cells. Analysis the relative levels NAD<sup>+</sup> their ratio after 24 hour treatment cell line model with a range concentrations (0.5-100 nM) either GNE-618 (A-B) or OT-82 (C-D). All were compared to cells treated amount DMSO present in highest concentration utilized drugs.</p>
<p>Real-time invasion analysis of UOK262 and UOK365 cells treated with OT-82. Real-time demonstrating cell line over 5 days (120 hrs) was performed (A) to show that DMSO (used as the vehicle for OT-82) did not affect in comparison untreated (B) demonstrate effects OT-82 treatment at either 1 nM or 10 alone (DMSO) non-invasive control (no serum lower chamber). In each case, a representative graph from one three separate experiments is shown. (C) The inhibition repeats dose shown line....
<p>In vitro analysis of NAMPT inhibition on glycolysis in FH-deficient tumor cells. (A) Effects the inhibitor OT-82 (100 nM) extracellular acidification rate (ECAR) UOK262 and UOK365 HLRCC cell lines RPTEC normal line. (B) Representation different effects versus DMSO at time point 5 (designated by a star) after injection glucose UOK262, UOK365, RPTEC. 2-DG, 2-deoxyglucose.</p>
<p>Structural figures of NAMPT inhibitors.</p>
<p>In vivo effects of NAMPT inhibitors in HLRCC xenograft models. Mean body weights are constant throughout the drug study for animals harboring UOK262 xenografts (A) and UOK365 (B; shown Figure 3A-B, <i>n</i> = 10 mice per arm, 95mg/kg OT-82 8 week duration). (C-D) H&E stained sections retinas obtained from NSG treated with vehicle or 5 days. (E-F) Caspase 3 95 mg/kg Histological were evaluated signs retinal toxicity by a trained veterinary pathologist. No overt...
<div>Abstract<p>Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited syndrome caused by germline pathogenic variants in the fumarate hydratase (<i>FH</i>) gene. Affected individuals are at risk for developing cutaneous uterine leiomyomas aggressive FH-deficient carcinoma (RCC) with a papillary histology. Due to disrupted tricarboxylic acid cycle, kidney cancers rely on aerobic glycolysis energy production, potentially creating compensatory metabolic...
<p>Expression levels of NAD<sup>+</sup> biosynthetic and salvage pathway genes in HLRCC tumors, normal kidney samples pan-kidney data from TCGA. (A) Overview pathways. (B-E) Box plots for selected NAD+ derived RNA-seq analysis tumors specimens. (F) TCGA data. NAMPT (nicotinamide phosphoribosyltransferase), NAPRT (nicotinate phosphoribosyltransferase ), QPRT (quinolinate NMNAT mononucleotide adenylyl transferase), KIRP (kidney renal papillary cancer), CIMP (CpG island...
<p>Validation studies to evaluate inhibition of additional HLRCC cell lines by NAMPT inhibitors. A) Effects the inhibitor GNE-618 on viability in FH <sup>-/</sup>- cells UOK348, UOK271, UOK350, UOK268, UOK365, restored UOK268WT and non-transformed kidney epithelial RPTEC. Cell was assessed Titer-Glo assay at 96 h. B) OT-82 -/- RPTEC.</p>
<p>Proliferation analysis of UOK268 and RPTEC in response to OT-82 nicotinic acid rescue NAD<sup>+</sup>/NADH depletion. (A-B) or cells were grown 96 well plates from an initial plating 2,000 cellular confluency was monitored real-time by Incucyte S3 Live-Cell Imaging System. After 24 hours measurements treated with either DMSO, 1 nM OT-82, 5 10 plus mM nicotinamide mononucleotide (NMN) evaluated for additional days. (C-D) The effect NMN on depletion is shown. (E) Effects...
<p>Cell proliferation rates of HLRCC cell lines treated with low and high concentrations NAMPT inhibitors. A) Effect OT-82 at 0.8nM or 100nM (left) GNE-618 8nM 200nM (right) on UOK262 after 96 hours. B) UOK268 C) UOK365 hours.</p>
<p>HLRCC spheroid characterization and OT-82 effect on 3D culture. A) UOK262 (B) UOK365 spheroids plated at different cell densities (8000, 4000, 2000 cells/well in triplicate) after 24h, showing degrees of aggregation. Cell viability (C) (D) treated with GNE-618 (1 nM-500 nM) or (0.2 nM-100 assessed Cell-Titer Glo assay decreases a dose dependent manner.</p>
<p>Time course study design for imaging and OT-82 treatment hyperpolarized pyruvate 13C-MRSI. Post MRSI was performed 5 hours post dose #2.</p>
<p>Pharmacokinetic profile of OT-82 in nude and NSG mice. (A) Bioanalysis plasma concentrations were made using a validated LC-MS/MS assay (<i>n</i>=3 mice, 50 mg/kg, 7 intervals; <i>n</i>=3 75mg/kg, intervals). (B) Pharmacokinetic parameters calculated after single dose OT-82. The data from all mice each group pooled together to assume one “average” mouse per group.</p>
<p>NAMPT immunohistochemical analysis in HLRCC tumors and normal kidney. (A) In patient #1, both a primary kidney tumor (upper panel) an associated metastatic mass (lower demonstrated strong NAMPT staining. Surrounding non-tumor tissues show little (B) #4, shows staining comparison to tissue present on the same slide panel). (C) #5, Material from this was used derive UOK262 cell line, which similar positive when grown as xenograft (D) #6, Matching H&E is included for all samples...
Triple-negative breast cancer (TNBC) is an aggressive form of cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce metastasis, we developed small molecule inhibitors target drivers Rho GTPases Rac Cdc42. Of these, MBQ-167 inhibits both Cdc42 IC50s 103 78 nmol/L, respectively; consequently, p21-activated kinase (PAK) signaling, cell proliferation, migration, mammosphere growth; induces cell-cycle arrest apoptosis; decreases HER2-type...
Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 Cdc42 in breast cancer cells mouse models metastasis. To identify compounds with increased activity, a panel MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-168 EHop-097, inhibit activation Rac1B...
Abstract Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited syndrome caused by germline pathogenic variants in the fumarate hydratase (FH) gene. Affected individuals are at risk for developing cutaneous uterine leiomyomas aggressive FH-deficient carcinoma (RCC) with a papillary histology. Due to disrupted tricarboxylic acid cycle, kidney cancers rely on aerobic glycolysis energy production, potentially creating compensatory metabolic vulnerabilities. This study conducted...
Abstract Metastasis continues to be the primary cause of cancer-related death. Therefore, we focus on designing small molecules inhibitors block metastasis. The Rho GTPase family members Rac1, and Cdc42 are critical regulators cancer cell migration invasion, thus, Rac1 is activated by Guanine Nucleotide Exchange Factors (GEFs), which promote exchange GDP GTP. In most cancers, homologous hyperactivated due overexpression GEFs. designed activation interaction with their Our lead compound...
<p>Supplementary Figures</p>
<div>Abstract<p>Triple-negative breast cancer (TNBC) is an aggressive form of cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce metastasis, we developed small molecule inhibitors target drivers Rho GTPases Rac Cdc42. Of these, MBQ-167 inhibits both Cdc42 IC<sub>50</sub>s 103 78 nmol/L, respectively; consequently, p21-activated kinase (PAK) signaling, cell proliferation, migration, mammosphere growth; induces...
<p>Supplementary Figures</p>