A5066473505- Cytokine Signaling Pathways and Interactions
- Cancer, Hypoxia, and Metabolism
- Glioma Diagnosis and Treatment
- Mitochondrial Function and Pathology
- Cancer Immunotherapy and Biomarkers
- Autophagy in Disease and Therapy
- Histone Deacetylase Inhibitors Research
- CAR-T cell therapy research
- Amino Acid Enzymes and Metabolism
- Cancer Research and Treatments
- Virus-based gene therapy research
- Epigenetics and DNA Methylation
- Monoclonal and Polyclonal Antibodies Research
- Bioactive Compounds and Antitumor Agents
- Nanoplatforms for cancer theranostics
- Endoplasmic Reticulum Stress and Disease
- Adenosine and Purinergic Signaling
- Cancer-related Molecular Pathways
- Synthesis and Biological Evaluation
- Immunotherapy and Immune Responses
- Advanced biosensing and bioanalysis techniques
- Biomedical Text Mining and Ontologies
- Protein Degradation and Inhibitors
- DNA Repair Mechanisms
- Genomics, phytochemicals, and oxidative stress
Xilio Therapeutics (United States)
2020-2023
Massachusetts General Hospital
2020-2021
Harvard University
2020-2021
Texas Tech University Health Sciences Center
2015-2020
Texas Tech University
2015-2020
// Hanumantha Rao Madala 1 , Surendra R. Punganuru Francis Ali-Osman 2 Ruiwen Zhang 3 and Kalkunte S. Srivenugopal Department of Biomedical Sciences, School Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA Surgery the Brain Tumor Duke University, Durham, NC, Pharmacological Pharmaceutical College Houston, Correspondence to: Srivenugopal, email: Kalkunte.Srivenugopal@ttuhsc.edu Keywords: disulfiram; MGMT; glioma; chemotherapy; nanoparticles Received: September 12,...
The Near-infrared Fluorescence (NIRF) molecular imaging of cancer is known to be superior in sensitivity, deeper penetration, and low phototoxicity compared other modalities. In view an increased need for efficient targeted agents, we synthesized a NAD(P)H quinone oxidoreductase 1 (NQO1)-activatable NIR fluorescent probe (NIR-ASM) by conjugating dicyanoisophorone (ASM) fluorophore with the NQO1 substrate propionic acid (QPA). remained non-fluorescent until activation NQO1, whose expression...
Background: O6-Methylguanine-DNA methyltransferase (MGMT) is a unique antimutagenic DNA repair protein that plays crucial role in conferring resistance to various alkylating agents brain tumor therapy. In this study, we exploited the susceptibility of active site Cys145 MGMT for thiolation and nitrosylation, both which inactivate enzyme. Methods: We designed redox perturbing glutathione mimetic, platinated homoglutathione disulfide (hGTX) by adding small amounts cisplatin (1000:10) used...
Whether the antimutagenic DNA repair protein MGMT works solo in human cells and if it has other cellular functions is not known. Here, we show that associates with PCNA turn, cell cycle inhibitor, p21cip1 glioblastoma cancer lines. was shown to harbor a nearly perfect PCNA-Interacting Protein (PIP box) motif. Isogenic p53-null H1299 were engineered express p21 by two different procedures. Reciprocal immunoprecipitation/western blotting, Far-western confocal microscopy confirmed specific...
Human NAD(P)H quinone oxidoreductase-1 (hNQO1) is an important cancer-related biomarker, which shows significant overexpression in malignant cells. Developing effective method for detecting NQO1 activity with high sensitivity and selectivity tumors holds a great potential cancer diagnosis, treatment, management. In the present study, we report new dicyanoisophorone (DCP) based fluorescent probe (NQ-DCP) capable of monitoring hNQO1 vitro vivo both ratiometric turn-on model. NQ-DCP was...
Tumor heterogeneity and drug resistance pose severe limitations to chemotherapy of colorectal cancers (CRCs) necessitating innovative approaches trigger multiple cytocidal events for increased efficacy. Here, we developed a hybrid called KSS19 by combining the COX-2 selective NSAID rofecoxib with cis-stilbene found in combretastatin A4 (CA4), problematic, but potent antimicrotubule anti-angiogenesis agent. The structural design completely prevented isomerization CA4 its biologically inactive...
Abstract IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells tumors. However, systemic administration been accompanied considerable toxicity, prompting interest researching alternatives to drive preferential bioactivity tumor. Here, we have generated XTX301, tumor-activated linked human Fc protein via protease cleavable linker pharmacologically inactivated an receptor subunit beta 2 masking...
Under conditions of inherent or induced mitochondrial dysfunction, cancer cells manifest overlapping metabolic phenotypes, suggesting that they may be targeted via a common approach. Here, we use multiple oxidative phosphorylation (OXPHOS)-competent and incompetent cell pairs to demonstrate treatment with α-ketoglutarate (aKG) esters elicits rapid death OXPHOS-deficient by elevating intracellular aKG concentrations, thereby sequestering nitrogen from aspartate through glutamic-oxaloacetic...
The molecular basis of anticancer and apoptotic effects R-goniothalamin (GON), a plant secondary metabolite was studied. We show that induction oxidative stress reactivation mutant p53 underlie the strong cytotoxic GON against breast cancer cells. While not toxic to MCF10a epithelial cells, SKBR3 cells harboring an R175H were highly sensitive (IC50 = 7.3 µM). Flow cytometry other pertinent assays showed GON-induced abundant reactive oxygen species (ROS), glutathione depletion, protein...
<div>Abstract<p>IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells tumors. However, systemic administration IL12 been accompanied considerable toxicity, prompting interest researching alternatives to drive preferential bioactivity tumor. Here, we have generated XTX301, tumor-activated linked human Fc protein via protease cleavable linker pharmacologically inactivated an receptor...
<p>Supplemental Figure S1: A representative triplex fluorescent western blot image showing cleavage of XTX301 in primary human tumor specimens. Antibodies against IL-12 (Green), IL-12Rβ2 (Red) and IgG (Blue) were used, a merged is shown the figure. The 145 Kda band intact or non-cleavable construct, 85Kda cleaved XTX301/unmasked green arrow indicates free released upon XTX301. % mXT301 refers to percentage molecule compared total (intact cleaved) detected by using IL-12R2 signal.</p>
<div>Abstract<p>IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells tumors. However, systemic administration IL12 been accompanied considerable toxicity, prompting interest researching alternatives to drive preferential bioactivity tumor. Here, we have generated XTX301, tumor-activated linked human Fc protein via protease cleavable linker pharmacologically inactivated an receptor...
<p>Supplemental Figure S4: Gating strategy for multi-color flow cytometry analysis of tumor-infiltrating and splenic immune cell populations.</p>
<p>Supplemental Figure S2: XTX301 demonstrates enhanced activity upon proteolytic cleavage in primary cells. (a) Primary mouse splenocytes were pre-activated with PMA & Ionomycin and then incubated varying doses of rm IL-12 murine surrogate test articles for 24 hours, supernatants assessed by IFN- ELISA. (b) Human peripheral blood mononuclear cells (PBMCs) preactivated + 4 days (c) Cynomolgus monkey PBMCs rhIL-12 hours evaluated production ELISA.</p>
<p>Supplemental Figure S5: IFN- production in plasma: MC38 tumor-bearing mice were treated with the indicated doses of mXT301 or unmasked control. Plasma concentration was measured by MSD assay at time points. The data represent mean ± SEM, N = 3 to 5 per group, and level assessed a two-way ANOVA Bonferroni’s post-hoc pairwise comparison test compared vehicle (PBS) animals (*p < 0.05, **p 0.005, ****p 0.0001)</p>
<p>Supplemental Figure S3: Repeated mXTX301 dosing was well tolerated and resulted in dose dependent TGI mice bearing large (~360mm3) MC38 tumors (a) C57BL/6J were implanted subcutaneously with tumor cells received a single intravenous injection of mXTX301, unmasked control, or vehicle (PBS) at indicated levels (N=12 per group). Tumor measurements taken two/three times week. Animals euthanized due to health issues body weight loss. The data represent individual survival curves. CR:...
<p>Supplemental Figure S7: XTX301 caused transient and reversible changes to LFTs other safety parameters in NHP a repeat dose GLP toxicology study. Male female NHPs (N=3/sex; 2/sex for recovery animals) were administered by intravenous infusion once weekly total of four doses, followed four-week period. Changes (a) aspartate aminotransferase, (b) alanine (c) lymphocytes, (d) albumin, (e) IFN- fully the main study animals. All values are shown as mean ± SD. The reference ranges,...