3 research outputs found
Human Serum Albumin-Delivered [Au(PEt<sub>3</sub>)]<sup>+</sup> Is a Potent Inhibitor of T Cell Proliferation
Using
a modular library format in conjunction with cell viability
(MTS) and flow cytometry assays, 90 cationic complexes [Au<b>PL</b>]<sup><i>n</i>+</sup> (<b>P</b> = phosphine ligand; <b>L</b> = thiourea derivative or chloride) were studied for their
antiproliferative activity in CD8<sup>+</sup> T lymphocyte cells.
The activity of the compounds correlates with the steric bulk of the
phosphine ligands. Thiourea serves as a leaving group that is readily
replaced by cysteine thiol (NMR, ESI-MS). Taking advantage of selective
thiourea ligand exchange, the fragments [AuÂ(PEt<sub>3</sub>)]<sup>+</sup> and [AuÂ(JohnPhos)]<sup>+</sup> (JohnPhos = 1,1′-biphenyl-2-yl)Âdi-<i>tert</i>-butylphosphine) in compounds <b>1</b> and <b>2</b> were transferred to recombinant human serum albumin (rHSA).
PEt<sub>3</sub> promoted efficient modification of Cys34 in HSA (<b>HSA-1</b>), whereas use of bulky JohnPhos as a carrier ligand
led to serum protein nonspecifically modified with multiple gold adducts
(<b>HSA-2</b>) (Ellman’s test, ESI-TOF MS). <b>HSA-1</b>, but not <b>HSA-2</b>, strongly inhibits T cell proliferation
at nanomolar doses. The potential role of HSA as a delivery vehicle
in gold-based autoimmune disease treatment is discussed
DataSheet_1_Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSMRO.docx
Redox metabolism is increasingly investigated in cancer as driving regulator of tumor progression, response to therapies and long-term patients’ quality of life. Well-established cancer therapies, such as radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. However, the ability to integrate redox information across signaling and metabolic networks to facilitate discovery and broader investigation of redox-regulated pathways in cancer remains a key unmet need limiting the advancement of new cancer therapies. To overcome this challenge, we developed a new constraint-based computational method (COSMro) and applied it to a Head and Neck Squamous Cell Cancer (HNSCC) model of radiation resistance. This novel integrative approach identified enhanced capacity for H2S production in radiation resistant cells and extracted a key relationship between intracellular redox state and cholesterol metabolism; experimental validation of this relationship highlights the importance of redox state in cellular metabolism and response to radiation.</p
DataSheet_2_Redox integration of signaling and metabolism in a head and neck cancer model of radiation resistance using COSMRO.xlsx
Redox metabolism is increasingly investigated in cancer as driving regulator of tumor progression, response to therapies and long-term patients’ quality of life. Well-established cancer therapies, such as radiotherapy, either directly impact redox metabolism or have redox-dependent mechanisms of action defining their clinical efficacy. However, the ability to integrate redox information across signaling and metabolic networks to facilitate discovery and broader investigation of redox-regulated pathways in cancer remains a key unmet need limiting the advancement of new cancer therapies. To overcome this challenge, we developed a new constraint-based computational method (COSMro) and applied it to a Head and Neck Squamous Cell Cancer (HNSCC) model of radiation resistance. This novel integrative approach identified enhanced capacity for H2S production in radiation resistant cells and extracted a key relationship between intracellular redox state and cholesterol metabolism; experimental validation of this relationship highlights the importance of redox state in cellular metabolism and response to radiation.</p