Optimized Carbohydrate-Based Nanogel Formulation to Sensitize Hypoxic Tumors.

Solid tumors are often poorly vascularized, which impairs oxygen supply and drug delivery to the cells. This often leads to genetic and translational adaptations that promote tumor progression, invasion, metastasis, and resistance to conventional chemo-/radiotherapy and immunotherapy. A hypoxia-directed nanosensitizer formulation of a hypoxia-activated prodrug (HAP) was developed by encapsulating iodoazomycin arabinofuranoside (IAZA), a 2-nitroimidazole nucleoside-based HAP, in a functionally modified carbohydrate-based nanogel, facilitating delivery and accrual selectively in the hypoxic head and neck and prostate cancer cells.

High-Throughput Analysis Reveals miRNA Upregulating α-2,6-Sialic Acid through Direct miRNA-mRNA Interactions.

Chemical biology has revealed the importance of sialic acids as a major signal in physiology and disease. The terminal modification α-2,6-sialic acid is controlled by the enzymes ST6GAL1 and ST6GAL2. Dysregulation of this glycan impacts immunological recognition and cancer development.

Identification of proteins and cellular pathways targeted by 2-nitroimidazole hypoxic cytotoxins.

Tumour hypoxia negatively impacts therapy outcomes and continues to be a major unsolved clinical problem. Nitroimidazoles are hypoxia selective compounds that become entrapped in hypoxic cells by forming drug-protein adducts. They are widely used as hypoxia diagnostics and have also shown promise as hypoxia-directed therapeutics.

Prolonged mitotic arrest induced by Wee1 inhibition sensitizes breast cancer cells to paclitaxel.

Wee1 kinase is a crucial negative regulator of Cdk1/cyclin B1 activity and is required for normal entry into and exit from mitosis. Wee1 activity can be chemically inhibited by the small molecule MK-1775, which is currently being tested in phase I/II clinical trials in combination with other anti-cancer drugs. MK-1775 promotes cancer cells to bypass the cell-cycle checkpoints and prematurely enter mitosis.

A novel role of farnesylation in targeting a mitotic checkpoint protein, human Spindly, to kinetochores.

Kinetochore (KT) localization of mitotic checkpoint proteins is essential for their function during mitosis. hSpindly KT localization is dependent on the RZZ complex and hSpindly recruits the dynein-dynactin complex to KTs during mitosis, but the mechanism of hSpindly KT recruitment is unknown. Through domain-mapping studies we characterized the KT localization domain of hSpindly and discovered it undergoes farnesylation at the C-terminal cysteine residue.

Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint-silencing protein.

The mitotic checkpoint (or spindle assembly checkpoint) is a fail-safe mechanism to prevent chromosome missegregation by delaying anaphase onset in the presence of defective kinetochore-microtubule attachment. The target of the checkpoint is the E3 ubiquitin ligase anaphase-promoting complex/cyclosome. Once all chromosomes are properly attached and bioriented at the metaphase plate, the checkpoint needs to be silenced.

Rac2 is critical for neutrophil primary granule exocytosis.

Neutrophil degranulation is important in many inflammatory disorders, although the intracellular mechanisms underlying this process remain poorly understood. The Rho GTPase, Rac2, has been implicated in control of degranulation in earlier studies. We hypothesized that Rac2 selectively regulates neutrophil primary granule release.

Administration of tyrosyl radical-oxidized HDL inhibits the development of atherosclerosis in apolipoprotein E-deficient mice.

Objective: Tyrosyl radical-oxidized HDL (tyrHDL) increases the ability of cells to donate cholesterol to apolipoprotein (apo) A-I for HDL particle formation. We tested whether treatment with tyrHDL raises endogenous HDL cholesterol levels and decreases atherosclerosis development in apoE-deficient mice.

Methods And Results: Tyrosyl radical oxidation of mouse HDL induced formation of apoAI-AII heterodimers and enhanced the ability of mouse HDL to deplete cultured fibroblasts of their regulatory pool of cholesterol.