curcumin and 1-methylpropyl-2-imidazolyl-disulfide

Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.

Topics: Apoptosis; Auranofin; Bortezomib; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Disulfides; Drug Resistance, Neoplasm; Humans; Imidazoles; Leukocytes, Mononuclear; Multiple Myeloma; Nitriles; Oxidative Stress; Reactive Oxygen Species; Sulfones; Thioredoxin Reductase 1; Thioredoxins; Transcription Factor RelA

Botulinum neurotoxins consist of a metalloprotease linked via a conserved interchain disulfide bond to a heavy chain responsible for neurospecific binding and translocation of the enzymatic domain in the nerve terminal cytosol. The metalloprotease activity is enabled upon disulfide reduction and causes neuroparalysis by cleaving the SNARE proteins. Here, we show that the thioredoxin reductase-thioredoxin protein disulfide-reducing system is present on synaptic vesicles and that it is functional and responsible for the reduction of the interchain disulfide of botulinum neurotoxin serotypes A, C, and E. Specific inhibitors of thioredoxin reductase or thioredoxin prevent intoxication of cultured neurons in a dose-dependent manner and are also very effective inhibitors of the paralysis of the neuromuscular junction. We found that this group of inhibitors of botulinum neurotoxins is very effective in vivo. Most of them are nontoxic and are good candidates as preventive and therapeutic drugs for human botulism.

Topics: Animals; Botulinum Toxins; Cerebral Cortex; Curcumin; Cytoplasm; Disulfides; Enzyme Activation; Enzyme Inhibitors; Imidazoles; Male; Mice; Neurons; Paralysis; Serotyping; Synaptic Vesicles; Synaptosomal-Associated Protein 25; Thioredoxin-Disulfide Reductase; Thioredoxins