1-methylpropyl-2-imidazolyl-disulfide and Neoplasms

Thioredoxin is a redox-sensitive molecule that has pleiotropic cellular effects, such as the control of proliferation, redox states and apoptosis, and is often upregulated in malignancy. The system controls the activation of a number of transcription factors through sulphydryl transfer and, through its activity on hypoxia inducible factor 1alpha, it is able to regulate vascular endothelial growth factor levels and hence angiogenesis. The thioredoxin protein has been shown to be upregulated in hypoxic regions of certain tumours, suggesting that inhibitors could potentially exhibit enhanced hypoxic toxicity and/or indirect anti-angiogenic effects. Evidence of this is becoming apparent in the literature. The current report reviews the thioredoxin system as an anticancer drug target and focuses upon two recent compounds, PMX464 and PX12, which reportedly inhibit this important pathway.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Benzothiazoles; Cattle; Cyclohexanones; Disulfides; Endothelial Cells; Humans; Hydroquinones; Hypoxia; Hypoxia-Inducible Factor 1; Imidazoles; Neoplasms; Thioredoxins; Transcription Factors; Vascular Endothelial Growth Factor A

Biomira Inc, following its acquisition of ProlX Pharmaceutical Corp, is developing PX-12, an inhibitor of thioredoxin, for the potential treatment of cancer. PX-12 has completed phase I clinical trials.

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Contraindications; Disulfides; Drug Evaluation, Preclinical; Humans; Imidazoles; Neoplasms; Structure-Activity Relationship; Thioredoxins

This phase I trial assessed the safety, dose limiting toxicity (DLT) and pharmacodynamics of PX-12 in adult patients with advanced refractory cancers.. PX-12 was administered to sequential cohorts as a 72-h infusion utilizing a portable infusion pump on days 1, 2, and 3 of a 21-day cycle at a starting dose level of 300 mg/m(2)/day and escalating dose levels till DLT was observed. Plasma thioredoxin (Trx-1), vascular endothelial growth factor (VEGF) and FGF-2 (fibroblast growth factor) levels were measured predose and during infusion of PX-12.. Patients (n = 14) were enrolled to the following dose cohorts, 300 mg/m(2) (n = 3), 400 mg/m(2) (n = 10) and 500 mg/m(2) (n = 1). Common grade 1/2 toxicities included fatigue, taste alteration and odor caused by expired drug metabolite. DLTs were one episode each of grade 3 hypoxia at the 400 mg/m(2) and grade 3 reversible pneumonitis at the 500 mg/m(2) dose levels. Best response was stable disease in a patient with rectal cancer. Predose Trx-1 levels (n = 12) ranged from 5.1 to 30.0 ng/mL (median 12.6 ng/mL).. PX-12 administered at 400 mg/m(2)/day by 72-hour infusion appears safe and tolerable. Inhibition of thioredoxin is a strategy worth evaluation with next generation of inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Disulfides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fibroblast Growth Factor 2; Humans; Imidazoles; Infusions, Intravenous; Male; Middle Aged; Neoplasm Staging; Neoplasms; Small Molecule Libraries; Thioredoxins; Vascular Endothelial Growth Factor A

Thioredoxin-1 (Trx-1) is a cellular redox protein that promotes tumor growth, inhibits apoptosis, and up-regulates hypoxia-inducible factor-1alpha and vascular endothelial growth factor. Objectives of this study were to determine safety, tolerability, pharmacodynamics, and pharmacokinetics of PX-12, a small-molecule inhibitor of Trx-1.. Thirty-eight patients with advanced solid tumors received PX-12 at doses of 9 to 300 mg/m(2), as a 1- or 3-h i.v. infusion on days 1 to 5, repeated every 3 weeks.. At the 300 mg/m(2) dose level, one patient experienced a reversible episode of pneumonitis during the first cycle, and a second patient developed pneumonitis after the second cycle. Doses up to 226 mg/m(2) were well tolerated, and grade 3/4 events were uncommon (<3% of patients). The limiting factor on this dosing schedule was pungent odor caused by expired drug metabolite, 2-butanethiol. The best response was stable disease in seven patients (126-332 days). Whereas PX-12 was not detectable following the infusion, the C(max) of its inactive metabolite, 2-mercaptoimidazole, increased linearly with dose. PX-12 treatment lowered plasma Trx-1 concentrations in a dose-dependent manner.. PX-12, the first Trx-1 inhibitor to enter clinical trials, was tolerated up to a dose of 226 mg/m(2) by a 3-h infusion. Based on pharmacodynamic and pharmacokinetic data, a trial of prolonged infusion schedule of PX-12 has been initiated.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Disulfides; Dose-Response Relationship, Drug; Female; Humans; Imidazoles; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Thioredoxins

Thioredoxin-1 (Trx-1) is a small redox protein that is overexpressed in many human tumors, where it is associated with aggressive tumor growth and decreased patient survival. Trx-1 is secreted by tumor cells and is present at increased levels in the plasma of cancer patients. PX-12 is an irreversible inhibitor of Trx-1 currently in clinical development as an antitumor agent. We have used SELDI-TOF mass spectroscopy to measure plasma Trx-1 from patients treated with PX-12 during a phase I study. Mean plasma Trx-1 levels at pretreatment were significantly elevated in the cancer patients at 182.0 ng/mL compared with 27.1 ng/mL in plasma from healthy volunteers. PX-12 treatment significantly lowered plasma Trx-1 in cancer patients having the highest plasma Trx-1 pretreatment levels. High-plasma vascular endothelial growth factor (VEGF) levels have been correlated to decreased patient survival. PX-12 treatment also significantly lowered plasma VEGF levels in cancer patients with high pretreatment VEGF levels. SELDI-TOF mass spectrometry identified seven additional plasma proteins whose levels decreased after PX-12 administration, one of which was identified as a truncated form of transthyretin. The results of this study suggest that the lowering of elevated levels of plasma Trx-1 in cancer patients may provide a surrogate for the inhibition of tumor Trx-1 by PX-12. Furthermore, PX-12 decreases plasma VEGF levels that may contribute to the antitumor activity of PX-12.

Topics: Animals; Antineoplastic Agents; Disulfides; Drug Monitoring; Humans; Imidazoles; Male; Mice; Mice, Inbred C57BL; Neoplasms; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thioredoxins; Vascular Endothelial Growth Factor A

Necroptosis is an immunogenic cell death program that is associated with a host of human diseases, including inflammation, infections, and cancer. Receptor-interacting protein kinase 3 (RIPK3) and its substrate mixed lineage kinase domain-like protein (MLKL) are required for necroptosis activation. Specifically, RIPK3-dependent MLKL phosphorylation promotes the assembly of disulfide bond-dependent MLKL polymers that drive the execution of necroptosis. However, how MLKL disulfide bond formation is regulated is not clear. In this study we discovered that the MLKL-modifying compound necrosulfonamide cross-links cysteine 86 of human MLKL to cysteine 32 of the thiol oxidoreductase thioredoxin-1 (Trx1). Recombinant Trx1 preferentially binds to monomeric MLKL and blocks MLKL disulfide bond formation and polymerization

Topics: Cell Death; Disulfides; HeLa Cells; Humans; Imidazoles; Neoplasm Proteins; Neoplasms; Protein Binding; Protein Kinases; Protein Multimerization; Thioredoxins

Thioredoxin-1 (Trx-1) redox signaling regulates multiple aspects of cell growth and survival, and elevated tumor levels of Trx-1 have been associated with decreased patient survival. PX-12, an inhibitor of Trx-1 currently in clinical development, has been found to decrease tumor levels of the HIF-1α transcription factor. SSAT1 has been reported to bind to HIF-1α and RACK1, resulting in oxygen-independent HIF-1 ubiquitination and degradation. SSAT2, a related protein, stabilizes the interaction of the VHL protein and elongin C with HIF-1 leading to oxygen-dependent HIF-1α ubiquitination and degradation. We investigated the effects of PX-12 and Trx-1 on SSAT1, SSAT2, and inhibition of HIF-1α.. A panel of cell lines was treated with PX-12 to investigate its effects on SSAT1 and SSAT2 expression, and on HIF-1α protein levels. We also evaluated the regulation of SSAT1 through the Nrf2 and PMF-1, two trans-acting transcription factors.. We found that PX-12 increased nuclear Nrf2 activity and antioxidant response element binding. PX-12 also increased the expression of SSAT1 but not SSAT2 in a PMF-1-dependent manner that was independent of Trx-1. Inhibition of Nrf2 or PMF-1 prevented the increase in SSAT1 caused by PX-12.. The results show that PX-12, acting independently of Trx-1, increases nuclear Nrf2, which interacts with PMF-1 to increase the expression of SSAT1. The degradation of HIF-1α that results from binding with SSAT1 may explain the decrease in HIF-1α caused by PX-12 and could contribute to the antitumor activity of PX-12.

Topics: Acetyltransferases; Antineoplastic Agents; Antioxidants; Cell Hypoxia; Cell Line, Transformed; Cell Line, Tumor; Disulfides; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Imidazoles; Isoenzymes; Neoplasm Proteins; Neoplasms; NF-E2-Related Factor 2; Response Elements; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Thioredoxins; Transcription Factors