Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in the treatment of human cancer. Based on positive preclinical and clinical studies, bortezomib was subsequently ...approved for the clinical use as a front-line treatment for newly diagnosed multiple myeloma patients and for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this drug has become the staple of treatment. The approval of bortezomib by the US Food and Drug Administration (FDA) represented a significant milestone as the first proteasome inhibitor to be implemented in the treatment of malignant disease. Bortezomib has shown a positive clinical benefit either alone or as a part of combination therapy to induce chemo-/radio-sensitization or overcome drug resistance. One of the major mechanisms of bortezomib associated with its anticancer activity is through upregulation of NOXA, which is a proapoptotic protein, and NOXA may interact with the anti-apoptotic proteins of Bcl-2 subfamily Bcl-X(L) and Bcl-2, and result in apoptotic cell death in malignant cells. Another important mechanism of bortezomib is through suppression of the NF-κB signaling pathway resulting in the down-regulation of its anti-apoptotic target genes. Although the majority of success achieved with bortezomib has been in hematological malignancies, its effect toward solid tumors has been less than encouraging. Additionally, the widespread clinical use of bortezomib continues to be hampered by the appearance of dose-limiting toxicities, drug-resistance and interference by some natural compounds. These findings could help guide physicians in refining the clinical use of bortezomib, and encourage basic scientists to generate next generation proteasome inhibitors that broaden the spectrum of efficacy and produce a more durable clinical response in cancer patients. Other desirable applications for the use of proteasome inhibitors include the development of inhibitors against specific E3 ligases, which act at an early step in the ubiquitin-proteasome pathway, and the discovery of less toxic and novel proteasome inhibitors from natural products and traditional medicines, which may provide more viable drug candidates for cancer chemoprevention and the treatment of cancer patients in the future.
Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would ...offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity.
To summarize the anti-cancer effects of Disulfiram through a thorough patent review.
This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy.
Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug.
For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.
Based on the central role of the ubiquitin-proteasome system (UPS) in the degradation of cellular proteins, proteasome inhibition has been considered an attractive approach for anticancer therapy. ...Deubiquitinases (DUBs) remove ubiquitin conjugates from diverse substrates; therefore, they are essential regulators of the UPS. DUB inhibitors, especially the inhibitors of proteasomal DUBs are becoming a research hotspot in targeted cancer therapy. Previous studies have shown that metal complexes, such as copper and zinc complexes, can induce cancer cell apoptosis through inhibiting UPS function. Moreover, we have found that copper pyrithione inhibits both 19S proteasome-associated DUBs and 20S proteasome activity with a mechanism distinct from that of the classical 20S proteasome inhibitor bortezomib. In the present study, we reveal that (i) nickel pyrithione complex (NiPT) potently inhibits the UPS via targeting the 19S proteasome-associated DUBs (UCHL5 and USP14), without effecting on the 20S proteasome; (ii) NiPT selectively induces proteasome inhibition and apoptosis in cultured tumor cells and cancer cells from acute myeloid leukemia human patients; and (iii) NiPT inhibits proteasome function and tumor growth in nude mice. This study, for the first time, uncovers a nickel complex as an effective inhibitor of the 19S proteasomal DUBs and suggests a potentially new strategy for cancer treatment.
Next to water, tea is the most popular beverage in the world. The most abundant and active compound in green tea is (-)-epigallocatechin-3-gallate (EGCG), which is extensively studied for its ...cancer-preventive and anti-cancer activities as well as its cellular targets. One potential molecular target of EGCG is the proteasome. While molecular docking and structure-activity relationship (SAR) analysis suggests that the ester carbon of EGCG is important for mediating its proteasome-inhibitory activity, EGCG is very unstable under physiological conditions. Therefore, a series of analogs were synthesized aiming to improve stability and bioavailability of EGCG. Among them, peracetate-protected or the prodrug of EGCG was found to have increased bioavailability, stability, and proteasome-inhibitory activities against various human cancer cells and tumors compared to EGCG, suggesting its potential use for cancer prevention and treatment. Epidemiological studies have indicated that green tea consumption is associated with the reduced risk of cancers, especially associated with the reduced risk of late stage of cancers. This risk reduction may be attributed not only to proteasome inhibition, but also to numerous other intracellular molecules targeted by EGCG that are involved in cell cycle regulation, apoptosis, angiogenesis, and metastasis.
A successful example of high-Cr oxide dispersion strengthened (ODS) steels development is introduced with showing key technologies to overcome the issues to meet material requirements for next ...generation nuclear systems as well as fusion blanket systems. Corrosion issue requires Cr concentration more than 14wt.%, but aging embrittlement issue requires it less than 16wt.%. An addition of 4wt.%Al is effective to improve corrosion resistance of 16wt.%Cr-ODS steel in supercritical water (SCW) and lead–bismuth eutectics (LBE), while it is detrimental to high-temperature strength. An addition of small amount of Zr or Hf results in a significant increase in creep strength at 973K in Al-added ODS steels. Feasibility of high-Cr ODS steel without Al addition is assessed for fusion application in terms of corrosion resistance in SCW.
Copper is an essential element for multiple biological processes. Its concentration is elevated to a very high level in cancer tissues for promoting cancer development through processes such as ...angiogenesis. Organic chelators of copper can passively reduce cellular copper and serve the role as inhibitors of angiogenesis. However, they can also actively attack cellular targets such as proteasome, which plays a critical role in cancer development and survival. The discovery of such molecules initially relied on a step by step synthesis followed by biological assays. Today high-throughput chemistry and high-throughput screening have significantly expedited the copper-binding molecules discovery to turn "cancer-promoting" copper into anti-cancer agents.
The phase and metal/oxide interface structure of the nanometer-scale particles in an Al-alloyed high-Cr oxide dispersion strengthened ferritic steel extruded at 1150
°C and 1050
°C were characterized ...by high-resolution transmission electron microscopy and diffraction contrast techniques, including weak beam electron microscopy. After extrusion at 1150
°C, yttrium–aluminum–hexagonal (YAH, YAlO
3) and yttrium–aluminum–perovskite (YAP, YAlO
3) oxides (diameter ⩽10
nm) constitute ∼55% and 38% of the particles, respectively; ∼78% of the particles (4.5–10
nm in diameter), which include 40% YAH oxide and 38% YAP phase with misfit (translational) moiré fringe spacing of 2.15
nm and 1.65
nm, respectively, are semi-coherent with the matrix. After extrusion at 1050
°C, almost all the particles are YAH phase, and ∼86.5% (diameter <4.5
nm) are coherent with the matrix. The coherency of the oxides is size dependent. The crystallographic orientation correlations of the oxides and matrix were found.
A new project, high intensity heavy ion accelerator facility (HIAF), is currently under design and construction in China. The HIAF front end, composed of electron cyclotron resonance (ECR) ion ...sources, low energy beam transport (LEBT) and radio frequency quadrupole (RFQ), will produce and provide beams of ions with a mass up to uranium at a beam energy of0.5MeV/u. The typical beam intensity is designed up to 2 emA for the uranium beam with a charge state of35+. This paper presents an overall design of the front end for HIAF and discusses several key issues in the design. By modeling the beam extraction from the ECR source, we got a reliable starting beam condition to perform the design. Transverse coupling of the beam from the source was elaborated. To relieve the coupling we implanted two solenoids after the source. Space charge effect in the charge state selection of the ion source was evaluated. An overall space charge compensation degree of no less than 70% was predicted. A beam dynamics simulation was performed by using the initial particle distribution obtained from the extraction modeling. The simulation resulted in development of a beam collimation system in the LEBT to confine the transverse emittance. The RFQ design will follow the development of LEAF-RFQ at Institute of Modern Physics, which has successfully commissioned with several beams and demonstrated as an excellent design. Recent beam commissioning results of LEAF-RFQ will also be presented in this paper.
Emerging data demonstrate promising results of related haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HCT) for the treatment of hematologic malignancies. Data about G-CSF ...primed PBSC as reliable source of graft with myeloablative conditioning are lacking. We updated the outcomes in 130 adult patients with high-risk hematologic malignancies who received haplo-PBSC transplantation consecutively under busulfan-based conditioning. PBSC were freshly isolated and infused without ex vivo T-cell depletion into the recipients. Myeloid recovery was achieved in 99.2% patients with full donor chimerism. The cumulative incidence of acute grade 3-4 GvHD, overall and extensive chronic GvHD was 14.9%, 38.6% and 16.5%, respectively. The 3-year non-relapse mortality rate was 24.1%. Non-remission prior to transplant was associated with higher incidence of relapse (P=0.006), inferior overall survival (P=0.017) and leukemia-free survival (P=0.024). These data suggest that PBSC is a reliable graft source in haploidentical, unmanipulated transplant settings under myeloablative conditioning in patients with high-risk hematologic malignancies.
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