Our previous study showed that the novel proteasome inhibitor NPI-0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM-xenografts demonstrated that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase-1 clinical trial of NPI-0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI-0052 using human MM xenograft murine model. Our results showed that NPI-0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin-like (CT-L, beta5), trypsin-like (T-L, beta2), and caspase-like (C-L, beta1) activities in extra-vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound (3H-NPI-0052) in mice demonstrated that NPI-0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S-bearing mice with NPI-0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427841 | PMC |
| http://dx.doi.org/10.1111/j.1365-2141.2010.08144.x | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Biosynthesis of lactacystin as a proteasome inhibitor.
Commun Chem
January 2025
Graduate School of Engineering, Hokkaido University, N13-W8, Kita-ku, Sapporo, Hokkaido, 060-8628, Japan.
Lactacystin is an irreversible proteasome inhibitor isolated from Streptomyces lactacystinicus. Despite its importance for its biological activity, the biosynthesis of lactacystin remains unknown. In this study, we identified the lactacystin biosynthetic gene cluster by gene disruption and heterologous expression experiments.
View Article and Find Full Text PDFHypoxia-induced degradation of FTO promotes apoptosis by unmasking RACK1-mediated activation of MTK1-JNK1/2 pathway.
J Adv Res
January 2025
College of Animal Science and Technology, Nanjing Agricultural University, Weigang 1, Nanjing 210095, China. Electronic address:
Introduction: Hypoxia, a condition characterized by inadequate oxygen supply to tissues, triggers various cellular responses, including apoptosis. The RNA demethylase FTO has been shown to exert anti-apoptotic effects, but its functions independent of RNA demethylase-particularly those involving protein-protein interactions-during hypoxia remain unclear.
Objectives: This study aimed to elucidate the cytoprotective mechanism of FTO in preventing apoptosis under hypoxic stress.
The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria.
Cell Mol Life Sci
January 2025
State Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), Aerospace Center Hospital, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through the continuous accumulation of misfolded proteins and damaged organelles. This review delineates the roles of two complementary and synergistic degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, in the degradation of misfolded proteins and damaged organelles for intracellular recycling. We emphasize the interconnected decision-making processes of degradation systems in maintaining cellular homeostasis, such as the biophysical state of substrates, receptor oligomerization potentials (e.
View Article and Find Full Text PDFAssociation of Proteasome Activity and Pool Heterogeneity with Markers Determining the Molecular Subtypes of Breast Cancer.
Cancers (Basel)
January 2025
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Background: Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed.
View Article and Find Full Text PDFCabozantinib Selectively Induces Proteasomal Degradation of p53 Somatic Mutant Y220C and Impedes Tumor Growth.
J Biol Chem
January 2025
Department of Hepatopancreatobiliary Surgery, Suzhou Ninth Hospital Affiliated to Soochow University; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China. Electronic address:
Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors, and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!