(Immuno)proteasomes as therapeutic target in acute leukemia

Cloos, Jacqueline; Roeten, Margot S. F.; Franke, N.; Meerloo, Johan van; Zweegman, Sonja; Kaspers, Gertjan J. L.; Jansen, Gerrit

doi:10.1007/s10555-017-9699-4

Cited by 32 publications

(33 citation statements)

References 155 publications

(169 reference statements)

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“…If proteasome inhibitor therapies impair bone growth and density, this would have significant implications for the administration of these drugs to children in order to treat any condition, not just osteosarcoma. Around a dozen clinical trials have been conducted, and more are underway, evaluating proteasome inhibitors for a number of pediatric cancers, mostly leukemias, 86 as well as for suppressing transplant rejection. 87 None of these studies have unveiled any effect of proteasome inhibitors on participants' bones, but emergence of such late effects would not be expected given the short-term nature of these trials (and the poor survival of many participants).…”

Section: Discussionmentioning

confidence: 99%

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Patatsos

Shekhar

Hawkins

2018

Vet Comparative Oncology

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Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed.

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Section: Discussionmentioning

confidence: 99%

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Patatsos

Shekhar

Hawkins

2018

Vet Comparative Oncology

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“…The proteomic data suggested that that the level of the relatively low abundant proteasome subunit beta type-8 (PSMB8) (β5i) was decreased in ibuprofen treated male mice (Supplemental Table 1). During stress conditions, the constitutive proteasome β1, β2 and β5 subunits of 20 S proteasome are replaced by β1i, β2i, and β5i immunoproteasome counterparts [24][25][26] . Western blotting data showed that the expression levels of β5i immunoproteasome subunit was significantly decreased in ibuprofen treated male livers, consistent with the proteomic data ( Fig.…”

Section: Proteasome Dysfunctionmentioning

confidence: 99%

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

Tiwari

Mishra

Salemi

et al. 2020

Sci Rep

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Ibuprofen, an inhibitor of prostanoid biosynthesis, is a common pharmacological agent used for the management of pain, inflammation and fever. However, the chronic use of ibuprofen at high doses is associated with increased risk for cardiovascular, renal, gastrointestinal and liver injuries. The underlying mechanisms of ibuprofen-mediated effects on liver remain unclear. To determine the mechanisms and signaling pathways affected by ibuprofen (100 mg/kg/day for seven days), we performed proteomic profiling of male mice liver with quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) using ten-plex tandem mass tag (TMT) labeling. More than 300 proteins were significantly altered between the control and ibuprofen-treated groups. The data suggests that several major pathways including (1) energy metabolism, (2) protein degradation, (3) fatty acid metabolism and (4) antioxidant system are altered in livers from ibuprofen treated mice. Independent validation of protein changes in energy metabolism and the antioxidant system was carried out by Western blotting and showed sex-related differences. Proteasome and immunoproteasome activity/expression assays showed ibuprofen induced gender-specific proteasome and immunoproteasome dysfunction in liver. The study observed multifactorial gender-specific ibuprofen-mediated effects on mice liver and suggests that males and females are affected differently by ibuprofen. Ibuprofen, a propionic acid derivative, is the most common over-the-counter nonsteroidal anti-inflammatory (NSAID) drug used to treat fever, pain, inflammation and many other disorders 1. It has been included as a major medicine in the Essential Drugs List of the World Health Organization 2. Ibuprofen at low over-the-counter doses (800-1200 mg/day) is used to treat muscular aches, backaches, toothaches, and fever. At higher doses (1800-2400 mg/day), ibuprofen is prescribed for the treatment of chronic conditions such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis 3. Ibuprofen is a non-selective inhibitor of the cyclo-oxygenase (COX) isozymes COX-1 and COX-2 that converts arachidonic acid into prostaglandins including thromboxane and prostacyclin 1. The anti-inflammatory, antipyretic and analgesic effects of ibuprofen are mediated through the inhibition of prostaglandins E2 (PGE2) and I2 (PGI2) production by blocking COX activity 1. Both PGE2 and PGI2 are pro-inflammatory prostanoids that increase vascular permeability, promote leukocyte infiltration and increase edema formation 4. The clearance of ibuprofen is mediated through oxidative metabolism by multiple cytochrome P450 (CYP) enzymes (CYP2C9, CYP2C8) to inactive primary metabolites including 3-hydroxy-ibuprofen, carboxy ibuprofen and 2-hydroxy-ibuprofen 5,6. Most of the ibuprofen is metabolized in liver, while only a small percentage of unchanged drug is excreted in the urine 5. The liver plays a key role in energy metabolism and is essential for whole body homeostasis via the regulation of glucose, lipid, and amino acid ...

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“…15 In addition, responses to PI in other hematological malignancies have been contradictory. 6,16,17 Similarly, promising preclinical data obtained with PI in models of solid tumors have not been confirmed in the clinic, 15 probably as a consequence of impaired drug distribution, requiring higher dosages, not applicable for the toxic effects. Therefore, the design of a new generation of ubiquitinproteasome pathway inhibitors and the identification of novel combination strategies is essential to overcome resistance and broaden the applicability of this class of drugs to other hematological malignancies, and possibly to solid tumors.…”

Section: Introductionmentioning

confidence: 99%

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies

Bergaggio¹,

Riganti

Garaffo³

et al. 2019

Blood

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Proteasome inhibitors (PI) are extensively used for the therapy of multiple myeloma (MM) and mantle cell lymphoma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PI, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of US Food and Drug Administration–approved PI with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, mantle cell lymphoma, and Burkitt lymphoma cell lines. CFZ/AGI-6780 treatment increased death of primary CD138+ cells from MM patients and exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone marrow–derived stromal cells. Mechanistically, the CFZ/AGI-6780 combination significantly decreased tricarboxylic acid cycle activity and adenosine triphosphate levels as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduced the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD+-dependent deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors impaired IDH2 activity and increased MM cell death. Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PI, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PI to other malignancies.

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(Immuno)proteasomes as therapeutic target in acute leukemia

Cited by 32 publications

References 155 publications

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

Gender-specific changes in energy metabolism and protein degradation as major pathways affected in livers of mice treated with ibuprofen

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies

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