High chymotrypsin-like activity in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of a better response and longer PFS

Romaniuk, Wioletta; Bołkuń, Łukasz; Kalita, Joanna; Galar, Marzenna; Bernatowicz, Malgorzata; Ostrowska, H; Kłoczko, Janusz

doi:10.1007/s00277-018-3393-7

Cited by 2 publications

(2 citation statements)

References 26 publications

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“…The proteasome inhibitor carfilzomib impairs the recycling of misfolded proteins, leading to ER stress and cell death. Over the past 20 years, inhibition of the proteasome chymotrypsin‐like activity has shown clinical efficacy in patients with hematological malignancies [ 39 ]. More recently, a preclinical work has provided evidence that carfilzomib may have activity also in solid tumors [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Preclinical efficacy of carfilzomib in BRAF‐mutant colorectal cancer models

Maione,

Oddo,

Galvagno

et al. 2024

Molecular Oncology

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Serine/threonine‐protein kinase B‐raf (BRAF) mutations are found in 8–15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF‐mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF‐mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune‐mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic‐damage‐associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF‐mutant murine tumors and mobilized the danger‐signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug‐treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T‐cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF‐mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF‐mutant colorectal cancer patients.

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Section: Discussionmentioning

confidence: 99%

Preclinical efficacy of carfilzomib in BRAF‐mutant colorectal cancer models

Maione,

Oddo,

Galvagno

et al. 2024

Molecular Oncology

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“…Enzymatically active extracellular proteasomes have also been revealed in human plasma and cerebrospinal fluid [8][9][10]. Proteomic analysis of affinity-purified extracellular proteasomes revealed that extracellular proteasomes do not contain 19S or PA200 regulatory particles and are represented exclusively by the 20S complex [11].…”

Section: Introductionmentioning

confidence: 99%

Plasma Exosomes of Patients with Breast and Ovarian Tumors Contain an Inactive 20S Proteasome

et al. 2021

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Exosomes are directly involved in governing of physiological and pathological conditions of an organism through the transfer of information from producing to receiving cells. It can be assumed that exosomes are one of the key players of tumor dissemination since they are very stable and small enough to penetrate from various tissues into biological fluids and then back, thus interacting with tissue target cells. We evaluated the enzymatic activity and the level of 20S proteasome in tissue and exosomes of healthy females (n = 39) and patients with ovarian (n = 50) and breast (n = 108) tumors to reveal the critical role of exosomal cargo in the mediation of different types of metastases. Exosomes from plasma and ascites were isolated and characterized in according to International Society for Extracellular Vesicles guidelines. The level of 20S proteasome in tissue and exosomes was determined using Western blot analysis. Chymotrypsin- and caspase-like (ChTL and CL, respectively) peptidase activities of the proteasomes were determined using fluorogenic Suc-LLVY-AMC and Cbz-LLG-AMC substrates, respectively. We observed increased levels of 20S proteasome in ovarian cancer tissue and luminal B subtype breast cancer tissue as well as in plasma exosomes from cancer patients. Moreover, the level of the 20S proteasome in plasma exosomes and ascites exosomes in patients with ovarian tumors is comparable and higher in ovarian cancer patients with low volume ascites than in patients with moderate and high-volume ascites. We also found increased ChTL and CL activities in breast cancer and ovarian cancer tissues, as well as in peritoneal metastases in ovarian cancer, while proteasomal activity in exosomes from plasma of healthy females and all patients, as well as from ascites of ovarian tumor patients were lower than detection limit of assay. Thus, regardless of the type of tumor metastasis (lymphogenous or peritoneal), the exosomes of cancer patients were characterized by an increased level of 20S proteasome, which do not exhibit enzymatic activity.

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High chymotrypsin-like activity in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of a better response and longer PFS

Cited by 2 publications

References 26 publications

Preclinical efficacy of carfilzomib in BRAF‐mutant colorectal cancer models

Preclinical efficacy of carfilzomib in BRAF‐mutant colorectal cancer models

Plasma Exosomes of Patients with Breast and Ovarian Tumors Contain an Inactive 20S Proteasome

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