Bortezomib for the treatment of multiple myeloma

Scott, Kathleen M.; Hayden, Patrick; Howman, Andrew; Wheatley, Keith; Coyne, Imelda

doi:10.1002/14651858.cd010816

Cited by 7 publications

(6 citation statements)

References 16 publications

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“…The study also confirmed that, MALAT‐1 was shown to promote autophagy in MM through modulation of HMGB1. Bortezomib is a standard drug for the treatment of relapsed MM verified by phase 2 and 3 trials [Dimopoulos et al, ; Scott et al, ]. The overexpression of MALAT‐1 prominently reversed the combining 3‐MA with bortezomib‐mediated repression of MM cell survival, suggesting that MALAT‐1 may be an effective target for autophagy inhibition in MM.…”

Section: Discussionmentioning

confidence: 99%

LncRNA MALAT‐1 Elevates HMGB1 to Promote Autophagy Resulting in Inhibition of Tumor Cell Apoptosis in Multiple Myeloma

Gao

et al. 2017

J of Cellular Biochemistry

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Long non-coding RNAs (lncRNAs) can participate in the pathological process of multiple myeloma (MM) via regulation of specific gene expression and function. This research aimed to study the role of MALAT-1 and the underlying mechanism in MM. In this study, the expression of MALAT-1 and HMGB1 protein in the bone marrow mononuclear cells from MM patients at different stages and in MM cell lines was determined by qRT-PCR and western blot, respectively. The endogenous expression of MALAT-1 and HMGB1 was modulated using lentivirus vectors transfection. CHX chase assay and RIP analyses were performed to explore the interaction between MALAT-1 and HMGB1 in MM. Nude mouse xenograft was made and used for in vivo experiment study. The expression of MALAT-1 and HMGB1 in the bone marrow mononuclear cells from patients with untreated multiple myeloma was dramatically increased, as well as in MM cell lines, KM3 and U266; while MALAT-1 expression and HMGB1 protein level both decreased significantly in complete remission patients. Furthermore, MALAT-1 knockdown facilitated the degradation of HMGB1 at the post-translational level via increase of the ubiquitination of HMGB1 in MM cells. MALAT-1 was shown to promote autophagy in MM through upregulation of HMGB1. In vivo, MALAT-1 knockdown could inhibit tumor growth significantly in tumor-bearing mice and reduced the protein expressions of HMGB1, Beclin-1, and LC3B in tumor tissues. LncRNA MALAT-1 increases the expression level of HMGB1 in MM thereby promotes autophagy resulting in the inhibition of apoptosis. J. Cell. Biochem. 118: 3341-3348, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

LncRNA MALAT‐1 Elevates HMGB1 to Promote Autophagy Resulting in Inhibition of Tumor Cell Apoptosis in Multiple Myeloma

Gao

et al. 2017

J of Cellular Biochemistry

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“…Antineoplastic activity derives from diverse actions such as blocking antiapoptotic genes, down-regulating survival signals, preventing efflux of cytotoxic agents, promoting DNA stabilization for cleaving, and by other mechanisms. The potential of proteasome inhibition has been translated to successful therapies in hematologic malignancies including multiple myeloma and mantle cell lymphoma[ 20 , 21 ]. However, in solid tumors, proteasome inhibition has not met with similar success and no benefit has been shown, despite extensive clinical investigations[ 22 , 23 ].…”

Section: Proteasomementioning

confidence: 99%

Proteasome regulators in pancreatic cancer

Murugan¹,

Voutsadakis²

2022

WJGO

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Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.

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“…M ultiple myeloma (MM) is an incurable malignant plasma cell disease associated with overproduction of monoclonal immunoglobulin (M-protein), suppression of normal immunoglobulin synthesis, kidney and bone marrow failure, hypercalcemia, and skeletal destruction. (1) While the disease remains incurable, overall survival has improved significantly with the introduction of novel therapies, such as immune modulating drugs, (2) proteasome inhibitors (PIs), (3) and the anti-CD38 antibody daratumumab. (4) Despite developments in disease management, bone disease remains a major concern.…”

Section: Introductionmentioning

confidence: 99%

Increased Bone Volume by Ixazomib in Multiple Myeloma: 3-Month Results from an Open Label Phase 2 Study

Diaz‐delCastillo

Gundesen

Andersen

et al. 2020

Journal of Bone and Mineral Research

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Multiple myeloma (MM) is an incurable bone marrow cancer characterized by the development of osteolytic lesions due to the myeloma-induced increase in osteoclastogenesis and decrease in osteoblastic activity. The standard treatment of MM often involves proteasome inhibitors (PIs), which can also have a beneficial off-target bone anabolic effect. However, long-term treatment with PIs is unadvised due to their high side-effect burden and inconvenient route of administration. Ixazomib is a new-generation, oral PI that is generally well tolerated; however, its bone effect remains unknown. Here, we describe the 3-month results of a single-center phase II clinical trial investigating the effect of ixazomib treatment on bone formation and bone microstructure. Thirty patients with MM in stable disease not receiving antimyeloma treatment for ≥3 months and presenting ≥2 osteolytic lesions received monthly ixazomib treatment cycles. Serum and plasma samples were collected at baseline and monthly thereafter. Sodium 18 F-Fluoride positron emission tomography (NaF-PET) whole-body scans and trephine iliac crest bone biopsies were collected before and after three treatment cycles. The serum levels of bone remodeling biomarkers suggested an early ixazomib-induced decrease in bone resorption. NaF-PET scans indicated unchanged bone formation ratios; however, histological analyses of bone biopsies revealed a significant increase in bone volume per total volume after treatment. Further analyses of bone biopsies showed unchanged osteoclast number and COLL1A1 High -expressing osteoblasts on bone surfaces. Next, we analyzed the superficial bone structural units (BSUs), which represent each recent microscopic bone remodeling event. Osteopontin staining revealed that following treatment, significantly more BSUs were enlarged (>200,000 μm 2 ), and the distribution frequency of their shape was significantly different from baseline. Overall, our data suggest that ixazomib induces overflow remodeling-based bone formation by decreasing the level of bone resorption and promoting longer bone formation events, making it a potentially valuable candidate for future maintenance treatment.

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Bortezomib for the treatment of multiple myeloma

Cited by 7 publications

References 16 publications

LncRNA MALAT‐1 Elevates HMGB1 to Promote Autophagy Resulting in Inhibition of Tumor Cell Apoptosis in Multiple Myeloma

LncRNA MALAT‐1 Elevates HMGB1 to Promote Autophagy Resulting in Inhibition of Tumor Cell Apoptosis in Multiple Myeloma

Proteasome regulators in pancreatic cancer

Increased Bone Volume by Ixazomib in Multiple Myeloma: 3-Month Results from an Open Label Phase 2 Study

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