The effects of proteasome inhibitors on bone remodeling in multiple myeloma

Zangari, Maurizio; Suva, Larry J.

doi:10.1016/j.bone.2016.02.019

Cited by 40 publications

(35 citation statements)

References 90 publications

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“…Preclinical and clinical data also showed that these inhibitors have a beneficial effect on bone remodeling by stimulating bone formation and suppressing bone resorption (21). In this study, we demonstrated in culture and in an animal model that suppressing the 26S proteasome by proteasome inhibitors accelerates DNA repair in osteoblasts and protects them from radiationinduced apoptosis, thus protecting bones from radiation damage.…”

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confidence: 50%

“…It has been well documented that Bzb treatment increases bone-forming markers, such as alkaline phosphatase, and suppresses bone resorption markers, such as CTX and TRAP-5b, in patients with multiple myeloma (41). Preclinical studies showed that Bzb primarily stimulates bone formation by promoting osteoblast differentiation using multifaceted mechanisms, such as up-regulation of Runx2 activity, active b-catenin level, osterix, and vitamin D signaling, stabilization of Runx2 protein, and downregulation of DKK1, a Wnt pathway inhibitor (21). Our study uncovered a new mechanism for the anabolic bone action of Bzb, i.e., stimulation of DNA repair to preserve osteoblasts after radiation insult.…”

Section: Discussionmentioning

confidence: 99%

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Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis

et al. 2017

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Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

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confidence: 50%

Section: Discussionmentioning

confidence: 99%

Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis

et al. 2017

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“…Bortezomib promoted osteoblast differentiation from mesenchymal stem cells in vitro . Consistent with that observation, proteasome inhibitor treatment has been noted to restore bone homeostasis in human multiple myeloma patients, by stimulating differentiation of bone‐forming osteoblasts, while suppressing the maturation and activity of pro‐resorptive osteoclasts . In contrast, bortezomib has also been reported to impair bone growth in young mice, through chondrocyte toxicity .…”

Section: Introductionmentioning

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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“…By contrast, treatment with bortezomib resulted in increases in homogenous contrast agent uptake within the BM in both femur and tibia. Bortezomib causes significant marrow remodeling, resulting in reduction in osteoclast activity and cytokine secretion, and inhibition of tumor‐induced angiogenesis . At the same time, healing and tumor cell death induced by bortezomib may also generate increased inflammation, which may result in an increase in contrast uptake within high tumor burden regions after relapse.…”

Section: Discussionmentioning

confidence: 95%

Longitudinal preclinical magnetic resonance imaging of diffuse tumor burden in intramedullary myeloma following bortezomib therapy

et al. 2019

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Multiple myeloma (MM) is a largely incurable, debilitating hematologic malignancy of terminally differentiated plasma cells in the bone marrow (BM). Identification of therapeutic response is critical for improving outcomes and minimizing costs and off‐target toxicities. To assess changes in BM environmental factors and therapy efficacy, there is a need for noninvasive, nonionizing, longitudinal, preclinical methods. Here, we demonstrate the feasibility of preclinical magnetic resonance imaging (MRI) for longitudinal imaging of diffuse tumor burden in a syngeneic, immunocompetent model of intramedullary MM. C57Bl/KaLwRij mice were implanted intravenously with 5TGM1‐GFP tumors and treated with a proteasome inhibitor, bortezomib, or vehicle control. MRI was performed weekly with a Helmholtz radiofrequency coil placed on the hind leg. Mean normalized T1‐weighted signal intensities and T2 relaxation times were quantified for each animal following manual delineation of BM regions in the femur and tibia. Finally, tumor burden was quantified for each tissue using hematoxylin and eosin staining. Changes in T2 relaxation times correlated strongly to cell density and overall tumor burden in the BM. Median T2 relaxation times and regional T1‐weighted contrast uptake were shown to be most relevant in identifying posttherapy disease stage in this model of intramedullary MM. In summary, our results highlighted potential preclinical MRI markers for assessing tumor burden and BM heterogeneity following bortezomib therapy, and demonstrated the application of longitudinal imaging with preclinical MRI in an immunocompetent, intramedullary setting.

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The effects of proteasome inhibitors on bone remodeling in multiple myeloma

Cited by 40 publications

References 90 publications

Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis

Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation‐induced osteoporosis

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

Longitudinal preclinical magnetic resonance imaging of diffuse tumor burden in intramedullary myeloma following bortezomib therapy

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