The Role of Proteasome Inhibitors in Multiple Myeloma Bone Disease and Bone Metastasis: Effects on Osteoblasts and Osteocytes
19 May 2021-Applied Sciences (Multidisciplinary Digital Publishing Institute)-Vol. 11, Iss: 10, pp 4642
TL;DR: PIs have been recently proven to also be efficacious in blocking MM-induced osteocyte death providing new possible therapeutic use in the management of bone loss, and the conjugation of PIs with bisphosphonates showed good results in terms of bone anabolic activity.
Abstract: The alterations of bone remodeling are typical of multiple myeloma (MM) patients where the uncoupled and unbalanced bone remodeling caused the onset of osteolytic lesions. Moreover, bone metastasis occurs in the majority of patients with breast and prostate cancer. Skeletal-related events negatively impact on quality of life by increasing the vulnerability to fractures. Several bone-targeting treatments have been developed to control bone pain and pathological fractures, including bisphosphonates and Denosumab. Nevertheless, these agents act by inhibiting osteoclast activity but do not improve bone formation. Proteasome inhibitors (PIs) have shown bone anabolic effects and encouraging results in stimulating osteoblast differentiation and bone healing. Among these, the first-in-class bortezomib and the second-generation PIs, carfilzomib, and ixazomib regulate the bone remodeling process by controlling the degradation of several bone proteins. PIs have been recently proven to also be efficacious in blocking MM-induced osteocyte death providing new possible therapeutic use in the management of bone loss. PIs have significant side effects that limit their use as bone anabolic strategy. Multiple alternative approaches have been made. The conjugation of PIs with bisphosphonates, which can target them to bone, showed good results in terms of bone anabolic activity. However, the clinical implications of these effects require further investigations.
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TL;DR: In this paper, the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications is discussed.
Abstract: Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients' quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.
25 citations
01 Jan 2019
TL;DR: In this paper, the authors discuss the mechanisms regulating the uncoupled bone remodelling in multiple myeloma (MM) and summarizes current advances in the treatment of MBD, including antiresorptive agents that are only partially effective due to their inability to repair the existing lesions.
Abstract: Multiple myeloma (MM) is the second most common haematological malignancy and is characterized by a clonal proliferation of neoplastic plasma cells within the bone marrow. MM is the most frequent cancer involving the skeleton, causing osteolytic lesions, bone pain and pathological fractures that dramatically decrease MM patients' quality of life and survival. MM bone disease (MBD) results from uncoupling of bone remodelling in which excessive bone resorption is not compensated by new bone formation, due to a persistent suppression of osteoblast activity. Current management of MBD includes antiresorptive agents, bisphosphonates and denosumab, that are only partially effective due to their inability to repair the existing lesions. Thus, research into agents that prevent bone destruction and more importantly repair existing lesions by inducing new bone formation is essential. This review discusses the mechanisms regulating the uncoupled bone remodelling in MM and summarizes current advances in the treatment of MBD. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
15 citations
TL;DR: The selected N-heterocycle derivatives possess promising medicinal properties that could be utilized for future drug discovery, including oxazolone, oxazole, and oxadiazole.
Abstract: This study focuses on selected potent N-heterocycle scaffolds, including oxazolone, oxazole, and oxadiazole. Numerous studies have examined their biological activity against cancer, infectious diseases, and, importantly, inflammation. Thus, efforts have been made to computationally predict and investigate the drug-like properties of these reported N-heterocycle derivatives. In this study, 19 articles have been reviewed for anticancer, antimicrobial, and anti-inflammatory activity of N-heterocycle compounds. The most potent compounds were examined for their pharmacokinetic properties and drug-like properties using the SwissADME web server. Moreover, a target prediction was performed using the Molinspiration web server to predict possible biological targets. A total of 30 compounds were selected for their potent biological activity as determined by IC 50 , minimum inhibitory concentration, and edema inhibition for cancer, infection, and inflammation, respectively. Our computational predictions showed that all compounds have the recommended molecular weight except for C5, C6, and I5. Furthermore, the C2, C3, C8, M1, M2, M4, I1, and I4 compounds are expected to have blood–brain barrier permeability, suggesting central nervous activity. Additionally, most of the compounds showed acceptable gastrointestinal absorption. Target prediction studies suggested that compounds could modulate their biological responses via channel modulators and receptors to different degrees. The selected N-heterocycle derivatives possess promising medicinal properties that could be utilized for future drug discovery.
References
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TL;DR: Data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity.
5,050 citations
TL;DR: Osteopetrotic mutants have provided a wealth of information about the genes that regulate the differentiation of osteoclasts and their capacity to resorb bone.
Abstract: Osteoporosis, a disease endemic in Western society, typically reflects an imbalance in skeletal turnover so that bone resorption exceeds bone formation. Bone resorption is the unique function of the osteoclast, and anti-osteoporosis therapy to date has targeted this cell. The osteoclast is a specialized macrophage polykaryon whose differentiation is principally regulated by macrophage colony-stimulating factor, RANK ligand, and osteoprotegerin. Reflecting integrin-mediated signals, the osteoclast develops a specialized cytoskeleton that permits it to establish an isolated microenvironment between itself and bone, wherein matrix degradation occurs by a process involving proton transport. Osteopetrotic mutants have provided a wealth of information about the genes that regulate the differentiation of osteoclasts and their capacity to resorb bone.
3,604 citations
TL;DR: The most common human cancers — lung, breast and prostate — have a great avidity for bone, leading to painful and untreatable consequences.
Abstract: The most common human cancers --lung, breast and prostate -- have a great avidity for bone, leading to painful and untreatable consequences. What makes some cancers, but not others, metastasize to bone, and how do they alter its physiology? Some of the molecular mechanisms that are responsible have recently been identified, and provide new molecular targets for drug development.
2,367 citations
TL;DR: Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.
Abstract: background This study compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma who had received one to three previous therapies. methods We randomly assigned 669 patients with relapsed myeloma to receive either an intravenous bolus of bortezomib (1.3 mg per square meter of body-surface area) on days 1, 4, 8, and 11 for eight three-week cycles, followed by treatment on days 1, 8, 15, and 22 for three five-week cycles, or high-dose dexamethasone (40 mg orally) on days 1 through 4, 9 through 12, and 17 through 20 for four five-week cycles, followed by treatment on days 1 through 4 for five four-week cycles. Patients who were assigned to receive dexamethasone were permitted to cross over to receive bortezomib in a companion study after disease progression. results Patients treated with bortezomib had higher response rates, a longer time to progression (the primary end point), and a longer survival than patients treated with dexamethasone. The combined complete and partial response rates were 38 percent for bortezomib and 18 percent for dexamethasone (P<0.001), and the complete response rates were 6 percent and less than 1 percent, respectively (P<0.001). Median times to progression in the bortezomib and dexamethasone groups were 6.22 months (189 days) and 3.49 months (106 days), respectively (hazard ratio, 0.55; P<0.001). The oneyear survival rate was 80 percent among patients taking bortezomib and 66 percent among patients taking dexamethasone (P=0.003), and the hazard ratio for overall survival with bortezomib was 0.57 (P=0.001). Grade 3 or 4 adverse events were reported in 75 percent of patients treated with bortezomib and in 60 percent of those treated with dexamethasone. conclusions Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.
2,333 citations
TL;DR: Bone metastasis causes severe bone pain and can result in fractures without any injury, as well as other life-threatening conditions, and patients with prostate cancer who usually have bone metastasis that shows increased new bone formation also have increased bone destruction in the same lesions.
Abstract: Extract: Cancer frequently spreads to bone, a process termed bone metastasis. Up to 70% of patients with breast cancer or prostate cancer, and 15 to 30% of patients with lung, colon, bladder or kidney cancer develop bone metastasis. Once tumors go to bone, such as in patients with breast cancer or prostate cancer, they are incurable, and only 20% of patients with breast cancer are still alive five years after they are found to have bone metastasis. It is estimated that about 350,000 people die with bone metastasis each year in the United States. Bone metastasis causes severe bone pain and can result in fractures without any injury, as well as other life-threatening conditions. There are two major types of bone metastasis, one in which bone destruction is the predominant feature and the other one in which new bone formation is predominant. Bone metastasis where bone destruction is the predominant feature is known as osteolytic, and that in which new bone formation is the primary feature is called osteoblastic. This classification for metastasis is really two extremes of a continuum because many patients can have both osteolytic and osteoblastic or mixtures of both in their bone metastasis. In fact, patients with prostate cancer who usually have bone metastasis that shows increased new bone formation also have increased bone destruction in the same lesions.
2,287 citations