Targeting CCR1 for the Treatment of Osteolytic Bone Disease in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2503-2503
Author(s):  
Sonia Vallet ◽  
Noopur Raje ◽  
MariaTeresa Fulciniti ◽  
Kenji Ishitsuka ◽  
Teru Hideshima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Clinical Trials ◽  
Bone Disease ◽  
Cell Number ◽  
In Vivo Studies ◽  
Protective Effects ◽  
Osteolytic Bone Disease

Abstract Osteolytic bone disease (OBD) is a frequent complication of multiple myeloma (MM), affecting 70 to 80% of the patients. OBD is characterized by imbalanced bone remodeling, due to decreased osteoblast (OB) number and increased osteoclast (OC) formation and activity. MM cells secrete osteoclastogenic factors, such as receptor activator of nuclear factor kappa B ligand (RANKL) and CCL3. In turn, OC support MM cell proliferation and survival, thus promoting a positive feedback that exacerbates bone resorption. Chemokines modulate osteoclastogenesis and promote MM cell proliferation, in particular CCL3 and its receptor CCR1 play an important role in mediating OBD in MM. MLN3897 (Millennium Pharmaceuticals, Cambridge) is a novel small molecule specific antagonist of human CCR1 (IC50 0.8 nM). It has a favorable toxicity profile in healthy volunteers and is currently undergoing phase II clinical trials in rheumatoid arthritis and multiple sclerosis. Here we evaluate the effects of MLN3897 on OC function and activity, as well as OC-MM cell interactions. Our in vitro data demonstrates a dual mechanism of action for MLN3897: it inhibits osteoclastogenesis and also overcomes the protective effects conferred by OC on MM cells. Our data further shows inhibition of OC formation and function by 40 and 70%, respectively, following MLN3897 treatment. This is mediated via inhibition of the fusion process and is accompanied by downregulation of pERK and c-fos signaling. To analyze its effect on MM cells, we verified CCR1 and CCR5 expression levels on MM1.S (15% and 3.6%) and OPM1 (3.8 and 0.7%). Our data show that OC secrete high levels of CCL3 which triggers MM cell migration; and that MLN3897 abrogates these effects by inhibiting the PI3K/Akt pathway. Moreover, MLN3897 overcomes the proliferative advantage conferred by OC on MM cells, as demonstrated in INA6, MM1.S and MM patient derived primary cells. OC induced MM cell proliferation is mediated by adhesion and cytokine secretion, and MLN3897 abrogates both MM cell-to-OC adhesion and interleukin-6 (IL6) secretion by OC in a co-culture system, thereby resulting in decreased MM cell survival and proliferation. To confirm these in vitro results, in vivo studies in a SCID-hu mouse model are underway. Implanted SCID-Hu INA-6 bearing mice are treated with twice daily oral MLN3897 for 3 weeks. The evaluation of osteolytic lesions and OC, OB and endothelial cell number; and tumor burden will be presented. Our in vitro results therefore show novel biologic sequelae of CCL3 and its inhibition on both osteoclastogenesis and MM cell growth. Our in vivo experiments will further validate the role of CCR1 in a human BM microenvironment-MM model, providing the framework for clinical trials of MLN3897 for the treatment of OBD in MM.

scholarly journals Additive Benefits of Radium-223 Dichloride and Bortezomib Combination in a Systemic Multiple Myeloma Mouse Model

2021 ◽  
Vol 22 (11) ◽  
pp. 5570
Author(s):  
Mari I. Suominen ◽  
Jenni Mäki-Jouppila ◽  
Anna Huhtinen ◽  
Birgitta Sjöholm ◽  
Jukka P. Rissanen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Combination Therapy ◽  
Combination Treatment ◽  
Bone Disease ◽  
Bone Cells ◽  
Osteolytic Lesion ◽  
Radium 223 ◽  
Osteolytic Bone Disease

Osteolytic bone disease is a hallmark of multiple myeloma (MM) mediated by MM cell proliferation, increased osteoclast activity, and suppressed osteoblast function. The proteasome inhibitor bortezomib targets MM cells and improves bone health in MM patients. Radium-223 dichloride (radium-223), the first targeted alpha therapy approved, specifically targets bone metastases, where it disrupts the activity of both tumor cells and tumor-supporting bone cells in mouse models of breast and prostate cancer bone metastasis. We hypothesized that radium-223 and bortezomib combination treatment would have additive effects on MM. In vitro experiments revealed that the combination treatment inhibited MM cell proliferation and demonstrated additive efficacy. In the systemic, syngeneic 5TGM1 mouse MM model, both bortezomib and radium-223 decreased the osteolytic lesion area, and their combination was more effective than either monotherapy alone. Bortezomib decreased the number of osteoclasts at the tumor–bone interface, and the combination therapy resulted in almost complete eradication of osteoclasts. Furthermore, the combination therapy improved the incorporation of radium-223 into MM-bearing bone. Importantly, the combination therapy decreased tumor burden and restored body weights in MM mice. These results suggest that the combination of radium-223 with bortezomib could constitute a novel, effective therapy for MM and, in particular, myeloma bone disease.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals Tip60 Suppresses Cholangiocarcinoma Proliferation and Metastasis via PI3k-AKT

2018 ◽  
Vol 50 (2) ◽  
pp. 612-628 ◽  
Author(s):  
Yaodong Zhang ◽  
Guwei Ji ◽  
Sheng Han ◽  
Zicheng Shao ◽  
Zefa Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Progression ◽  
Venous Invasion ◽  
In Vivo Studies ◽  
Akt Pathway ◽  
Rank Test ◽  
Aberrant Expression ◽  
Proliferation And Metastasis

Background/Aims: Aberrant expression of Tip60 is associated with progression in many cancers. However, the role of Tip60 in cancer progression remains contradictory. The aim of this study was to investigate the clinical significance, biological functions and underlying mechanisms of Tip60 deregulation in cholangiocarcinoma (CCA) for the first time. Methods: Quantitative real-time PCR (QRT-PCR), western blotting and immunohistochemistry staining (IHC) were carried out to measure Tip60 expression in CCA tissues and cell lines. Kaplan–Meier analysis and the log-rank test were used for survival analysis. In vitro, cell proliferation was evaluated by flow cytometry and CCK-8, colony formation, and EDU assays. Migration/ invasion was evaluated by trans-well assays. Phosphokinase array was used to confirm the dominant signal regulated by Tip60. Tumor growth and metastasis were demonstrated in vivo using a mouse model. Results: Tip60 was notably downregulated in CCA tissues, which was associated with greater tumor size, venous invasion, and TNM stage. Down-regulation of Tip60 was associated with tumor progression and poorer survival in CCA patients. In vitro and in vivo studies demonstrated that Tip60 suppressed growth and metastasis throughout the progression of CCA. We further identified the PI3K/AKT pathway as a dominant signal of Tip60 and suggested that Tip60 regulated CCA cell proliferation and metastasis via PT3K-AKT pathway. Pearson analysis revealed that PTEN was positively correlated with the Tip60 level in CCA tissues. Conclusion: Tip60, as a tumor suppressor in CCA via the PI3K/AKT pathway, might be a promising therapeutic target or prognostic marker for CCA.

Focus on the therapeutic efficacy of 3BNC117 against HIV-1: In vitro studies, in vivo studies, clinical trials and challenges

2017 ◽  
Vol 52 ◽  
pp. 44-50 ◽  
Author(s):  
Zhi-Jun Liu ◽  
Jing Bai ◽  
Feng-Li Liu ◽  
Xiang-Yang Zhang ◽  
Jing-Zhang Wang
Keyword(s):  
Clinical Trials ◽  
Therapeutic Efficacy ◽  
In Vitro Studies ◽  
In Vivo Studies ◽  
Hiv 1

scholarly journals Increased circulating LDL cholesterol increases myeloma tumour burden in vivo

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
Beatriz Gamez
Keyword(s):  
Bone Disease ◽  
Dietary Intervention ◽  
Dietary Cholesterol ◽  
Cholesterol Diet ◽  
Tumour Burden ◽  
Benign Condition ◽  
Myeloma Cells ◽  
Osteolytic Bone Disease

Gámez B., Morris EV., Olechnowicz S., Sowman, A., Turner, C. and Edwards CM.   Multiple myeloma (MM) is a fatal malignancy characterized by an expansion of malignant plasma cells in the bone marrow (BM) and associated with osteolytic bone disease. MM is preceded by the benign condition, monoclonal gammopathy of undetermined significance (MGUS). Understanding MGUS progression and development of MM bone disease is key for patient management. We and others have previously demonstrated that diet-induced obesity promotes myeloma progression, but the mechanisms underlying this remain unknown. The aim of the current study was to determine the effect of dietary cholesterol on MM development. A 2% cholesterol diet was used to increase circulating LDL in mice. Mice were randomly distributed to either a) cholesterol diet 4 weeks prior to 5TGM1 MM inoculation (pretreatment) or b) cholesterol diet 4 weeks prior to MM inoculation and continued for the entire experiment (continuous). Mice on the continuous cholesterol diet had increased tumour burden, associated with an increase in lipid droplet content of MM cells. No differences in tumour burden were seen in those mice where cholesterol diet was halted at time of MM inoculation. In vitro, myeloma cells cultured with delipidated FBS had a 50% reduction in viability after 72 hours. Rich cholesterol content lipoproteins (LDL) but not VLDL could restore MM cell viability, suggesting that cholesterol is responsible for this lipid-depletion effect. Taken together, our results show that high cholesterol promotes myeloma and results in a higher lipid content in myeloma cells, ultimately increasing BM tumour burden. Pretreatment with a cholesterol diet did not alter disease progression suggesting a direct pro-tumourigenic effect of cholesterol. These results demonstrate both the detrimental effect of cholesterol on myeloma progression and the potential for dietary intervention approaches.

scholarly journals Contribution to the biological interest of Valeriana officinalis: an update

2021 ◽  
Vol 42 ◽  
pp. e67649
Author(s):  
Marta Sánchez ◽  
Elena González-Burgos ◽  
Irene Iglesias ◽  
M. Pilar Gómez-Serranillos Cuadrado
Keyword(s):  
Clinical Trials ◽  
Nervous System ◽  
Biological Activities ◽  
In Vivo Studies ◽  
Neuroprotective Activity ◽  
Future Research ◽  
Valeriana Officinalis ◽  
Valerenic Acid

Valeriana officinalis L. (Caprifoliaceae family) has been traditionally used to treat mild nervous tension and sleep problems. The basis of these activities are mainly attributed to valerenic acid through the modulation of the GABA receptor. Moreover, V. officinalis is claimed to have other biological activities such as cardiovascular benefits, anticancer, antimicrobial and spasmolytic.  The current review aims to update the biological and pharmacological studies (in vitro, in vivo and clinical trials) of V. officinalis and its major secondary metabolites in order to guide future research. Databases PubMed, Science Direct and Scopus were used for literature search including original papers written in English and published between 2014 and 2020. There have been identified 33 articles which met inclusion criteria. Most of these works were performed with V. officinalis extracts and only a few papers (in vitro and in vivo studies) evaluated the activity of isolated compounds (valerenic acid and volvalerenal acid K). In vitro studies focused on studying antioxidant and neuroprotective activity. In vivo studies and clinical trials mainly investigated activities on the nervous system (anticonvulsant activity, antidepressant, cognitive problems, anxiety and sleep disorders). Just few studies were focused on other different activities, highlight effects on symptoms of premenstrual and postmenopausal syndromes. Valeriana officinalis continues to be one of the medicinal plants most used by today's society for its therapeutic properties and whose biological and pharmacological activities continue to arouse great scientific interest as evidenced in recent publications. This review shows scientific evidence on traditional uses of V. officinalis on nervous system.

scholarly journals HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Fengjie Jiang ◽  
Xiaozhu Tang ◽  
Chao Tang ◽  
Zhen Hua ◽  
Mengying Ke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Aberrant Expression ◽  
The Stability ◽  
Induced Apoptosis ◽  
Proliferation In Vitro

AbstractN6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic RNAs while accumulating studies suggest that m6A aberrant expression plays an important role in cancer. HNRNPA2B1 is a m6A reader which binds to nascent RNA and thus affects a perplexing array of RNA metabolism exquisitely. Despite unveiled facets that HNRNPA2B1 is deregulated in several tumors and facilitates tumor growth, a clear role of HNRNPA2B1 in multiple myeloma (MM) remains elusive. Herein, we analyzed the function and the regulatory mechanism of HNRNPA2B1 in MM. We found that HNRNPA2B1 was elevated in MM patients and negatively correlated with favorable prognosis. The depletion of HNRNPA2B1 in MM cells inhibited cell proliferation and induced apoptosis. On the contrary, the overexpression of HNRNPA2B1 promoted cell proliferation in vitro and in vivo. Mechanistic studies revealed that HNRNPA2B1 recognized the m6A sites of ILF3 and enhanced the stability of ILF3 mRNA transcripts, while AKT3 downregulation by siRNA abrogated the cellular proliferation induced by HNRNPA2B1 overexpression. Additionally, the expression of HNRNPA2B1, ILF3 and AKT3 was positively associated with each other in MM tissues tested by immunohistochemistry. In summary, our study highlights that HNRNPA2B1 potentially acts as a therapeutic target of MM through regulating AKT3 expression mediated by ILF3-dependent pattern.

A review on Remdesivir: A broad-spectrum antiviral molecule for possible COVID-19 treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Jabeena Khazir ◽  
Tariq Maqbool ◽  
Bilal Ahmad Mir
Keyword(s):  
Clinical Trials ◽  
Broad Spectrum ◽  
Ebola Virus ◽  
Controlled Trial ◽  
In Vivo Studies ◽  
Therapeutic Drug ◽  
Viral Agent ◽  
Double Blind

: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus strain and the causative agent of COVID-19 was identified to have emerged in Wuhan, China, in December 2019 [1]. This pandemic situation and magnitude of suffering has led to global effort to find out effective measures for discovery of new specific drugs and vaccines to combat this deadly disease. In addition to many initiatives to develop vaccines for protective immunity against SARS-CoV-2, some of which are at various stages of clinical trials researchers worldwide are currently using available conventional therapeutic drugs with potential to combat the disease effectively in other viral infections and it is believed that these antiviral drugs could act as a promising immediate alternative. Remdesivir (RDV), a broad-spectrum anti-viral agent, initially developed for the treatment of Ebola virus (EBOV) and known to show promising efficiency in in vitro and in vivo studies against SARS and MERS coronaviruses, is now being investigated against SARS-CoV-2. On May 1, 2020, The U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for RDV to treat COVID-19 patients [2]. A number of multicentre clinical trials are on-going to check the safety and efficacy of RDV for the treatment of COVID-19. Results of published double blind, and placebo-controlled trial on RDV against SARS-CoV-2, showed that RDV administration led to faster clinical improvement in severe COVID-19 patients compared to placebo. This review highlights the available knowledge about RDV as a therapeutic drug for coronaviruses and its preclinical and clinical trials against COVID-19.

scholarly journals Research Status of Mesenchymal Stem Cells in Liver Transplantation

2019 ◽  
Vol 28 (12) ◽  
pp. 1490-1506 ◽  
Author(s):  
Yu You ◽  
Di-guang Wen ◽  
Jian-ping Gong ◽  
Zuo-jin Liu
Keyword(s):  
Stem Cells ◽  
Liver Transplantation ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
In Vivo Studies ◽  
Cell Contact ◽  
Clinical Effects ◽  
Clinical Safety

Liver transplantation has been deemed the best choice for end-stage liver disease patients but immune rejection after surgery is still a serious problem. Patients have to take immunosuppressive drugs for a long time after liver transplantation, and this often leads to many side effects. Mesenchymal stem cells (MSCs) gradually became of interest to researchers because of their powerful immunomodulatory effects. In the past, a large number of in vitro and in vivo studies have demonstrated the great potential of MSCs for participation in posttransplant immunomodulation. In addition, MSCs also have properties that may potentially benefit patients undergoing liver transplantation. This article aims to provide an overview of the current understanding of the immunomodulation achieved by the application of MSCs in liver transplantation, to discuss the problems that may be encountered when using MSCs in clinical practice, and to describe some of the underlying capabilities of MSCs in liver transplantation. Cell–cell contact, soluble molecules, and exosomes have been suggested to be critical approaches to MSCs’ immunoregulation in vitro; however, the exact mechanism, especially in vivo, is still unclear. In recent years, the clinical safety of MSCs has been proven by a series of clinical trials. The obstacles to the clinical application of MSCs are decreasing, but large sample clinical trials involving MSCs are still needed to further study their clinical effects.

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