Human Osteosarcoma
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2021 ◽  
Vol 22 (18) ◽  
pp. 9976
Jose Maria Zapico ◽  
Lourdes Acosta ◽  
Miryam Pastor ◽  
Loganathan Rangasamy ◽  
Laura Marquez-Cantudo ◽  

Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase MMP-13 is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1′ heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound 9a has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.

Aging ◽  
2021 ◽  
Jie Gu ◽  
Bo Dai ◽  
Xuchao Shi ◽  
Zhennian He ◽  
Yuanlin Xu ◽  

2021 ◽  
Vol 11 (1) ◽  
Masanori Kawano ◽  
Tatsuya Iwasaki ◽  
Ichiro Itonaga ◽  
Yuta Kubota ◽  
Kazuhiro Tanaka ◽  

AbstractInteraction with surrounding healthy cells plays a major role in the growth and metastasis of osteosarcoma. In this study, we hypothesized that humoral factors, which do not require direct contact with cells, are involved in the interaction between osteosarcoma and the surrounding cells. We identified the humoral factor involved in the association between tumor cells and surrounding normal cells using a co-culture model and investigated the significance of our findings. When human osteosarcoma cells (MG63) and human mesenchymal stem cells (hMSCs) were co-cultured and comprehensively analyzed for changes in each culture group, we found that the expression of chemokine (CC motif) ligand 26 (CCL26) was significantly enhanced. We also analyzed the changes in cell proliferation in co-culture, enhanced interaction with administration of recombinant CCL26 (rCCL26), reduced interaction with administration of anti-CCL26 antibodies, changes in invasive and metastatic abilities. CCL26 levels, motility, and invasive capability increased in the co-culture group and the group with added rCCL26, compared to the corresponding values in the MG63 single culture group. In the group with added CCL26 neutralizing antibodies, CCL26 level decreased in both the single and co-culture groups, and motility and invasive ability were also reduced. In a nude mice lung metastasis model, the number of lung metastases increased in the co-culture group and the group with added rCCL26, whereas the number of tumors were suppressed in the group with added neutralizing antibodies compared to those in the MG63 alone. This study identified a possible mechanism by which osteosarcoma cells altered the properties of normal cells to favorably change the microenvironment proximal to tumors and to promote distant metastasis.

Aging ◽  
2021 ◽  
Kexiang Zhang ◽  
Song Wu ◽  
Hongwei Wu ◽  
Li Liu ◽  
Jiahui Zhou

2021 ◽  
Vol Volume 14 ◽  
pp. 4791-4804
Weijie Chen ◽  
Su Wu ◽  
Yang Huang ◽  
Tingting Zhang ◽  
Hao Dong ◽  

Songou Zhang ◽  
Lei He ◽  
Jinxiang Shang ◽  
Long Chen ◽  
Yifan Xu ◽  

Background: Carvacrol is a monoterpenic phenol extracted from traditional Chinese herbs, including oregano and thyme. Currently, carvacrol has been widely studied for its therapeutic role in central nervous system diseases, liver diseases and digestive system cancer. Objective: However, the role of carvacrol in osteosarcoma and its underlying molecular mechanism remain elusive. Here, we aimed to examine the anticancer effects of carvacrol on osteosarcoma. Methods: The effects of carvacrol on the osteosarcoma proliferation capacity were revealed by CCK-8 and colony formation assays. Flow cytometry and Hoechst assays were used to determine the effects of carvacrol on osteosarcoma cell apoptosis. The effect of carvacrol on migration and invasion of osteosarcoma cells was determined by wound healing and transwell tests. Protein expression was evaluated by WB assays. The suppressive effects of carvacrol on osteosarcoma in vivo were examined by a xenograft animal model, immunohistochemistry and HE staining. Results: We demonstrated that carvacrol treatment reduced viability and inhibited the colony formation of U2OS and 143B cells in a concentration-dependent manner. Apoptotic cell number increased after exposure to carvacrol. Meanwhile, the expression of Bax increased, and that of Bcl-2 decreased by carvacrol treatment. In addition, the MMP-9 expression and migration and invasion of 143B and U2OS cells were inhibited by carvacrol. We also found that these carvacrol-induced effects on osteosarcoma are associated with the regulation of the Wnt/β-catenin signaling pathway. Conclusion: Our findings suggest that carvacrol suppresses proliferation, migration, invasion and promotes apoptosis in osteosarcoma cells, in part by regulating the Wnt/β-catenin signaling pathway.

2021 ◽  
pp. 1-8
Guo Dai ◽  
Di Zheng ◽  
Gaiwei Liu ◽  
Qi Song

This study aimed to investigate the effectiveness of anticancer therapy combining a cytotoxic chemotherapeutic agent, cisplatin (DDP), and a vascular disruptive drug, combretastatin A4 phosphate (CA4P), in osteosarcoma. First, a human osteosarcoma-xenografted mice model was established. Second, the transplanted tumor models were treated with DDP and CA4P in combination or as monotherapy. Third, the therapeutic effects and the mechanism of the drug combination in the inhibition of transplanted tumors was studied. Finally, the toxic effects of the drugs were observed and recorded. The results showed that DDP combined with CA4P significantly inhibited the growth and lung metastasis of transplanted tumors compared with the monotherapy drug group and vehicle control group. Histopathological analysis revealed that apoptotic and necrotic cell death significantly increased in the combination group, and combined treatment significantly inhibited the proliferation of osteosarcoma cells compared with either agent alone or the vehicle control. Additionally, no obvious toxic effects were observed in the combination group. These results indicate that the combined effects of DDP and CA4P on the progression of human osteosarcoma in vivo were superior to that of either agent alone. DDP combined with CA4P exerted synergistic effects at lower concentrations and promoted apoptosis and necrosis, as well as inhibited proliferation of osteosarcoma cells, but it did not increase the systemic toxic effects of chemotherapy. Our findings highlight CA4P as an effective anticancer agent candidate for combination with DDP in clinical applications to treat osteosarcoma.

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4199
Haydee M. Torres ◽  
Ashley M. VanCleave ◽  
Mykayla Vollmer ◽  
Dakota L. Callahan ◽  
Austyn Smithback ◽  

Dysregulation of histone deacetylases (HDACs) is associated with the pathogenesis of human osteosarcoma, which may present an epigenetic vulnerability as well as a therapeutic target. Domatinostat (4SC-202) is a next-generation class I HDAC inhibitor that is currently being used in clinical research for certain cancers, but its impact on human osteosarcoma has yet to be explored. In this study, we report that 4SC-202 inhibits osteosarcoma cell growth in vitro and in vivo. By analyzing cell function in vitro, we show that the anti-tumor effect of 4SC-202 involves the combined induction of cell-cycle arrest at the G2/M phase and apoptotic program, as well as a reduction in cell invasion and migration capabilities. We also found that 4SC-202 has little capacity to promote osteogenic differentiation. Remarkably, 4SC-202 revised the global transcriptome and induced distinct signatures of gene expression in vitro. Moreover, 4SC-202 decreased tumor growth of established human tumor xenografts in immunodeficient mice in vivo. We further reveal key targets regulated by 4SC-202 that contribute to tumor cell growth and survival, and canonical signaling pathways associated with progression and metastasis of osteosarcoma. Our study suggests that 4SC-202 may be exploited as a valuable drug to promote more effective treatment of patients with osteosarcoma and provide molecular insights into the mechanism of action of class I HDAC inhibitors.

Khaliunsarnai Tsogtbaatar ◽  
Diana A. Sousa ◽  
Debora Ferreira ◽  
Atakan Tevlek ◽  
Halil Murat Aydın ◽  

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