Adjuvant Biophysical Therapies in Osteosarcoma

Carina, Valeria; Costa, Viviana; Sartori, Maria; Bellavia, Daniele; Luca, Angela De; Raimondi, Lavinia; Fini, Milena; Giavaresi, G.

doi:10.3390/cancers11030348

Cited by 51 publications

(34 citation statements)

References 160 publications

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“…Current standard management of osteosarcoma consists in multi-modal treatment including surgery, multi-agent chemotherapy (including doxorubicin (DOX)) and radiotherapy, yielding to 60% of the 5-year survival rate, while less than 20% of patients with metastatic disease or relapsed osteosarcoma reach a long-term survival [ 2 , 3 ]. However, none of these conventional treatments are effective in combating the tumor progression, and continuing high rates of limb amputation, pulmonary metastasis and normal tissue toxicity remain unresolved issues [ 4 ]. Thus, new effective and safe strategies, in particular targeted therapies, are clearly required [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Internalization of Nanoparticles Following Ionizing Radiation Leads to Mitotic Catastrophe in MG-63 Human Osteosarcoma Cells

Popescu

Straticiuc

Mustăciosu

et al. 2020

IJMS

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This study aims to investigate whether ionizing radiation combined with doxorubicin-conjugated iron oxide nanoparticles (NP-DOX) improves the internalization and cytotoxic effects of the nano-carrier-mediated drug delivery in MG-63 human osteosarcoma cells. NP-DOX was designed and synthesized using the co-precipitation method. Highly stable and crystalline nanoparticles conjugated with DOX were internalized in MG-63 cells through macropinocytosis and located in the perinuclear area. Higher nanoparticles internalization in MG-63 cells previously exposed to 1 Gy X-rays was correlated with an early accumulation of cells in G2/M, starting at 12 h after treatment. After 48 h, the application of the combined treatment led to higher cytotoxic effects compared to the individual treatment, with a reduction in the metabolic capacity and unrepaired DNA breaks, whilst a low percent of arrested cells, contributing to the commitment of mitotic catastrophe. NP-DOX showed hemocompatibility and no systemic cytotoxicity, nor histopathological alteration of the main organs.

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Section: Introductionmentioning

confidence: 99%

“…However, none of these conventional treatments are effective in combating the tumor progression, and continuing high rates of limb amputation, pulmonary metastasis and normal tissue toxicity remain unresolved issues [ 4 ]. Thus, new effective and safe strategies, in particular targeted therapies, are clearly required [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Internalization of Nanoparticles Following Ionizing Radiation Leads to Mitotic Catastrophe in MG-63 Human Osteosarcoma Cells

Popescu

Straticiuc

Mustăciosu

et al. 2020

IJMS

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“…In vivo the effectiveness of PDT has been demonstrated in OS animal models [34,67,68]. Moreover, PDT has been previously successfully used to treat sarcomas in a group of patients in which PDT inhibits the local recurrence after intralesional tumor resection [38,[69][70][71].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells mediated delivery of photoactive nanoparticles inhibits osteosarcoma growth in vitro and in a murine in vivo ectopic model

Lenna

Bellotti

Duchi

et al. 2020

J Exp Clin Cancer Res

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Background: Osteosarcoma (OS) is an aggressive malignant neoplasm that still suffers from poor prognosis in the case of distal metastases or occurrence of multi-drug resistance. It is therefore crucial to find novel therapeutic options able to go beyond these limitations and improve patients' survival. The objective of this study is to exploit the intrinsic properties of mesenchymal stromal cells (MSCs) to migrate and infiltrate the tumor stroma to specifically deliver therapeutic agents directly to cancer cells. In particular, we aimed to test the efficacy of the photoactivation of MSCs loaded with nanoparticles in vitro and in a murine in vivo ectopic osteosarcoma model. Methods: AlPcS 4 @FNPs were produced by adding tetra-sulfonated aluminum phthalocyanine (AlPcS 4) to an aqueous solution of positively charged poly-methyl methacrylate core-shell fluorescent nanoparticles (FNPs). The photodynamic therapy (PDT) effect is achieved by activation of the photosensitizer AlPcS 4 in the near-infrared light with an LED source. Human MSCs were isolated from the bone marrow of five donors to account for inter-patients variability and used in this study after being evaluated for their clonogenicity, multipotency and immunophenotypic profile. MSC lines were then tested for the ability to internalize and retain the nanoparticles, along with their migratory properties in vitro. Photoactivation effect was evaluated both in a monolayer (2D) co-culture of AlPcS 4 @FNPs loaded MSCs with human OS cells (SaOS-2) and in tridimensional (3D) multicellular spheroids (AlPcS 4 @FNPs loaded MSCs with human OS cells, MG-63). Cell death was assessed by AnnexinV/PI and Live&Dead CalceinAM/EthD staining in 2D, while in the 3D co-culture, the cell killing effect was measured through ATP content, CalceinAM/EthD staining and TEM imaging. We also evaluated the effectiveness of AlPcS 4 @FNPs loaded MSCs as delivery systems and the ability of the photodynamic treatment to kill cancer cells in a subcutaneous mouse model of OS by bioluminescence imaging (BLI) and histology. Results: MSCs internalized AlPcS 4 @FNPs without losing or altering their motility and viability in vitro. Photoactivation of AlPcS 4 @FNPs loaded MSCs induced high level of OS cells death in the 2D co-culture. Similarly, in the 3D co-culture (MSCs:OS ratios 1:1 or 1:3), a substantial decrease of both MSCs and OS cells viability was observed. Notably, when increasing the MSCs:OS ratio to 1:7, photoactivation still caused more than 40% cells death. When tested in an in vivo ectopic OS model, AlPcS4@FNPs loaded MSCs were able to decrease OS growth by 68% after two cycles of photoactivation.

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“…to a combination of surgery and adjuvant chemotherapy (6). However, the overall survival rate of patients with OS remains unsatisfactory, with ~50% developing fatal lung metastases in the advanced stages of disease (7).…”

Section: Metastasis-associated Gene Mapk15 Promotes the Migration Andmentioning

confidence: 99%

Metastasis‑associated gene MAPK15 promotes the migration and invasion of osteosarcoma cells via the c‑Jun/MMPs pathway

Yang

Zeng

et al. 2020

Oncol Lett

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Osteosarcoma (OS) is the most common and destructive primary bone malignancy to affect children and adolescents. Metastases remain the primary cause of death in patients with OS. In the present study, weight gene co-expressed network analysis (WGCNA) and differentially-expressed gene analysis were used to identify key genes associated with the metastasis of OS. Reverse transcription-quantitative PCR and immunohistochemical staining were then used to detect the expression levels of these key genes in OS tissues, and to determine the hub genes of interest. Wound-healing and transwell assays, in addition to a lung metastasis model, were used to detect the effects of the hub genes on OS cell proliferation and metastasis in vitro and in vivo. Using WGCNA and differential expression analysis, deleted in lung and esophageal cancer protein 1 (DLEC1), Forkhead box J1 (FOXJ1) and mitogen-activated protein kinase 15 (MAPK15) were predicted to be key metastasis-associated genes, and highly expressed in metastatic OS tissues; among them, the protein and mRNA expression levels of MAPK15 were most significantly increased in our OS tissues from patients who exhibited metastases at diagnosis, and thus MAPK15 was determined to be a metastasis-associated hub gene to further study. Furthermore, inhibiting MAPK15 expression significantly decreased OS cell metastasis in vitro and in vivo, as well as suppressing c-Jun/matrix metalloproteinase (MMP)-associated pathways. Overexpression of MAPK15 activated the c-Jun/MMPs pathway and promoted OS cell metastasis, while inhibition of c-Jun blocked this effect. Taken together, MAPK15 was indicated to be an OS metastasis-associated gene, and was confirmed to promote the migration and invasion of OS cells via the c-Jun/MMP pathway. MAPK15 may therefore be an effective target for the treatment of OS.

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Adjuvant Biophysical Therapies in Osteosarcoma

Cited by 51 publications

References 160 publications

Enhanced Internalization of Nanoparticles Following Ionizing Radiation Leads to Mitotic Catastrophe in MG-63 Human Osteosarcoma Cells

Enhanced Internalization of Nanoparticles Following Ionizing Radiation Leads to Mitotic Catastrophe in MG-63 Human Osteosarcoma Cells

Mesenchymal stromal cells mediated delivery of photoactive nanoparticles inhibits osteosarcoma growth in vitro and in a murine in vivo ectopic model

Metastasis‑associated gene MAPK15 promotes the migration and invasion of osteosarcoma cells via the c‑Jun/MMPs pathway

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