Osteosarcomas: Treatment Strategies

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 22368

Special Issue Editor

Special Issue Information

Dear Colleagues,

Osteosarcoma, also known as bone tumor, generally affects children and adolescents. According to the latest cancer statistics, osteosarcoma was ranked as having the lowest five-year relative survival rate among the most common childhood and adolescent cancers in the United Sates. Since modern therapeutic methods have developed rapidly, the outcome for patients with osteosarcoma has improved. Typical treatments for osteosarcoma include surgery and intensive chemotherapy. However, with respect to recurrent and metastatic osteosarcoma, existing treatments, including surgery and chemotherapy, exhibit a limited therapeutic effect. Therefore, it is necessary to develop new therapeutic strategies to treat osteosarcoma. 

Pharmaceuticals invites both original research articles and reviews shedding light on recent challenges in developing therapeutic strategies for the treatment of osteosarcoma. Topics of interest include drug development, drug repositioning, selective optimization of the lead compound, and drug combinations. The collection of manuscripts will be published as a Special Issue of the journal.

Dr. See-Hyoung Park
Guest Editor

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Keywords

  • osteosarcoma
  • anti-cancer
  • apoptosis
  • natural compounds
  • target
  • drug

Published Papers (9 papers)

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Editorial

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3 pages, 197 KiB  
Editorial
Special Issue “Osteosarcomas: Treatment Strategies”
by See-Hyoung Park
Pharmaceuticals 2023, 16(9), 1233; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16091233 - 31 Aug 2023
Viewed by 605
Abstract
This Special Issue, titled “Osteosarcomas: Treatment Strategies”, aims to overview the recent and future research trends related to the treatment of osteosarcoma [...] Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)

Research

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20 pages, 4908 KiB  
Article
Multiple Effects of Resveratrol on Osteosarcoma Cell Lines
by Angela De Luca, Daniele Bellavia, Lavinia Raimondi, Valeria Carina, Viviana Costa, Milena Fini and Gianluca Giavaresi
Pharmaceuticals 2022, 15(3), 342; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030342 - 11 Mar 2022
Cited by 16 | Viewed by 2622
Abstract
Osteosarcoma (OS) is the most common primary bone sarcoma affecting the life of pediatric patients. The clinical treatment faces numerous difficulties, including the adverse effects of chemotherapies, chemoresistance, and recurrences. In this study, the effects of resveratrol (RSV), a natural polyphenol, on OS [...] Read more.
Osteosarcoma (OS) is the most common primary bone sarcoma affecting the life of pediatric patients. The clinical treatment faces numerous difficulties, including the adverse effects of chemotherapies, chemoresistance, and recurrences. In this study, the effects of resveratrol (RSV), a natural polyphenol, on OS cell lines were investigated to evaluate its action as an adjuvant therapy to the current chemotherapy regimens. RSV exhibited multiple tumor-suppressing activities on OS cell lines, inducing a series of critical events. We found (1) a cell growth inhibition due to an increase in cell distress, which was, in part, due to the involvement of the AKT and caspase-3 pathways, (2) an increase in cellular differentiation due to major gene expression levels of the osteoblastic differentiation genes, (3) an inhibition of IL-6 secretion due to an epigenetic effect on the IL-6 promoter, and (4) an inhibition of OS cells migration related to the decrease in IL-8 secretion levels due to an epigenetic effect on its promoter. Finally, the cotreatment of RSV with doxorubicin and cisplatin increased their cytotoxic effect on OS cells. Although further investigations are mandatory, it seems RSV might be a promising therapeutic adjuvant agent for OS cell treatment, exerting an antitumor effect when combined with chemotherapy. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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11 pages, 2582 KiB  
Article
Radioimmunotherapy Targeting IGF2R on Canine-Patient-Derived Osteosarcoma Tumors in Mice and Radiation Dosimetry in Canine and Pediatric Models
by Jaline Broqueza, Chandra B. Prabaharan, Kevin J. H. Allen, Rubin Jiao, Darrell R. Fisher, Ryan Dickinson, Valerie MacDonald-Dickinson, Maruti Uppalapati and Ekaterina Dadachova
Pharmaceuticals 2022, 15(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010010 - 22 Dec 2021
Cited by 6 | Viewed by 2409
Abstract
Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to [...] Read more.
Background: Osteosarcoma (OS) has an overall patient survival rate of ~70% with no significant improvements in the last two decades, and novel effective treatments are needed. OS in companion dogs is phenotypically close to human OS, which makes a comparative oncology approach to developing new treatments for OS very attractive. We have recently created a novel human antibody, IF3 to IGF2R, which binds to this receptor on both human and canine OS tumors. Here, we evaluated the efficacy and safety of radioimmunotherapy with 177Lu-labeled IF3 of mice bearing canine-patient-derived tumors and performed canine and human dosimetry calculations. Methods: Biodistribution and microSPECT/CT imaging with 111In-IF3 was performed in mice bearing canine OS Gracie tumors, and canine and human dosimetry calculations were performed based on these results. RIT of Gracie-tumor-bearing mice was completed with 177Lu-IF3. Results: Biodistribution and imaging showed a high uptake of 111In-IF3 in the tumor and spleen. Dosimetry identified the tumor, spleen and pancreas as the organs with the highest uptake. RIT was very effective in abrogating tumor growth in mice with some spleen-associated toxicity. Conclusions: These results demonstrate that RIT with 177Lu-IF3 targeting IGF2R on experimental canine OS tumors effectively decreases tumor growth. However, because of the limitations of murine models, careful evaluation of the possible toxicity of this treatment should be performed via nuclear imaging and image-based dosimetry in healthy dogs before clinical trials in companion dogs with OS can be attempted. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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10 pages, 1485 KiB  
Article
Assessing a Novel 3D Assay System for Drug Screening against OS Metastasis
by Natalie Koons, Nicole Amato, Scott Sauer, David Warshawsky, Dalit Barkan and Chand Khanna
Pharmaceuticals 2021, 14(10), 971; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100971 - 25 Sep 2021
Cited by 4 | Viewed by 2240
Abstract
Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed [...] Read more.
Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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23 pages, 4172 KiB  
Article
Anti-Metastatic and Anti-Angiogenic Effects of Curcumin Analog DK1 on Human Osteosarcoma Cells In Vitro
by Muhammad Nazirul Mubin Aziz, Nurul Fattin Che Rahim, Yazmin Hussin, Swee Keong Yeap, Mas Jaffri Masarudin, Nurul Elyani Mohamad, Muhammad Nadeem Akhtar, Mohd Azuraidi Osman, Yoke Kqueen Cheah and Noorjahan Banu Alitheen
Pharmaceuticals 2021, 14(6), 532; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060532 - 03 Jun 2021
Cited by 12 | Viewed by 3113
Abstract
Osteosarcoma (OS) is a life-threatening malignant bone tumor associated with poor prognosis among children. The survival rate of the patient is still arguably low even with intensive treatment provided, plus with the inherent side effects from the chemotherapy, which gives more unfavorable outcomes. [...] Read more.
Osteosarcoma (OS) is a life-threatening malignant bone tumor associated with poor prognosis among children. The survival rate of the patient is still arguably low even with intensive treatment provided, plus with the inherent side effects from the chemotherapy, which gives more unfavorable outcomes. Hence, the search for potent anti-osteosarcoma agent with promising safety profile is still on going. Natural occurring substance like curcumin has gained a lot of attention due to its splendid safety profile as well as it pharmacological advantages such as anti-metastasis and anti-angiogenesis. However, natural curcumin was widely known for its poor cellular uptake, which undermines all potential that it possesses. This prompted the development of synthetically synthesized curcuminoid analog, known as (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2- en-1-one (DK1). In this present study, in vitro scratch assay, transwell migration/invasion assay, HUVEC tube formation assay, and ex vivo rat aortic ring assays were performed in order to investigate the anti-metastatic and anti-angiogenic potential of DK1. For further comprehension of DK1 mechanism on human osteosarcoma cell lines, microarray gene expression analysis, quantitative polymerase chain reaction (qPCR), and proteome profiler were adopted, providing valuable forecast from the expression of important genes and proteins related to metastasis and angiogenesis. Based on the data gathered from the bioassays, DK1 was able to inhibit the metastasis and angiogenesis of human osteosarcoma cell lines by significantly reducing the cell motility, number of migrated and invaded cells as well as the tube formation and micro-vessels sprouting. Additionally, DK1 also has significantly regulated several cancer pathways involved in OS proliferation, metastasis, and angiogenesis such as PI3K/Akt and NF-κB in both U-2 OS and MG-63. Regulation of PI3K/Akt caused up-regulation of genes related to metastasis inhibition, namely, PTEN, FOXO, PLK3, and GADD45A. Meanwhile, NF-κB pathway was regulated by mitigating the expression of NF-κB activator such as IKBKB and IKBKE in MG-63, whilst up-regulating the expression of NF-κB inhibitors such as NFKBIA and NFKBIE in U-2 OS. Finally, DK1 also has successfully hindered the metastatic and angiogenic capability of OS cell lines by down-regulating the expression of pro-metastatic genes and proteins like MMP3, COL11A1, FGF1, Endoglin, uPA, and IGFBP2 in U-2 OS. Whilst for MG-63, the significantly down-regulated oncogenes were Serpin E1, AKT2, VEGF, uPA, PD-ECGF, and Endoglin. These results suggest that curcumin analog DK1 may serve as a potential new anti-osteosarcoma agent due to its anti-metastatic and anti-angiogenic attributes. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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16 pages, 8720 KiB  
Article
GO-Y078, a Curcumin Analog, Induces Both Apoptotic Pathways in Human Osteosarcoma Cells via Activation of JNK and p38 Signaling
by Peace Wun-Ang Lu, Renn-Chia Lin, Jia-Sin Yang, Eric Wun-Hao Lu, Yi-Hsien Hsieh, Meng-Ying Tsai, Ko-Hsiu Lu and Shun-Fa Yang
Pharmaceuticals 2021, 14(6), 497; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060497 - 24 May 2021
Cited by 15 | Viewed by 2361
Abstract
Osteosarcoma is the most common primary bone malignancy in teenagers and continues to confer a generally poor prognosis due to its highly metastatic potential. Poor solubility in water and instability of curcumin limits its bioavailability for use in the adjuvant situation to improve [...] Read more.
Osteosarcoma is the most common primary bone malignancy in teenagers and continues to confer a generally poor prognosis due to its highly metastatic potential. Poor solubility in water and instability of curcumin limits its bioavailability for use in the adjuvant situation to improve the prognosis and the long-term survival of patients with osteosarcoma. To further obtain information regarding the apoptosis induced by a new curcumin analog, GO-Y078, in human osteosarcoma cells, flow cytometric analysis, annexin V-FITC/PI apoptosis staining assay, human apoptosis array, and Western blotting were employed. GO-Y078 dose-dependently decreased viabilities of human osteosarcoma U2OS, MG-63, 143B, and Saos-2 cells and induced sub-G1 fraction arrest and apoptosis in U2OS and 143B cells. In addition to the effector caspase 3 and poly adenosine diphosphate-ribose polymerase, GO-Y078 significantly activated both initiators of extrinsic caspase 8 and intrinsic caspase 9, whereas cellular inhibitors of apoptosis 1 (cIAP-1) and X-chromosome-linked IAP (XIAP) in U2OS and 143B cells were significantly repressed. Moreover, GO-Y078 increased phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2, and p38 in U2OS and 143B cells. Using inhibitors of JNK (JNK-in-8) and p38 (SB203580), GO-Y078′s increases in cleaved caspases 8, 9, and 3 could be expectedly suppressed, but they could not be affected by co-treatment with the ERK inhibitor (U0126). Altogether, GO-Y078 simultaneously induces both apoptotic pathways and cell arrest in U2OS and 143B cells through activating JNK and p38 signaling and repressing IAPs. These findings contribute to a better understanding of the mechanisms responsible for GO-Y078′s apoptotic effects on human osteosarcoma cells. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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19 pages, 2864 KiB  
Article
ICG-001, an Inhibitor of the β-Catenin and cAMP Response Element-Binding Protein Dependent Gene Transcription, Decreases Proliferation but Enhances Migration of Osteosarcoma Cells
by Geoffroy Danieau, Sarah Morice, Sarah Renault, Régis Brion, Kevin Biteau, Jérôme Amiaud, Marie Cadé, Dominique Heymann, Frédéric Lézot, Franck Verrecchia, Françoise Rédini and Bénédicte Brounais-Le Royer
Pharmaceuticals 2021, 14(5), 421; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050421 - 01 May 2021
Cited by 7 | Viewed by 2670
Abstract
High-grade osteosarcomas are the most frequent malignant bone tumors in the pediatric population, with 150 patients diagnosed every year in France. Osteosarcomas are associated with low survival rates for high risk patients (metastatic and relapsed diseases). Knowing that the canonical Wnt signaling pathway [...] Read more.
High-grade osteosarcomas are the most frequent malignant bone tumors in the pediatric population, with 150 patients diagnosed every year in France. Osteosarcomas are associated with low survival rates for high risk patients (metastatic and relapsed diseases). Knowing that the canonical Wnt signaling pathway (Wnt/β-catenin) plays a complex but a key role in primary and metastatic development of osteosarcoma, the aim of this work was to analyze the effects of ICG-001, a CBP/β-catenin inhibitor blocking the β-catenin dependent gene transcription, in three human osteosarcoma cell lines (KHOS, MG63 and 143B). The cell proliferation and migration were first evaluated in vitro after ICG-001 treatment. Secondly, a mouse model of osteosarcoma was used to establish the in vivo biological effect of ICG-001 on osteosarcoma growth and metastatic dissemination. In vitro, ICG-001 treatment strongly inhibits osteosarcoma cell proliferation through a cell cycle blockade in the G0/G1 phase, but surprisingly, increases cell migration of the three cell lines. Moreover, ICG-001 does not modulate tumor growth in the osteosarcoma mouse model but, rather significantly increases the metastatic dissemination to lungs. Taken together, these results highlight, despite an anti-proliferative effect, a deleterious pro-migratory role of ICG-001 in osteosarcoma. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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14 pages, 4629 KiB  
Article
Potential Antimetastatic Effect of Timosaponin AIII against Human Osteosarcoma Cells through Regulating the Integrin/FAK/Cofilin Axis
by Yi-Hsien Hsieh, Wen-Hung Hsu, Shun-Fa Yang, Chung-Jung Liu, Ko-Hsiu Lu, Pei-Han Wang and Renn-Chia Lin
Pharmaceuticals 2021, 14(3), 260; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030260 - 14 Mar 2021
Cited by 12 | Viewed by 2080
Abstract
Timosaponin AIII (TSAIII) is a steroidal saponin which demonstrates anti-tumour activities. However, the effect of TSAIII on human osteosarcoma cells remains largely unknown. In this study, we demonstrated that TSAIII exerted a significant inhibitory effect on the distribution of cytoskeletal F-actin and cytoskeletal-related [...] Read more.
Timosaponin AIII (TSAIII) is a steroidal saponin which demonstrates anti-tumour activities. However, the effect of TSAIII on human osteosarcoma cells remains largely unknown. In this study, we demonstrated that TSAIII exerted a significant inhibitory effect on the distribution of cytoskeletal F-actin and cytoskeletal-related proteins, which contributed to the suppression of cell migration and invasion, without inhibiting cell growth or apoptosis. In the synergistic inhibitory analysis, cotreatment of TSAIII with αVβ3 integrin inhibitor [Cyclo(RGDyK)] or focal adhesion kinase (FAK) inhibitor (PF-573228) exerted greater synergistic inhibitory effects on the expression of Intergin αVβ3/FAK/cofilin axis, thus inhibiting the migration and invasion capacities of human osteosarcoma cells. TSAIII was demonstrated to significantly inhibit the pulmonary metastasis formation of human osteosarcoma cells in vivo in metastasis animal models. These findings reveal the inhibitory effects of TSAIII on the metastasis progression of human osteosarcoma cells and the regulation of integrin-αVβ3-FAK-Src and TESK1/p-cofilin mediated cytoskeletal F-actin pathway. Therefore, TSAIII might represent a novel strategy for the auxiliary treatment of human osteosarcoma cells. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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Review

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19 pages, 1129 KiB  
Review
Osteosarcoma in Children: Not Only Chemotherapy
by Maura Argenziano, Chiara Tortora, Elvira Pota, Alessandra Di Paola, Martina Di Martino, Caterina Di Leva, Daniela Di Pinto and Francesca Rossi
Pharmaceuticals 2021, 14(9), 923; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090923 - 13 Sep 2021
Cited by 15 | Viewed by 2945
Abstract
Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with [...] Read more.
Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with localized OS, while it remains at 20% in case of metastases. The standard therapy for OS patients is represented by neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. The most used chemotherapy regimen for children is the combination of high-dose methotrexate, doxorubicin, and cisplatin. Considered that the necessary administration of high-dose chemotherapy is responsible for a lot of acute and chronic side effects, the identification of novel therapeutic strategies to ameliorate OS outcome and the patients’ life expectancy is necessary. In this review we provide an overview on new possible innovative therapeutic strategies in OS. Full article
(This article belongs to the Special Issue Osteosarcomas: Treatment Strategies)
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