Search Results (171)

High-grade osteosarcoma (HGOS) is the most common primary malignant bone tumor in children and adolescents. Poor response to chemotherapy is linked to worse prognosis and increased risk of recurrence and metastasis. However, current assessment methods, such as tumor necrosis evaluation, are time-consuming and delay treatment decisions. Thus, identifying molecular pathways and predictive biomarkers is essential for guiding early therapeutic strategies. In this study, RNA-seq analysis of HGOS tissues revealed enrichment of cholesterol biosynthesis and mitotic pathways in poor responders. Additionally, high HMGCR expression, as analyzed from TCGA data, was associated with poor prognosis in sarcoma. Functional validation using SaOS-2 cells, which exhibited poor drug sensitivity and elevated HMGCR levels, demonstrated that simvastatin enhanced the efficacy of cisplatin and doxorubicin by inducing mitochondrial-mediated apoptosis and downregulating anti-apoptotic proteins. Simvastatin also reduced cell migration and invasion by suppressing epithelial–mesenchymal transition and extracellular matrix degradation. Mechanistically, simvastatin disrupted Ras prenylation and inhibited downstream oncogenic signaling pathways, including Akt/mTOR and Akt/GSK3, which regulate survival and metastasis-associated gene expression. These findings suggest that the cholesterol biosynthesis pathway particularly plays a critical role in chemoresistance and metastasis in HGOS and may serve as a promising predictive molecular target for guiding early therapeutic strategies. Full article

Osteosarcoma (OSA) is the most common primary bone malignancy in dogs, characterized by aggressive growth and high metastatic potential. Despite advances in treatment, the prognosis for affected animals remains poor, mainly due to metastatic disease. Metastasis is a complex process that involves forming new blood vessels in the primary tumor (angiogenesis), intravasation, the transport of cancer cells to other locations, extravasation, and the growth of cancer cells in the secondary site. Gold nanoparticles (AuNPs), due to their unique physicochemical properties, are considered promising tools in cancer therapy, both as drug delivery systems and potential anti-metastatic agents. Previously, it has been demonstrated that 500 µg/mL glutathione-stabilized gold nanoparticles (Au-GSH NPs) inhibit cancer cell extravasation—one of the steps of the metastatic cascade. This study aimed to evaluate the anti-metastatic properties of Au-GSH NPs through their influence on OSA cell migration, proliferation, and colony formation in vitro, as well as their antiangiogenic properties on the chick embryo chorioallantoic (CAM) model. Additionally, we investigated whether these effects are associated with changes in alpha-2-macroglobulin (A2M) expression, as it was previously demonstrated to play an essential role in the metastatic cascade. Au-GSH NPs significantly inhibited migration and colony formation in canine osteosarcoma cells (from OSCA-8, OSCA-32, and D-17 cell lines) at 200 µg/mL concentrations. Interestingly, at 500 µg/mL, Au-GSH NPs inhibited angiogenesis on the CAM model and cancer cell migration, but fewer colonies were formed. These results may be directly related to the higher efficiency of Au-GSH NPs uptake by OSA cells at the dose of 200 μg/mL than at the dose of 500 μg/mL, as demonstrated using Microwave Plasma Atomic Emission Spectroscopy (MP-AES). Moreover, this is the first study that demonstrates a significant increase in A2M expression in cancer cells after Au-GSH NPs treatment. This study provides new insight into the potential use of Au-GSH NPs as anti-metastatic agents in canine osteosarcoma, indicating that their anti-metastatic properties may be related to A2M. However, further in vitro and in vivo studies are needed to explore the molecular mechanism underlying these effects and to evaluate the clinical relevance of AuNPs in veterinary oncology. Full article

Ginseng phytochemicals have attracted considerable attention for their potential therapeutic applications in bone-related diseases including osteosarcoma, osteoporosis, and osteoarthritis. Recent research has highlighted the promising effects of ginsenosides and polysaccharides from ginseng by studying multi-target effects and combination therapies in osteosarcoma progression. Beyond osteosarcoma, ginseng phytochemicals have been explored for their effects on osteoporosis. Various ginsenosides and ginseng extract were shown to regulate signaling pathways involved in activating osteoblast and inhibiting osteoclast in vitro and in vivo models. Ginseng ginsenosides have also demonstrated potential anti-osteoarthritic properties. Recent studies discussed how ginsenoside reduced inflammation and cartilage degradation as a therapeutic candidate for osteoarthritis management. In this review, we examine the anti-osteosarcoma, anti-osteoporotic, and anti-osteoarthritic activities of ginseng-derived phytochemicals reported in studies published between 2014 and 2024. This review also provides a comprehensive overview of the working mechanisms of these compounds in various model systems. Furthermore, we address the limitations of current research approaches and outline future directions to maximize the therapeutic application of ginseng phytochemicals in the management of bone-related diseases. Full article

Background: Osteosarcoma (OS) is a highly aggressive bone malignancy with limited treatment options and poor prognosis. This exploratory study aimed to identify molecular subtypes of early-stage, treatment-naive OS to guide precise therapeutic strategies. Methods: We analyzed RNA-seq data obtained from tumor tissues from 102 OS patients using a non-negative matrix factorization algorithm (NMF) to classify the tumors into three subtypes: S1, S2, and S3. Differential gene expression was evaluated using DESeq2, followed by functional enrichment analysis with clusterProfiler and CancerHallmarks. The tumor microenvironment was assessed through ESTIMATE and CIBERSORT, and drug sensitivity was predicted using OncoPredict. SAOS-2 and MG63 cells, representing the S1 subtype, were used in the viability essays to determine the effect of hesperidin, a natural phenolic compound noted for its anti-cancer potential, alone and in combination with doxorubicin and 5-fluorouracil. Results: This study revealed three OS subtypes: S1 was enriched in cell cycle regulation, vesicular transport, and RNA metabolism while S2 and S3 were enriched in pathways related to extracellular matrix organization and protein translation, respectively. S1 displayed high tumor purity, significant chemoresistance, and overexpression of KIF20 A, correlating with poor prognosis. AURKB, a hesperidin target, was implicated in S1 pathogenesis. In vitro, hesperidin significantly reduced the viability of SAOS-2 and MG63 cells and enhanced doxorubicin efficacy. Conclusions: Our findings support the molecular subclassification of OS, emphasizing subtype-specific mechanisms of tumor progression and chemoresistance, with hesperidin offering potential as a therapeutic adjunct for high-risk OS patients. Full article

Systemic chemotherapy is still the first-line treatment for cancer, and it’s associated with toxic side effects, chemoresistance, and ultimately cancer recurrence. Rapid gelling hydrogels can overcome this limitation by providing localized delivery of anti-cancer agents to solid tumors. Silk hydrogels are extremely biocompatible and suitable for anti-cancer drug delivery, but faster gelling formulations are needed. In this study, we introduce a rapid gelling hydrogel formulation (<3 min gelling time) due to chemical crosslinking between silk fibroin and curcumin, initiated by the addition of minute quantities of horseradish peroxidase (HRP) and hydrogen peroxide (H₂O₂). The novel observation in this study is that curcumin, while being a free-radical scavenger, also participates in accelerating silk di-tyrosine crosslinking in the presence of HRP and H₂O₂. Using UV-Vis, rheology, and time-lapse videos, we convincingly show that curcumin accelerates silk di-tyrosine crosslinking reaction in a concentration-dependent manner, and curcumin remains entrapped in the hydrogel post-crosslinking. FTIR results show an increase in secondary beta-sheet structures within hydrogels, with increasing concentrations of curcumin. Furthermore, we show that curcumin-silk di-tyrosine hydrogels are toxic to U2OS osteosarcoma cells, and most cancer cells are dead within short time scales of 4 h post-encapsulation. Full article

Osteosarcoma is a highly aggressive bone malignancy, particularly challenging in metastatic cases, with a 5-year survival rate remaining under 30%. Although doxorubicin (doxo) is a standard first-line chemotherapeutic agent, its clinical utility is often hindered by the development of drug resistance and associated systemic toxicity. Emerging evidence highlights the role of epigenetic alterations, particularly those involving histone deacetylases (HDACs), in promoting chemoresistance. In this context, the present study aimed to evaluate the therapeutic potential of combining doxo with the selective HDAC inhibitors, tasquinimod (Tas, targeting HDAC4) and PCI-34051 (PCI, targeting HDAC8), in SJSA-1 osteosarcoma cells. Utilizing both 2D and 3D in vitro models, the combination treatment (referred to as the T4 group) significantly reduced cell viability by 57.69% in 2D cultures and decreased spheroid volume by 35.19% in 3D models. The apoptotic response was markedly enhanced, with late apoptosis reaching 64.59% and necrosis at 32.07%, both surpassing the effects observed with doxo alone. Furthermore, wound healing assays demonstrated a 37.74% inhibition of migration, accompanied by a decreased expression of the matrix metalloproteinases MMP9 and MMP13. Mechanistically, the combination therapy led to the downregulation of protein kinase B (pAKT) and RUNX2, along with upregulation of apoptotic markers, including caspase 8, caspase 3, and cleaved caspase 3, indicating a disruption of key survival pathways. These findings suggest that dual HDAC inhibition with Tas and PCI can potentiate doxo efficacy by enhancing apoptosis, inhibiting proliferation, and reducing metastatic potential, thus offering a promising strategy to overcome chemoresistance in osteosarcoma. Further preclinical and clinical studies are required to validate these therapeutic benefits. Full article

Background: Angiogenesis, the process of new blood vessel formation, is critically regulated by a balance of pro- and anti-angiogenic factors. This process plays a central role in tumor progression and is modulated by tumor cells. Sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule acting via G-protein-coupled receptors (S1PR1–5), has emerged as a key mediator of vascular development and pathological angiogenesis in cancer. Consequently, targeting the S1P-S1PRs axis represents a promising strategy for antiangiogenic therapies. This study explores S1PR3 as a potential therapeutic target in osteosarcoma, the most common primary bone malignancy, which we have previously demonstrated to secrete S1P within the acidic tumor microenvironment. Methods: The effects of KRX-725-II and its derivatives, Tic-4-KRX-725-II and [D-Tic]4-KRX-725-II—pepducins acting as S1PR3 antagonists as allosteric modulators of GPCR activity—were tested on metastatic osteosarcoma cells (143B) for proliferation and migration inhibition. Anti-angiogenic activity was assessed using endothelial cells (HUVEC) through proliferation and tubulogenesis assays in 2D, alongside sprouting and migration analyses in a 3D passively perfused microfluidic chip. Results: S1PR3 inhibition did not alter osteosarcoma cell growth or migration. However, it impaired endothelial cell tubulogenesis up to 75% and sprouting up to 30% in respect to controls. Conventional 2D assays revealed reduced tubule nodes and length, while 3D microfluidic models demonstrated diminished sprouting area and maximum migration distance, indicating S1PR3’s role in driving endothelial cell differentiation. Conclusions: These findings highlight S1PR3 as a critical regulator of angiogenesis and posit its targeting as a novel anti-angiogenic strategy, particularly for aggressive, S1P-secreting tumors with pronounced metastatic potential and an acidic microenvironment. Full article

Cancer remains one of the most formidable diseases globally and continues to be a leading cause of mortality. While chemotherapeutic agents are crucial in cancer treatment, they often come with severe side effects. Furthermore, the development of acquired drug resistance poses a significant challenge in the ongoing battle against cancer. Combining these chemotherapeutic agents with plant-derived phenolic compounds offers a promising approach, potentially reducing side effects and counteracting drug resistance. Phytochemicals, the bioactive compounds found in plants, exhibit a range of health-promoting properties, including anticarcinogenic, antimutagenic, antiproliferative, antioxidant, antimicrobial, neuroprotective, and cardioprotective effects. Their ability to enhance treatment, coupled with their non-toxic, multi-targeted nature and synergistic potential when used alongside conventional drugs, underscores the growing importance of natural therapeutics. In this study, we investigated the anticancer effects of olaparib (OL), a small-molecule PARP inhibitor that has shown promising results in both preclinical and clinical trials, and gallic acid (GA), a phenolic compound, in olaparib-resistant human osteosarcoma U2OS cells (U2OS-PIR). Both parental U2OS and U2OS-PIR cell lines were treated with increasing concentrations of olaparib and gallic acid, and their cytotoxic effects were assessed using the WST-1 cell viability assay. The synergistic potential of OL and GA, based on their determined IC₅₀ values, was further explored in combination treatment. A colony survival assay revealed the combination’s ability to significantly reduce the colony-forming capacity of cancer cells. Additionally, the apoptotic effects of OL and GA, both individually and in combination, were examined in U2OS-PIR cells using acridine orange/ethidium bromide dual staining. The anti-angiogenic properties were assessed through a VEGF ELISA, while the expression of proteins involved in DNA damage and apoptotic signaling pathways was analyzed via Western blot. The results of this study demonstrate that gallic acid effectively suppresses cell viability and colony formation, particularly when used in combination therapy to combat OL resistance. Additionally, GA inhibits angiogenesis and induces DNA damage and apoptosis by modulating key apoptosis-related proteins, including cPARP, Bcl-2, and Bax. These findings highlight gallic acid as a potential compound for enhancing therapeutic efficacy in overcoming acquired drug resistance. Full article

Algae have great therapeutic value and have attracted a great deal of attention due to the abundance of bioactive compounds they contain, which may be the key to fighting diseases of various origins, such as skin cancer, breast cancer, or osteosarcoma. In this regard, global trends indicate that cancer is likely to become the leading cause of death and the main obstacle to increased life expectancy in the 21st century, which is related to multiple factors, including the various effects of climate change, which will continue to cause afflictions to human health. Then, excess exposure to ultraviolet radiation (UVR) causes damage to DNA, proteins, enzymes, and various cellular structures and leads to the development of cancer, premature aging of the skin (wrinkles, dryness, dilation of blood vessels, and loss of collagen and elastin), or alterations of the immune system. In addition, multidrug resistance (MDR) is characterized by the overexpression of efflux pumps, such as P-glycoprotein or P-gp, that expel chemotherapeutic drugs out of the cancer cell being the main obstacle to their efficacy. Some molecules inhibit efflux pumps when co-administered with antineoplastic agents, such as glycolipids. Mycosporin-like amino acids and glycolipids isolated from Sargassum have shown an important role as potential anticancer agents. The results show that glycolipids and mycosporin-like amino acids present in brown algae of the genus Sargassum exhibit cytotoxic effects on different types of cancer, such as breast cancer, leukemia, and osteosarcoma, which is a key criterion to be considered as a natural anti-cancer strategy; but, more in-depth in vitro studies are needed to represent them at the in vivo level, as well as their validation in preclinical assays. Full article

The active metabolite of vitamin D3, calcitriol (1,25D), is widely recognised for its direct anti-proliferative and pro-differentiation effects. However, 1,25D is calcaemic, which restricts its clinical use for cancer treatment. Non-calcaemic agonists of the vitamin D receptor (VDR) could be better candidates for cancer treatment. In this study, we examined the influence of the hydroxylated lithocholic acid derivative CAR-R on osteosarcoma (OS) cell (MG63) growth and differentiation. Treatment of MG63 cells with CAR-R inhibited growth under conventional and hypoxic conditions. Co-treating cells with CAR-R and a lysophosphatidic acid (LPA) analogue resulted in their differentiation, as supported by synergistic increases in alkaline phosphatase (ALP) activity. Under hypoxic conditions, however, this differentiation response was attenuated. The importance of observed increases in hypoxia inducible factors (HIFs) were investigated through targeted disruption using pharmacological and genetic approaches. Disruption elicited a reduction in ALP activity, suggesting an important role for HIFs in OS differentiation. Finally, we examined the expression of the VDR protein. Hypoxic MG63s expressed less VDR, with the levels increasing with CAR-R exposure. Whilst these findings are encouraging, future studies aimed at bolstering the pro-differentiating effect of CAR-R under hypoxic conditions are warranted if this agent is to gain traction in the treatment of OS. Full article

Cancer cells demonstrate remarkable resilience by adapting to oxidative stress and undergoing metabolic reprogramming, making oxidative stress a critical target for cancer therapy. This study explores, for the first time, the redox-dependent anticancer effects of Polydatin (PD), a glucoside derivative of resveratrol, on the human Osteosarcoma (OS) cells SAOS-2 and U2OS. Using cell-based biochemical assays, we found that cytotoxic doses of PD (100–200 µM) promote ROS production, deplete glutathione (GSH), and elevate levels of both total iron and intracellular malondialdehyde (MDA), which are key markers of ferroptosis. Notably, the ROS scavenger N-acetylcysteine (NAC) and the ferroptosis inhibitor ferrostatin-1 (Fer-1) partially reverse PD’s cytotoxic effects. Interestingly, PD’s ability to hinder cell adhesion and migration appears independent of its pro-oxidant effect. Analysis of the oxidative stress regulators SIRT1 and Nrf2 at the gene and protein levels using real-time PCR and Western blot indicates an early oxidative response to PD treatment. PD remains effective under tumor-like conditions of hypoxia and serum starvation, and sensitizes OS cells to ROS-inducing chemotherapeutics like doxorubicin (DOX) and cisplatin (CIS). Importantly, PD exhibits minimal toxicity to non-tumorigenic cells (hFOB), suggesting a favorable therapeutic profile. Overall, our findings underscore that PD-induced redox imbalance plays a crucial role in its anti-OS effects, warranting further exploration into the molecular mechanisms behind its pro-oxidant activity. Full article

Feline injection-site sarcomas (FISSs) are malignant skin tumors of mesenchymal origin arising at local post-vaccination (or injection) sites. In recent years, a fluorescence imaging technique based on probes targeting α_vβ₃ integrin has been effectively applied for the surgical complete resection of the tumor. In our study, we investigated the utility of a commercially available anti-α_v integrin polyclonal antibody for the histopathological evaluation of FISS’s surgical excision margins. We collected 10 formalin-fixed paraffin-embedded (FFPE) feline excisional biopsies with a histopathological diagnosis of FISS (7 fibrosarcomas and 3 pleomorphic sarcomas) and wide margin tissue, along with one subcutaneous injection-site granuloma and 6 osteosarcomas. Samples were processed for histology, and slides were stained for IHC with the anti-α_v integrin antibody. Immunostained slides were evaluated for the cellular localization and intensity of the staining in different neoplastic and non-neoplastic cell populations. Neoplastic and non-neoplastic spindle cells had cytoplasmic positivity in all fibrosarcomas. Inflammatory cells, including macrophages of the injection-site granuloma, were negative. Multinucleated giant cells in the pleomorphic sarcomas had an intense membranous positivity. Although the anti-α_v integrin antibody was ineffective for the histopathological evaluation of surgical excision margins, the membranous localization of α_v integrin in multinucleated giant cells of pleomorphic sarcomas suggests that it plays a role in the oncogenesis of this FISS variant. Full article

Background: Brain metastases in pediatric osteosarcoma are infrequent but associated with a dire prognosis. Methods: This retrospective study examined six pediatric patients at Johns Hopkins Hospital who developed brain metastases from osteosarcoma between April 2015 and November 2023. Results: Median survival post-brain metastasis was 2.5 months. The patients underwent various treatments, including chemotherapy, surgery, and radiation. Despite these interventions, outcomes were uniformly fatal. Notably, one patient survived over 13 months post-brain metastasis with a treatment regimen of cabozantinib and nivolumab along with surgical resection and radiation, highlighting the potential efficacy of multimodal treatment regimens. This case demonstrated changes in the immune microenvironment, hinting at an anti-tumoral response, although no histologic response was observed. Conclusions: These findings emphasize the critical need for vigilant clinical monitoring, especially in patients with new neurological symptoms. The study highlights the diagnostic challenges and the rapid progression of brain metastases, underscoring the necessity for further research. Prospective studies and clinical trials focusing on novel therapeutic strategies are essential to improve outcomes. Disease biology studies examining tumor features across primary, pulmonary, and brain metastatic sites may offer insights into the mechanisms of metastasis and potential therapeutic targets, providing a foundation for better management of this devastating complication. Full article

Human osteosarcoma (OS) is a rare tumor predominantly affecting long bones and characterized by a poor prognosis. Currently, the first line of intervention consists of the surgical resection of primary tumors combined with radiotherapy and chemotherapy, with a profound impact on the patient’s life. Since the surgical removal of OS frequently results in a large resection of bones, the use of biomaterials to sustain the stability of the remaining tissue and to stimulate bone regeneration is challenging. Moreover, residual neoplastic cells might be responsible for tumor recurrence. Here, we explored the potential of tellurium-ion-doped bioactive glass as a novel therapeutic intervention to both eradicate residual malignant cells and promote bone regeneration. Bioactive glass (BAG) has been extensively studied and employed in the field of regenerative medicine due to its osseointegration properties and ability to improve bone tissue regeneration. We found that the incorporation of tellurium (Te) in BAG selectively kills OS cells through ferroptosis while preserving the viability of hBMSCs and stimulating their osteodifferentiation. However, the mechanism of Te toxicity is still unclear: (i) Te-BAG generates lipid-ROS through LOXs activity but not iron overload; (ii) Te-dependent ferroptosis is mediated by GPX4 down-regulation; and (iii) the anti-ferroptotic activity of FSP1 is abrogated, whose expression confers the resistance of OS to the canonical induction of ferroptosis. Overall, our data show that Te-doped bioglass could represent an interesting biomaterial with both pro-ferroptotic activity towards residual cancer cells and pro-osteoregenerative activity. Full article

Osteosarcoma (OS) is the most severe bone tumor in children. A chemotherapy regimen includes a combination of high-dose Methotrexate (MTX), doxorubicin, and cisplatin. These drugs cause acute and chronic side effects, such as infections, thrombocytopenia, neutropenia, DNA damage, and inflammation. Therefore, to identify new therapeutic strategies, effective and with a safety profile, is necessary. The Hedgehog (Hh) signaling pathway involved in tumorigenesis is active in OS. Hh components Patched receptor 1 (PTCH1), Smoothened (SMO), and glioma-associated oncogene homolog transcription factors (GLI1 and GLI2) are overexpressed in OS cell lines and patient samples. Curcumin (CUR)—with antioxidant and anti-cancer properties—downregulates Hh components in cancer, inhibiting progression. This study investigates CUR effects on the MG-63 OS cell line, alone and combined with MTX, to propose a novel therapeutic approach. Our study suggests CUR as a novel therapeutic agent in OS, particularly when combined with MTX. Targeting the Hh signaling pathway, CUR and MTX showed significant pro-apoptotic effects, increasing the BAX/Bcl-2 ratio and total apoptotic cell percentage. They reduced the expression of Hh pathway components (PTCH1, SMO, GLI1, and GLI2), inhibiting OS cell proliferation, survival, and invasion. CUR and MTX combined determined a β-Catenin decrease and a trend toward reducing NF-kB and matrix metalloproteinases (MMP-2 and MMP-9). Our findings suggest CUR as a support to OS treatment, improving outcomes and reducing the adverse effects of current therapies. Full article