Vitexicarpin Induces Apoptosis and Inhibits Metastatic Properties via the AKT-PRAS40 Pathway in Human Osteosarcoma.

Osteosarcoma, which has poor prognosis after metastasis, is the most common type of bone cancer in children and adolescents. Therefore, plant-derived bioactive compounds are being actively developed for cancer therapy. Artemisia apiacea Hance ex Walp. is a traditional medicinal plant native to Eastern Asia, including China, Japan, and Korea. Vitexicarpin (Vitex), derived from A. apiacea, has demonstrated analgesic, anti-inflammatory, antitumour, and immunoregulatory properties; however, there are no published studies on Vitex isolated from the aerial parts of A. apiacea. Thus, this study aimed to evaluate the antitumour activity of Vitex against human osteosarcoma cells. In the present study, Vitex (>99% purity) isolated from A. apiacea induced significant cell death in human osteosarcoma MG63 cells in a dose- and time-dependent manner; cell death was mediated by apoptosis, as evidenced by the appearance of cleaved-PARP, cleaved-caspase 3, anti-apoptotic proteins (Survivin and Bcl-2), pro-apoptotic proteins (Bax), and cell cycle-related proteins (Cyclin D1, Cdk4, and Cdk6). Additionally, a human phosphokinase array proteome profiler revealed that Vitex suppressed AKT-dependent downstream kinases. Further, Vitex reduced the phosphorylation of PRAS40, which is associated with autophagy and metastasis, induced autophagosome formation, and suppressed programmed cell death and necroptosis. Furthermore, Vitex induced antimetastatic activity by suppressing the migration and invasion of MMP13, which is the primary protease that degrades type I collagen for tumour-induced osteolysis in bone tissues and preferential metastasis sites. Taken together, our results suggest that Vitex is an attractive target for treating human osteosarcoma.

Osteosarcoma-targeted Cu and Ce based oxide nanoplatform for NIR II fluorescence/magnetic resonance dual-mode imaging and ros cascade amplification along with immunotherapy.

BACKGROUND: As the lethal bone tumor, osteosarcoma often frequently occurs in children and adolescents with locally destructive and high metastasis. Distinctive kinds of nanoplatform with high therapeutical effect and precise diagnosis for osteosarcoma are urgently required. Multimodal optical imaging and programmed treatment, including synergistic photothermal-chemodynamic therapy (PTT-CDT) elicits immunogenetic cell death (ICD) is a promising strategy that possesses high bio-imaging sensitivity for accurate osteosarcoma delineating as well as appreciable therapeutic efficacy with ignorable side-effects. METHODS AND RESULTS: In this study, mesoporous Cu and Ce based oxide nanoplatform with Arg-Gly-Asp (RGD) anchoring is designed and successfully constructed. After loading with indocyanine green, this nanoplatform can be utilized for precisely targeting and efficaciously ablating against osteosarcoma via PTT boosted CDT and the closely following ICD stimulation both in vitro and in vivo. Besides, it provides off-peak fluorescence bio-imaging in the second window of near-infrared region (NIR II, 1000-1700 nm) and Magnetic resonance signal, serves as the dual-mode contrast agents for osteosarcoma tissue discrimination. CONCLUSION: Tumor targeted Cu&Ce based mesoporous nanoplatform permits efficient osteosarcoma suppression and dual-mode bio-imaging that opens new possibility for effectively diagnosing and inhibiting the clinical malignant osteosarcoma.

Epiberberine inhibits bone metastatic breast cancer-induced osteolysis.

ETHNOPHARMACOLOGICAL RELEVANCE: The anti-tumor related diseases of Coptidis Rhizoma (Huanglian) were correlated with its traditional use of removing damp-heat, clearing internal fire, and counteracting toxicity. In the recent years, Coptidis Rhizoma and its components have drawn extensive attention toward their anti-tumor related diseases. Besides, Coptidis Rhizoma is traditionally used as an anti-inflammatory herb. Epiberberine (EPI) is a significant alkaloid isolated from Coptidis Rhizoma, and exhibits multiple pharmacological activities including anti-inflammatory. However, the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis has not been demonstrated clearly. AIM OF THE STUDY: Bone metastatic breast cancer can lead to osteolysis via inflammatory factors-induced osteoclast differentiation and function. In this study, we try to analyze the effect of epiberberine on breast cancer and the inflammatory factors of metastatic breast cancer-induced osteolysis. METHODS: To evaluate whether epiberberine could suppress bone metastatic breast cancer-induced osteolytic damage, healthy female Balb/c mice were intratibially injected with murine triple-negative breast cancer 4T1 cells. Then, we examined the inhibitory effect and underlying mechanism of epiberberine on breast cancer-induced osteoclastogenesis in vitro. Xenograft assay was used to study the effect of epiberberine on breast cancer cells in vivo. Moreover, we also studied the inhibitory effects and underlying mechanisms of epiberberine on RANKL-induced osteoclast differentiation and function in vitro. RESULTS: The results show that epiberberine displayed potential therapeutic effects on breast cancer-induced osteolytic damage. Besides, our results show that epiberberine inhibited breast cancer cells-induced osteoclast differentiation and function by inhibiting secreted inflammatory cytokines such as IL-8. Importantly, we found that epiberberine directly inhibited RANKL-induced differentiation and function of osteoclast without cytotoxicity. Mechanistically, epiberberine inhibited RANKL-induced osteoclastogensis via Akt/c-Fos signaling pathway. Furthermore, epiberberine combined with docetaxel effectively protected against bone loss induced by metastatic breast cancer cells. CONCLUSIONS: Our findings suggested that epiberberine may be a promising natural compound for treating bone metastatic breast cancer-induced osteolytic damage by inhibiting IL-8 and is worthy of further exploration in preclinical and clinical trials.

c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy.

BACKGROUND: c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS: The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS: The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.

Polyphyllin I enhances tumor necrosis factor-related apoptosis-inducing ligand-induced inhibition of human osteosarcoma cell growth downregulating the Wnt/ß-catenin pathway.

OBJECTIVE: To investigate the synergistic effects of polyphyllin I (PPI) combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the growth of osteosarcoma cells through downregulating the Wnt/ß-catenin signaling pathway. METHODS: Cell viability, apoptosis and cell cycle distribution were examined using cell counting kit-8 and flow cytometry assays. The morphology of cancer cells was observed with inverted phase contrast microscope. The migration and invasion abilities were examined by xCELLigence real time cell analysis DP system and transwell assays. The expressions of poly (adenosine diphosphate-ribose) polymerase, C-Myc, Cyclin B1, cyclin-dependent kinases 1, N-cadherin, Vimentin, Active-ß-catenin, ß-catenin, p-glycogen synthase kinase 3ß (GSK-3ß) and GSK-3ß were determined by Western blotting assay. RESULTS: PPI sensitized TRAIL-induced decrease of viability, migration and invasion, as well as increase of apoptosis and cell cycle arrest of MG-63 and U-2 OS osteosarcoma cells. The synergistic effect of PPI with TRAIL in inhibiting the growth of osteosarcoma cells was at least partially realized through the inactivation of Wnt/ß-catenin signaling pathway. CONCLUSION: The combination of PPI and TRAIL is potentially a novel treatment strategy of osteosarcoma.

Co-delivery of siAEG-1 and doxorubicin to treat osteosarcoma via nanomicelles for azide-alkyne "click" conjugation of poly(l-lysine) dendrons onto Zein.

Astrocyte elevated gene-1 (AEG-1) oncogene is a notorious and evolving target in a variety of human malignancies including osteosarcoma. The RNA interference (RNAi) has been clinically proven to effectively knock down specific genes. To successfully implement RNAi in vivo, protective vectors are required not only to protect unstable siRNAs from degradation, but also to deliver siRNAs to target cells with controlled release. Here, we synthesized a Zein-poly(l-lysine) dendrons non-viral modular system that enables efficient siRNA-targeted AEG-1 gene silencing in osteosarcoma and encapsulation of antitumor drugs for controlled release. The rational design of the ZDP integrates the non-ionic and low immunogenicity of Zein and the positive charge of the poly(l-lysine) dendrons (DPLL) to encapsulate siRNA and doxorubicin (DOX) payloads via electrostatic complexes and achieve pH-controlled release in a lysosomal acidic microenvironment. Nanocomplexes-directed delivery greatly improves siRNA stability, uptake, and AEG-1 sequence-specific knockdown in 143B cells, with transfection efficiencies comparable to those of commercial lipofectamine but with lower cytotoxicity. This AEG-1-focused RNAi therapy supplemented with chemotherapy inhibited, and was effective in inhibiting the growth in of osteosarcoma xenografts mouse models. The combination therapy is an alternative or combinatorial strategy that can produce durable inhibitory responses in osteosarcoma patients.

Injectable Magnetic Hydrogel Filler for Synergistic Bone Tumor Hyperthermia Chemotherapy.

The therapeutic efficacy of bone tumor treatment is primarily limited by inadequate tumor resection, resulting in recurrence and metastasis, as well as the deep location of tumors. Herein, an injectable doxorubicin (DOX)-loaded magnetic alginate hydrogel (DOX@MAH) was developed to evaluate the efficacy of an alternating magnetic field (AMF)-responsive, chemothermal synergistic therapy for multimodality treatment of bone tumors. The prepared hydrogel exhibits a superior drug-loading capacity and a continuous DOX release. This multifunctionality can be attributed to the combined use of DOX for chemotherapy and iron oxide nanoparticle-containing alginate hydrogels as magnetic hyperthermia agents to generate hyperthermia for tumor elimination without the limit on penetration depth. Moreover, the hydrogel can be formed when in contact with the calcium ions, which are abundant in bone tissues; therefore, this hydrogel could perfectly fit the bone defects caused by the surgical removal of the bone tumor tissue, and the hydrogel could tightly attach the surgical margin of the bone to realize a high efficacy residual tumor tissue elimination treated by chemothermal synergistic therapy. The hydrogel demonstrates excellent hyperthermia performance, as evidenced by in vitro cytotoxicity tests on tumor cells. These tests reveal that the combined therapy based on DOX@MAH under AMF significantly induces cell death compared to single magnetic hyperthermia or chemotherapy. In vivo antitumor effects in tumor-bearing mice demonstrate that DOX@MAH injection at the tumor site effectively inhibits tumor growth and leads to tumor necrosis. This work not only establishes an effective DOX@MAH system as a synergistic chemothermal therapy platform for treating bone tumors but also sheds light on the application of alginate to combine calcium ions of the bone to treat bone defect diseases.

Systemic Cisplatin Does Not Affect the Bone Regeneration Process in a Critical Size Defect Murine Model.

Osteosarcoma (OS) is the most common primary malignant bone tumor, and the current standard of care for OS includes neoadjuvant chemotherapy, followed by an R0 surgical resection of the primary tumor, and then postsurgical adjuvant chemotherapy. Bone reconstruction following OS resection is particularly challenging due to the size of the bone voids and because patients are treated with adjuvant and neoadjuvant systemic chemotherapy, which theoretically could impact bone formation. We hypothesized that an osteogenic material could be used in order to induce bone regeneration when adjuvant or neoadjuvant chemotherapy is given. We utilized a biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of systemic chemotherapy in a murine critical size defect model. We found that in the presence of neoadjuvant or adjuvant chemotherapy, MHA/Coll is able to enhance and increase bone formation in a murine critical size defect model (11.16 ± 2.55 or 13.80 ± 3.18 versus 8.70 ± 0.81 mm3) for pre-op cisplatin + MHA/Coll (p-value = 0.1639) and MHA/Coll + post-op cisplatin (p-value = 0.1538), respectively, at 12 weeks. These findings indicate that neoadjuvant and adjuvant chemotherapy will not affect the ability of a biomimetic scaffold to regenerate bone to repair bone voids in OS patients. This preliminary data demonstrates that bone regeneration can occur in the presence of chemotherapy, suggesting that there may not be a necessity to modify the current standard of care concerning neoadjuvant and adjuvant chemotherapy for the treatment of metastatic sites or micrometastases.

Cucurbitacin B modulates M2 macrophage differentiation and attenuates osteosarcoma progression via PI3K/AKT pathway.

Osteosarcoma is a common malignant bone tumour characterised by an aggressive metastatic potential. The tumour microenvironment, particularly the M2-polarised macrophages, is crucial for tumour progression. Cucurbitacin B (CuB), a triterpenoid derivative, is recognised for its anti-inflammatory and antitumour properties. This study investigates CuB and its effect on M2 macrophage differentiation and osteosarcoma progression, aiming to contribute to new treatment strategies. In vitro, THP-1 monocytes were stimulated with PMA, IL-13 and IL-4 to induce differentiation into M2 macrophages. Additionally, the influence of CuB on the proliferation, migration and invasion of osteosarcoma cells in the context of M2 macrophages was scrutinised. Crucial signalling pathways, especially the PI3K/AKT pathway, affected by CuB were identified and validated. In vivo, the osteosarcoma model was employed to gauge the effects of CuB on tumour weight, lung metastasis, angiogenesis, cell proliferation and M2 macrophage markers. The results showed that CuB inhibited M2 macrophage differentiation, leading to reduced proliferation, migration and invasion of osteosarcoma cells. CuB manifested an inhibitory effect on the PI3K/AKT pathway during the differentiation of M2 macrophages. In mouse models, CuB markedly reduced the tumour weight and the number of lung metastases. It also reduced the expression of angiogenesis and cell proliferation markers in tumour tissues, decreased the quantity of M2 macrophages and their associated markers and pathway proteins. In conclusion, CuB impedes osteosarcoma progression by inhibiting M2 macrophage differentiation via the PI3K/AKT pathway, presenting the potential for therapeutic advancements in osteosarcoma treatment.

Regulation of the P53 tumor suppressor gene and the Mcl-2 oncogene expression by an active herbal component delivered through a smart thermo-pH-sensitive PLGA carrier to improve Osteosarcoma treatment.

Osteosarcoma (OS), a lethal malignancy, has witnessed an escalating incidence rate. Contemporary therapeutic strategies for this cancer have proven to be inadequate, primarily due to their extensive side effects and the lack of specificity in targeting the molecular pathways implicated in this disease. Consequently, this project is aimed to manufacture and characterize Poly (Lactic-co-glycolic acid) embodying curcumin, a phytocompound devoid of adverse effects which not only exerts an anti-neoplastic influence but also significantly modulates the genetic pathways associated with this malignancy. In this investigation, multiple formulations of PLGA-Cur were synthesized, and the choice of optimal formula was made considering the efficiency of nanoparticle encapsulation and the drug dispersion rate from synthesized PLGA. The selected formulation's physical and chemical attributes, such as its dimension, polydispersity index of the formulation, surface electrical charge, physical-spatial structure, and stability, were examined using methods, including Dynamic light scattering (DLS), Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), and spectrophotometry. Subsequently, the absence of interaction between the drug and the system was assessed using Fourier Transform Infrared Spectroscopy (FT-IR), and cellular uptake was evaluated using fluorescence microscopy. The smart system's responsiveness to environmental stimuli was determined using the dialysis bag method and its anti-tumor properties were investigated on the SAOS-2 cell line. Finally, to evaluate the system's genetic impact on bone cancer, the molecular quantification of the P53 tumor suppressor gene and the oncogene MCL-2 was analyzed using real-time PCR and their protein expression levels were also examined. The PLGAs synthesized in this study exhibited an encapsulation rate of 91.5 ± 1.16% and a maximum release rate of 71 ± 1%, which were responsive to various stimuli. The size of the PLGAs was 12.5 ± 321.2 nm, with an electric charge of -38.9 ± 2.6 mV and a PDI of 0.107, indicating suitable morphology and stability. Furthermore, both the system and the drug retained their natural properties after inoculation. The system was readily absorbed by cancer cells and effectively exerted its anti-cancer properties. Notably, the system had a significant impact on the mentioned genes' expression. The produced nanosystem, possessing optimal physicochemical properties, has the potential to enhance the anti-cancer efficacy of curcumin. This is achieved by altering molecular and genetic pathways within cancer cells, thereby positioning it as a viable adjunctive treatment modality and also synthesizing of this herbal base drug system consider as a completely novel method for cancer therapy that can efficiently modulate genetical pathways involved.

Augmented drug resistance of osteosarcoma cells within decalcified bone matrix scaffold: The role of glutamine metabolism.

Due to the lack of a precise in vitro model that can mimic the nature microenvironment in osteosarcoma, the understanding of its resistance to chemical drugs remains limited. Here, we report a novel three-dimensional model of osteosarcoma constructed by seeding tumor cells (MG-63 and MNNG/HOS Cl no. 5) within demineralized bone matrix scaffolds. Demineralized bone matrix scaffolds retain the original components of the natural bone matrix (hydroxyapatite and collagen type I), and possess good biocompatibility allowing osteosarcoma cells to proliferate and aggregate into clusters within the pores. Growing within the scaffold conferred elevated resistance to doxorubicin on MG-63 and MNNG/HOS Cl no. 5 cell lines as compared to two-dimensional cultures. Transcriptomic analysis showed an increased enrichment for drug resistance genes along with enhanced glutamine metabolism in osteosarcoma cells in demineralized bone matrix scaffolds. Inhibition of glutamine metabolism resulted in a decrease in drug resistance of osteosarcoma, which could be restored by α-ketoglutarate supplementation. Overall, our study suggests that microenvironmental cues in demineralized bone matrix scaffolds can enhance osteosarcoma drug responses and that targeting glutamine metabolism may be a strategy for treating osteosarcoma drug resistance.

Iron-Based Nanovehicle Delivering Fin56 for Hyperthermia-Boosted Ferroptosis Therapy Against Osteosarcoma.

Background: Although systemic chemotherapy is a standard approach for osteosarcoma (OS) treatment, its efficacy is limited by the inherent or acquired resistance to apoptosis of tumor cells. Ferroptosis is considered as an effective strategy capable of stimulating alternative pathways of cancer cell demise. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy. Methods and Results: A novel nanovehicle composed of arginine-glycine-aspartate (RGD) modified mesoporous silica-coated iron oxide loading Fin56 was rationally prepared (FSR-Fin56). With the RGD-mediated targeting affinity, FSR-Fin56 could achieve selective accumulation and accurate delivery of cargos into cancer cells. Upon exposure to NIR light, the nanovehicle could generate localized hyperthermia and disintegrate to liberate the therapeutic payload. The released Fin56 triggered the degradation of GPX4, while Fe3+ depleted the intracellular GSH pool, producing Fe2+ as a Fenton agent. The local rise in temperature, in conjunction with Fe2+-mediated Fenton reaction, led to a rapid and significant accumulation of ROS, culminating in LPOs and ferroptotic death. The outstanding therapeutic efficacy and safety of the nanovehicle were validated both in vitro and in vivo. Conclusion: The Fin56-loaded FSR nanovehicle could effectively disturb the redox balance in cancer cells. Coupled with NIR laser irradiation, the cooperative CDT and PTT achieved a boosted ferroptosis-inducing therapy. Taken together, this study offers a compelling strategy for cancer treatment, particularly for ferroptosis-sensitive tumors like osteosarcoma.

Exploration in the Mechanism of Ginsenoside Rg5 for the Treatment of Osteosarcoma by Network Pharmacology and Molecular Docking.

OBJECTIVE: Osteosarcoma is a primary malignancy originating from mesenchymal tissue characterized by rapid growth, early metastasis and poor prognosis. Ginsenoside Rg5 (G-Rg5) is a minor ginsenoside extracted from Panax ginseng C.A. Meyer which has been discovered to possess anti-tumor properties. The objective of current study was to explore the mechanism of G-Rg5 in the treatment of osteosarcoma by network pharmacology and molecular docking technology. METHODS: Pharmmapper, SwissTargetPrediction and similarity ensemble approach databases were used to obtain the pharmacological targets of G-Rg5. Related genes of osteosarcoma were searched for in the GeneCards, OMIM and DrugBank databases. The targets of G-Rg5 and the related genes of osteosarcoma were intersected to obtain the potential target genes of G-Rg5 in the treatment of osteosarccoma. The STRING database and Cytoscape 3.8.2 software were used to construct the protein-protein interaction (PPI) network, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) platform was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. AutoDock vina software was used to perform molecular docking between G-Rg5 and hub targets. The hub genes were imported into the Kaplan-Meier Plotter online database for survival analysis. RESULTS: A total of 61 overlapping targets were obtained. The related signaling pathways mainly included PI3K-Akt signaling pathway, Proteoglycans in cancer, Lipid and atherosclerosis and Kaposi sarcoma-associated herpesvirus infection. Six hub targets including PIK3CA, SRC, TP53, MAPK1, EGFR, and VEGFA were obtained through PPI network and targets-pathways network analyses. The results of molecular docking showed that the binding energies were all less than -7 kcal/mol. And the results of survival analysis showed TP53 and VEGFA affect the prognosis of sarcoma patients. CONCLUSION: This study explored the possible mechanism of G-Rg5 in the treatment of osteosarcoma using network pharmacology method, suggesting that G-Rg5 has the characteristics of multi-targets and multi-pathways in the treatment of osteosarcoma, which lays a foundation for the follow-up experimental and clinical researches on the therapeutic effects of G-Rg5 on osteosarcoma.

Black phosphorus-incorporated novel Ti-12Mo-10Zr implant for multimodal treatment of osteosarcoma.

The repair and reconstruction of large bone defects after bone tumor resection is still a great clinical challenge. At present, orthopedic implant reconstruction is the mainstream treatment for repairing bone defects. However, according to clinical feedback, local tumor recurrence and nonunion of bone graft are common reasons leading to the failure of bone defect repair and reconstruction after bone tumor resection, which seriously threaten the physical and mental health of patients. On this basis, here the self-developed low modulus Ti-12Mo-10Zr alloy (TMZ) was chosen as substrate material. To improve its biological activity and osteointegration, calcium, oxygen, and phosphorus co-doped microporous coating was prepared on TMZ alloy by microarc oxidation (MAO). Then, black phosphorus (BP) nanosheets were incorporated onto MAO treated TMZ alloy to obtain multifunctional composites. The obtained BP-MAO-TMZ implant exhibited excellent photothermal effects and effective ablation of osteosarcoma cancer cells under the irradiation of 808 nm near infrared laser, while no photothermal or therapeutic effects were observed for TMZ alloy. Meanwhile, the structure/component bionic coating obtained after MAO treatment as well as the P-driven in situ biomineralization performance after incorporation of BP nanosheets endowed BP-MAO-TMZ implant with synergistic promoting effect on MC3T3-E1 osteoblasts' activity, proliferation and differentiation ability. This study is expected to provide effective clinical solutions for problems of difficult bone regeneration and tumor recurrence after tumor resection in patients with bone tumors and to solve a series of medical problems such as poor prognosis and poor postoperative quality of patients life with malignant bone tumors.

Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by Dinaciclib through a Genome-Targeted Approach.

PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

Zuogui pill disrupt the malignant cycle in breast cancer bone metastasis through the Piezo1-Notch-1-GPX4 pathway and active molecules fishing.

BACKGROUND: Breast cancer bone metastasis is closely associated with the bone microenvironment. Zuogui Pill (ZGP), a clinically approved formulation in China, effectively regulates the bone microenvironment for the prevention and treatment of osteoporosis. PURPOSE: Few reports have utilized the ZGP for bone metastasis models. This study investigated the intervention and bone-protective properties of ZGP against breast cancer bone metastasis, explored the potential mechanism, and screened for its active compositions by molecules fishing. METHODS: To investigate the intervention efficacy of ZGP and its protein-level mechanism of action, the mouse bone metastasis model and in vitro cell co-culture model were constructed. Affinity ultrafiltration, molecular docking, cellular thermal shift assay and physical scale detection were used to investigate the affinity components of the RANKL protein in ZGP. RESULTS: The administration of ZGP combined with zoledronic acid inhibited the development of tumors and secondary lung metastasis in mice. This translated to a prolonged survival period and enhanced quality of life. ZGP could disrupt the malignant cycle by modulating the Piezo1-Notch-1-GPX4 signaling pathway in the "bone-cancer" communication in the cell co-culture model. Furthermore, 25 chemical components of ZGP were identified, with 10 active compounds exhibiting significant affinity for the RANKL protein. CONCLUSION: The findings of this work highlighted ZGP's potential for intervening in the progression of breast cancer bone metastasis. Thus, this investigation served as an experimental foundation for expanding the application scope of ZGP and for advancing drug development efforts in bone metastasis treatment.

Qilian Formula Inhibits Tumor Cell Growth in a Bone Metastasis Model of Lung Cancer.

BACKGROUND: Bone metastasis is frequently common in advanced lung cancer with the major issue of a pathological fracture. Previous studies suggested that Astragalus membranaceus (Qi) and Ampelopsis japonica (Lian), which are used as folk medicine in China, have potential effects on inhibiting tumor growth and protecting bones, respectively. In this study, an experiment on the inhibitory effect of the Qilian formula (AAF) in vivo was designed to examine tumor growth in bone and osteoclast formation. MATERIALS AND METHODS: The bone metastasis xenograft models were established by implanting NCI-H460-luc2 lung cancer cells into the right tibiae bones of mice. After confirming the model's viability through optical imaging 7 days post-implantation, 2 groups, namely the AAF group and the control group, were administered 0.3 mL of AAF extract (9 g/kg/day) or normal saline via intragastric delivery for a duration of 4 weeks. Throughout the study, we longitudinally assessed tumor burden, bone destruction, and weight-bearing capacity in vivo using reporter gene bioluminescence imaging (BLI), micro-CT, and dynamic weight-bearing (DWB) tests. Mechanistic insights were gained through Hematoxylin-eosin (H&E) staining, immunohistochemical (IHC) analysis, western blotting, and flow cytometry. RESULTS: Qilian formula produced significant inhibition to the progress of bone destruction and tumor burden in the right tibiae bone in the treatment group. It was further evidenced by molecular imaging in vivo via small animal micro-CT and BLI with parametric quantification, characterizing significantly lower uptake of BLI signal in the treated tumor lesions and improving the pathological changes in the microstructure of bone. Furthermore, DWB tests revealed that Qilian formula treatment significantly maintained the weight-bearing capacity. According to immunohistochemical analysis, the effect of the Qilian formula appeared to involve the suppression of osteoclast formation by lower expression of the tartrate-resistant acid phosphatase. Cell apoptosis and death induction were evidenced by a higher percentage of Bal2、BAX and caspase 3 expressions of Qilian formula-treated tumor tissues. CONCLUSIONS: Our study demonstrated a significant inhibitory effect of the Qilian formula on the progression of osteolytic invasion in vivo by suppressing osteoclastogenesis and promoting apoptotic cell death.

Network pharmacology-based research on the effect of Radix Astragali on osteosarcoma and the underlying mechanism.

To explore the anti-tumor effects of Radix Astragali on osteosarcoma and its mechanism. We analyzed the PPI network of Radix Astragali's potential targets for treating osteosarcoma and got the hub targets. We used KM curves to screen hub targets that could prolong sarcoma patients' survival time. We performed GO and KEGG enrichment analysis of Radix Astragali's potential targets and predicted Radix Astragali's molecular mechanism and function in treating osteosarcoma. The binding process between the hub targets, which could prolong sarcoma patients' survival time, and Radix Astragali was simulated through molecular docking. PPI network analysis of potential therapeutic targets discriminated 25 hub targets. The KM curves of the hub targets showed there were 13 hub targets that were effective in improving the 5-year survival rate of sarcoma patients. GO and KEGG enrichment demonstrated that Radix Astragali regulates multiple signaling pathways of osteosarcoma. Molecular docking results indicated that Radix Astragali could bind freely to the hub target, which could prolong the sarcoma patient's survival time. Radix Astragali act on osteosarcoma by regulating a signaling network formed by hub targets connecting multiple signaling pathways. Radix Astragali has the potential to become a drug for treating osteosarcoma and prolonging the sarcoma patient's survival time.

Network pharmacology-based research on the effect of Scutellaria baicalensis on osteosarcoma and the underlying mechanism.

To explore the anti-tumor effects of Scutellaria baicalensis on osteosarcoma and its mechanism. Network pharmacology and molecular docking techniques were applied to investigate the effect and mechanism of Scutellaria baicalensis on osteosarcoma (OS). We analyzed the protein-protein interaction (PPI) network for potential targets of Scutellaria baicalensis for treating osteosarcoma and identified hub targets. We used KM curves to screen for hub targets that could effectively prolong the survival time of OS patients. We systematically performed gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis of the Scutellaria baicalensis potential targets and predicted the Scutellaria baicalensis molecular mechanism and function in treating osteosarcoma. Through molecular docking, the binding process between the hub targets, which could prolong the survival time of sarcoma patients, and Scutellaria baicalensis was simulated. PPI network analysis of potential therapeutic targets discriminated 12 hub targets. The KM curves of the hub targets showed that upregulation of RXRA, RELA, ESR1, TNF, IL6, IL1B, and RB1 expression, and downregulation of MAPK1, VEGFA, MAPK14, CDK1, and PPARG expression were effective in improving the 5-year survival rate of OS patients. GO and KEGG enrichment demonstrated that Scutellaria baicalensis regulated multiple signaling pathways of OS. Molecular docking results indicated that Scutellaria baicalensis could bind freely to the above hub target, which could prolong the survival time of sarcoma patients. Scutellaria baicalensis acted on osteosarcoma by regulating a signaling network formed by hub targets connecting multiple signaling pathways. Scutellaria baicalensis appears to have the potential to serve as a therapeutic drug for osteosarcoma and to prolong the survival of OS patients.

Multi-Anticancer Activities of Phytoestrogens in Human Osteosarcoma.

Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.