curcumin and Bone-Neoplasms

The most prevalent primary bone malignancy among children and adolescents is osteosarcoma. The high mortality rate of osteosarcoma is due to lung metastasis. Despite the development of multi-agent chemotherapy and surgical resection, patients with osteosarcoma have a high metastasis rate and poor prognosis. Thus, it is necessary to identify novel therapeutic agents to improve the 5-year survival rate of these patients. Curcumin, a phytochemical compound derived from Curcuma longa, has been employed in treating several types of cancers through various mechanisms. Also, in vitro studies have demonstrated that curcumin could inhibit cell proliferation and induce apoptosis in osteosarcoma cells. Development in identifying signaling pathways involved in the pathogenesis of osteosarcoma has provided insight into finding new therapeutic targets for the treatment of this cancer. Targeting MAPK/ERK, PI3k/AKT, Wnt/β-catenin, Notch, and MircoRNA by curcumin has been evaluated to improve outcomes in patients with osteosarcoma. Although curcumin is a potent anti-cancer compound, it has rarely been studied in clinical settings due to its congenital properties such as hydrophobicity and poor bioavailability. In this review, we recapitulate and describe the effect of curcumin in regulating signaling pathways involved in osteosarcoma.

Topics: Adolescent; Bone Neoplasms; Child; Curcumin; Humans; Osteosarcoma; Phosphatidylinositol 3-Kinases; Signal Transduction

Osteosarcoma (osteogenic sarcoma), the most prevalent primary malignant bone tumor in adolescents, confers low survival rates in patients with metastatic disease. Dietary curcumin has a number of anticancer properties but has poor bioavailability. To improve the clinical applications of curcumin, several potential curcumin analogs and nanobased curcumin delivery systems have been developed. In this critical review, we address the biological and pharmacological characteristics of curcumin and its analogs, with an emphasis on strategies to improve the bioactivity and bioavailability of curcumin analogs that may increase their application in the treatment of potent human metastatic osteosarcoma. We highlight promising current multifunctional nanoformulations and three-dimensional printed scaffold systems utilized for the targeting and delivery of curcumin in human osteosarcoma cells. Our purpose is to drive further research on curcumin analogs and carriers to improve their bioavailability and anti-osteosarcoma bioactivity.

Topics: Adolescent; Bone Neoplasms; Curcumin; Drug Carriers; Humans; Osteosarcoma

Curcumin is a natural polyphenol phytochemical derived from turmeric with antioxidant, anti-inflammatory, and anticancer properties but is concerned about poor solubility in water, absorption, and metabolic stability. Potent metastatic osteosarcoma is the most common primary bone cancer in children, adolescents, and young adults. It is responsible for low survival rates because of its high rate of metastasis to the lungs. To improve poor bioavailability, numerous curcumin analogs were developed to possess anticancer characteristics through a variety of biological pathways involved in cytotoxicity, proliferation, autophagy, sensitizing chemotherapy, and metastases. This review provides an overview of their various pharmacological functions, molecular mechanisms, and therapeutic potential as a remedy for human osteosarcoma. To enhance therapeutic efficacy, several liposomal nanoparticles, nanocarriers, multifunctional micelles, and three-dimensional printed scaffolds have also been developed for the controlled delivery of curcumin targeting human osteosarcoma cells. Consequently, curcumin and several potential analogs and delivery formulations are optimistic candidates to improve the currently available strategy for human osteosarcoma. However, further insight into the mechanism of action of promising curcumin analogs and the development of carriers in clinical trials of osteosarcoma needs to be investigated to improve their overall potency and clinical utility, in particular the anti-metastatic effect.

Topics: Adolescent; Bone Neoplasms; Child; Curcumin; Humans; Nanoparticles; Osteosarcoma; Solubility

Accurate. Since sCD30 levels and sCD26/sCD30 ratios may contribute to the activity of the disease, they may be used to assess ITP disease activity.. hBMSCs and hFOB1.19 cells modulate the phenotype of PC3 prostate cancer cells and the expression of CD59 by activating the RANK/RANKL/OPG signaling pathway.. Results showed that the EEG responses at lower levels of the independent variables were significantly high than at higher levels; except for oxygen content, the EEG responses at lower levels were considerably lower than at a higher level. It also showed that an upsurge in the physical demand increased lifting frequency and replication and caused decreasing in alpha power, theta/beta, alpha/beta, (theta + alpha)/beta, (theta + alpha)/(alpha + beta) and increasing in the theta power and the gamma power. Furthermore, several interactions among independent variables had significant effects on the EEG responses.. The EEG implementation for the investigation of neural responses to physical demands allows for the possibility of newer nontraditional and faster methods of human performance monitoring. These methods provide effective and reliable results as compared to other traditional methods. This study will safeguard the physical capabilities and possible health risks of industrial workers. And the applications of these tasks can occur in almost all working environments (factories, warehouses, airports, building sites, farms, hospitals, offices, etc.) that are at high altitudes. It can include lifting boxes at a packaging line, handling construction materials, handling patients in hospitals, and cleaning.

Topics: Action Potentials; Adolescent; Adult; Aged; Alanine Transaminase; Analgesics; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Apoptosis; Arrhythmias, Cardiac; Atrial Fibrillation; Biological Transport; Biomarkers; Blood Gas Analysis; Blood-Brain Barrier; Blotting, Western; Bone and Bones; Bone Marrow; Bone Neoplasms; Brain; Breast Neoplasms; Calcium; Carbon Tetrachloride; Cartilage, Articular; Case-Control Studies; CD59 Antigens; CDC2 Protein Kinase; Celastrus; Cell Cycle; Cell Division; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemical Fractionation; Colitis, Ulcerative; Colon; Computer Simulation; Curcumin; Cyclin B1; Cymenes; Cytokines; Dextran Sulfate; Dipeptidyl Peptidase 4; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Ectodysplasins; Electroencephalography; Endothelial Cells; Epithelial Cells; Epithelial-Mesenchymal Transition; Exosomes; Female; Flavonoids; G2 Phase; Gene Expression Regulation; Glial Cell Line-Derived Neurotrophic Factor; Heart Atria; Heart Conduction System; Heart Ventricles; HeLa Cells; Hemodynamics; Humans; Image Interpretation, Computer-Assisted; Indoles; Inflammation; Interleukin-1beta; Interleukin-6; Iridoid Glycosides; Ki-1 Antigen; Lens, Crystalline; Lifting; Liver; Liver Cirrhosis; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Microelectrodes; Middle Aged; Models, Cardiovascular; Multiparametric Magnetic Resonance Imaging; Myeloid Differentiation Factor 88; NADPH Oxidase 1; Neoplasm Grading; NF-kappa B; Osteoarthritis; Osteoblasts; Osteoclasts; Oxidative Stress; Oxygen; Patch-Clamp Techniques; PC-3 Cells; Permeability; Peroxidase; Plant Extracts; Plant Leaves; Prostate; Prostatic Neoplasms; Protective Agents; Proto-Oncogene Proteins c-akt; Psychophysics; Purpura, Thrombocytopenic, Idiopathic; Rabbits; Rats; Rats, Sprague-Dawley; Recovery of Function; Retrospective Studies; RNA, Long Noncoding; ROC Curve; Safety; Shoes; Signal Transduction; Sodium; Sonication; Spinal Cord; Spinal Cord Injuries; Syringa; Tight Junctions; Tissue Inhibitor of Metalloproteinase-1; Toll-Like Receptor 2; Transforming Growth Factor beta2; Transient Receptor Potential Channels; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Umbilical Cord; Up-Regulation; Ventricular Function; Young Adult

The lack of site-specific chemotherapeutic agents to treat bone malignancy throws a significant challenge in the design of a delivery vehicle. The major scientific question posed in this study is, can we utilize curcumin-loaded magnesium oxide (MgO) doped 3D printed tricalcium phosphate (TCP) bone grafts as a localized delivery system that improves early stage

Topics: Animals; Bone Neoplasms; Curcumin; Magnesium Oxide; Osteosarcoma; Printing, Three-Dimensional; Rats; Staphylococcus aureus; Tissue Engineering; Tissue Scaffolds

Osteosarcoma (OS) is an aggressive tumor with a rare incidence. Extended surgical resections are the prevalent treatment for OS, which may cause critical-size bone defects. These bone defects lead to dysfunction, weakening the post-surgical quality of patients' life. Hence, an ideal therapeutic agent for OS should simultaneously possess anti-cancer and bone repair capacities. Curcumin (CUR) has been reported in OS therapy and bone regeneration. However, it is not clear how CUR suppresses OS development. Conventionally, CUR is considered a natural antioxidant in line with its capacity to promote the nuclear translocation of a nuclear transcription factor, nuclear factor erythroid 2 (NRF2). After nuclear translocation, NRF2 can activate the transcription of some antioxidases, thereby circumventing excess reactive oxygen species (ROS) that are deleterious to cells. Intriguingly, this research demonstrated that, in vitro, 10 and 20 μM CUR increased the intracellular ROS in MG-63 cells, damaged cells' DNA, and finally caused apoptosis of MG-63 cells, although increased NRF2 protein level and the expression of NRF2-regulated antioxidase genes were identified in those two groups.

Topics: Antioxidants; Apoptosis; Bone Neoplasms; Curcumin; Humans; NF-E2-Related Factor 2; Osteosarcoma; Reactive Oxygen Species

Novel drug delivery system was prepared and evaluated as for application in cancerous bone treatment. It had three stacked layers, including a drug-free layer, a cisplatin-loaded layer, and a curcumin-containing layer. Our previously characterized biomaterials, namely Zr-hydroxyapatite (Zr-HA) and alkaline-treated polycaprolactone (modified-PCL), were used as major components of the drug carrier. Polar-polar interactions between cisplatin and Zr-HA were modulated by the modified-PCL included, leading to increase of cisplatin release. Using β-cyclodextrin (β-CD) to entrap curcumin caused improvement of curcumin solubility and release. The 3D-construct was porous with internal interconnected pores according to SEM micrographs. Large amount of apatite was formed and proteins adsorbed on the scaffolds after immersed in physiologic buffer solution and in medium containing fetal bovine serum, respectively. Optimal concentrations of ascorbic acid and triamcinolone were used for induction of bone marrow stromal cells to become osteoblasts by expressing an enzyme marker, e.g., alkaline phosphatase. The prepared scaffolds were considered osteo-conductive and osteo-inductive. The concentrations of cisplatin and curcumin reached the IC

Topics: Animals; Bone Neoplasms; Bone Regeneration; Cisplatin; Curcumin; Drug Carriers; Durapatite; Polyesters; Tissue Scaffolds

Limitations in the current clinical management of critical-sized osseous defects have driven the need for multifunctional bone constructs. The ideal bone scaffold should possess advanced microarchitecture, well-defined pore interconnectivity, and supply biological signals, which actively guide and control tissue regeneration while simultaneously preventing post-implantation complications. Here, a natural medicine-based localized drug delivery from 3D printed scaffold is presented, which offers controlled release of curcumin, piperine from nano-sized polymeric micelles, and burst release of antibacterial carvacrol from the coating endowing the scaffold with their distinct, individual biological properties. This functionalized scaffold exhibits improved osteoblast (hFOB) cell attachment, 4-folds higher hFOB proliferation, and 73% increased hFOB differentiation while simultaneously providing cytotoxicity towards osteosarcoma cells with 61% lesser viability compared to control. In vitro, early tube formation (p < 0.001) indicates that the scaffolds can modulate the endothelial cellular network, critical for faster wound healing. The scaffold also exhibits 94% enhanced antibacterial efficacy (p < 0.001) against gram-positive Staphylococcus aureus, the main causative bacteria for osteomyelitis. Together, the multifunctional scaffolds provide controlled delivery of natural biomolecules from the nano-sized micelle-loaded 3D printed matrix for significant improvement in osteoblast proliferation, endothelial formation, osteosarcoma, and bacterial inhibition, guiding better bone regeneration for post-traumatic defect repair.

Topics: Anti-Bacterial Agents; Bone Neoplasms; Bone Regeneration; Calcium Phosphates; Curcumin; Humans; Micelles; Osteogenesis; Osteosarcoma; Printing, Three-Dimensional; Tissue Engineering; Tissue Scaffolds

Titanium and its alloy are clinically used as an implant material for load-bearing applications to treat bone defects. However, the lack of biological interaction between bone tissue and implant and the risk of infection are still critical challenges in clinical orthopedics. In the current work, we have developed a novel approach by first 1) modifying the implant surface using hydroxyapatite (HA) coating to enhance bioactivity and 2) integrating curcumin and epigallocatechin gallate (EGCG) in the coating that would induce chemopreventive and osteogenic potential and impart antibacterial properties to the implant. The study shows that curcumin and EGCG exhibit controlled and sustained release profiles in acidic and physiological environments. Curcumin and EGCG also show in vitro cytotoxicity toward osteosarcoma cells after 11 days, and the dual system shows a ~94 % reduction in bacterial growth, indicating their in vitro chemopreventive potential and antibacterial efficacy. The release of both curcumin and EGCG was found to be compatible with osteoblast cells and further promotes their growth. It shows a 3-fold enhancement in cellular viability in the dual drug-loaded implant compared to the untreated samples. These findings suggest that multifunctional HA-coated Ti6Al4V implants integrated with curcumin and EGCG could be a promising strategy for osteosarcoma inhibition and osteoblast cell growth while preventing infection.

Topics: Anti-Bacterial Agents; Bone Neoplasms; Curcumin; Durapatite; Humans; Osteosarcoma; Titanium

Curcuma has been used as an adjuvant treatment for osteosarcoma (OS) due to its anticancer compounds. However, the underlying mechanism remains unclear. Therefore, this study aimed to explore the mechanism of action of curcuma in the treatment of OS using network pharmacology and molecular docking. In this study, anticancer compounds were obtained from relevant literature, and curcuma-related targets and OS treatment targets were obtained from public databases. Protein‒protein interaction networks were constructed to screen out the hub genes using the STRING database and Cytoscape software. Cluster analysis of the protein modules was then performed using the Cytoscape MCODE plugin. Furthermore, Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed for common targets among curcuma targets and OS-related targets using the DAVID database. Finally, molecular docking was performed, and the results were verified by Auto dock Tool and PyMOL software. Our research identified 11 potential active compounds, 141 potential therapeutic targets and 14 hub genes for curcuma. AKT1, TNF, STAT3, EGFR, and HSP90AA1 were the key targets closely related to the PI3K/Akt signaling pathways, HIF-1 signaling pathways, ErbB signaling pathways, and FOXO signaling pathways, which are involved in angiogenesis, cancer cell proliferation, metastasis, invasion, and chemotherapy resistance in the microenvironment of OS. Molecular docking suggested that the core compound had a strong affinity for key targets, with a binding energy of less than - 5 kJ/mol. The study showed that curcuma-mediated treatment of OS was a complex process involving multiple compounds, targets, and pathways. This study will enhance the understanding of how curcuma affects the proliferation and invasion of OS cells and reveal the potential molecular mechanism underlying the effect of curcuma on OS lung metastasis and chemotherapy resistance.

Topics: Bone Neoplasms; Curcuma; Molecular Docking Simulation; Network Pharmacology; Osteosarcoma; Phosphatidylinositol 3-Kinases; Tumor Microenvironment

TGFβ signaling promotes progression of bone-metastatic (BMET) breast cancer (BCa) cells by driving tumor-associated osteolysis, a hallmark of BCa BMETs, thus allowing for tumor expansion within bone. Turmeric-derived bioactive curcumin, enriched in bone via local enzymatic deconjugation of inactive circulating curcumin-glucuronides, inhibits osteolysis and BMET progression in human xenograft BCa BMET models by blocking tumoral TGFβ signaling pathways mediating osteolysis. This is a unique antiosteolytic mechanism in contrast to current osteoclast-targeting therapeutics. Therefore, experiments were undertaken to elucidate the mechanism for curcumin inhibition of BCa TGFβ signaling and the application of this finding across multiple BCa cell lines forming TGFβ-dependent BMETs, including a possible role for bioactive curcumin metabolites in mediating these effects. Immunoblot analysis of TGFβ signaling proteins in bone tropic human (MDA-SA, MDA-1833, MDA-2287) and murine (4T1) BCa cells revealed uniform curcumin blockade of TGFβ-induced Smad activation due to down-regulation of plasma membrane associated TGFβR2 and cellular receptor Smad proteins that propagate Smad-mediated gene expression, resulting in downregulation of PTHrP expression, the osteolytic factor driving in vivo BMET progression. With the exception of early decreases in TGFβR2, inhibitory effects appeared to be mediated by oxidative metabolites of curcumin and involved inhibition of gene expression. Interestingly, while not contributing to changes in Smad-mediated TGFβ signaling, curcumin caused early activation of MAPK signaling in all cell lines, including JNK, an effect possibly involving interactions with TGFβR2 within lipid rafts. Treatment with curcumin or oxidizable analogs of curcumin may have clinical relevancy in the management of TGFβ-dependent BCa BMETs.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Humans; Mice; Oxidation-Reduction; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1

Topics: Bone Neoplasms; Bone Regeneration; Cell Line, Tumor; Cell Membrane Permeability; Combined Modality Therapy; Curcumin; Humans; Hydrogels; Hyperthermia, Induced; Indocyanine Green; Microspheres; Osteosarcoma

Osteosarcoma is a malignant tumor in bones that is common in children and adolescents. MicroRNAs (miRs) are small non-coding RNAs that are associated with various kinds of tumors. miR-21 is one of the most frequently overexpressed microRNAs in osteosarcoma. Curcumin is a naturally occurring phenolic compound that has antitumor properties. Curcumin significantly inhibits osteosarcoma. However, the role of miR-21 and its target gene, reversion-inducing cysteine-rich protein with kazal motifs (RECK), in the anticancer activity of curcumin against osteosarcoma remains unclear. The aim of this study is to investigate the effect(s) of curcumin on osteosarcoma cell proliferation and elucidate its molecular mechanism. Cell counting kit-8, colony formation and flow cytometry assays were performed to study cell proliferation and apoptosis. Real time-polymerase chain reaction was used to determine the expression of miR-21 and RECK. Wnt/β-catenin signaling pathway proteins were detected by Western Blot. We hereby show that curcumin upregulated the expression of RECK via miR-21, thereby subsequently regulating Wnt/β-catenin signaling leading to the inhibition of osteosarcoma.

Topics: Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; GPI-Linked Proteins; Humans; MicroRNAs; Osteosarcoma; Real-Time Polymerase Chain Reaction; Up-Regulation; Wnt Signaling Pathway

Combination therapy is a promising and prevalent strategy for osteosarcoma treatment. Curcumin (CUR), as a chemosensitizer, improves the antitumor effect of first‑line chemotherapy drugs. However, due to its poor solubility and instability in physiological conditions, the bioavailability of CUR is limited. In order to improve the physicochemical properties of natural CUR, β‑cyclodextrin was adopted to generate a β‑cyclodextrin curcumin (CD‑CUR) inclusion complex. A thermosensitive hydrogel, poly(D,L‑lactide‑co‑glycolide)-poly(ethylene‑glycol)‑poly(D,L‑lactide‑co‑glycolide), was selected and synthesized to co‑deliver doxorubicin (DOX) and CD‑CUR to tumor sites. The dual‑drug delivery system (gel+DOX+CD‑CUR) was prepared by mixing drugs with hydrogels and had a perfect sol‑gel phase transition temperature (18.3˚C for 20% concentration). Both DOX and CUR were released from hydrogels in a sustained manner in PBS (pH 7.4) medium. The combination therapy based on DOX+CD‑CUR exhibited higher antitumor activity than monotherapies in vitro. Combined CD‑CUR therapy significantly downregulated Bcl‑2 expression and upregulated caspase‑3 expression, suggesting that DOX combined with CD‑CUR treatment has a higher apoptosis‑inducing efficiency. The antitumor efficiency of the gel+DOX+CD‑CUR strategy was evaluated in K‑7 tumor‑bearing mice, and this localized combination therapy demonstrated a higher antitumor efficiency compared with free DOX+CD‑CUR or single‑drug strategies. There were no significant differences in body weight and histological changes of major organs in each group. Therefore, the present combination treatment based on hydrogel may be a feasible approach to co‑deliver DOX and CD‑CUR to osteosarcoma tumor sites in clinical practice.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Bone Neoplasms; Cell Line, Tumor; Curcumin; Disease Models, Animal; Doxorubicin; Drug Carriers; Drug Compounding; Feasibility Studies; Female; Humans; Hydrogels; Injections, Intralesional; Mice; Nanoparticles; Osteosarcoma; Polyesters; Polyethylene Glycols

Curcumin prevents bone loss in resorptive bone diseases and inhibits osteoclast formation, a key process driving bone loss. Curcumin circulates as an inactive glucuronide that can be deconjugated in situ by bone's high β-glucuronidase (GUSB) content, forming the active aglycone. Because curcumin is a common remedy for musculoskeletal disease, effects of microenvironmental changes consequent to skeletal development or disease on bone curcumin metabolism are explored.. Across sexual/skeletal development or between sexes in C57BL/6 mice ingesting curcumin (500 mg kg. Dietary polyphenols circulating as glucuronides may require in situ deconjugation for bone-protective effects, a process influenced by bone microenvironmental changes.

Topics: Aging; Animals; Bone and Bones; Bone Neoplasms; Curcumin; Female; Glucuronidase; Glucuronides; Male; Mice, Inbred C57BL; Osteogenesis; Osteolysis; Osteoporosis; Ovariectomy; Polyphenols; Quercetin

Metastatic (secondary) bone cancer is one of the major causes of death in patients with advanced cancer. A lack of options for the targeted delivery of a desired therapeutic payload to multiple tumour modules located in the bone is still one of the foremost hurdles in the treatment/prevention of metastatic bone cancer. Curcumin has a proven anticancer potential with known challenges for application as a pharmaceutical agent. We have previously shown that micellar formulations could overcome some of these challenges and enhances its anti-cancer activity. In this study, we have developed a targeted drug delivery system using bisphosphonate (alendronate) conjugated Pluronic F127 micelles that could efficiently target, and specifically deliver curcumin to the osteolytic tumour microenvironment in the bone. Characterization of the formulation of curcumin-encapsulated alendronate-conjugated micelles demonstrated that the micelles have nanoscale size (∼27 nm) with a positive surface charge (+2.87 mV) and 4% drug loading. The alendronate-conjugated micelles showed significant bone-targeting potential. Rapid binding of the micelles to hydroxyapatite surface suggested that these nanoparticles are promising carriers for effective and targeted delivery of curcumin to osteolytic tumours in the bone.

Topics: Alendronate; Antineoplastic Agents; Bone Neoplasms; Curcumin; Diphosphonates; Drug Carriers; Drug Delivery Systems; Drug Liberation; Durapatite; Micelles; Nanoparticles; Particle Size; Poloxamer; Polymers; Tumor Microenvironment

Osteosarcoma, the most prevalent malignant bone tumor in the pediatric age group, is responsible for the great majority of cancer-associated deaths owing to its highly metastatic potential. The anti-metastatic effects of the new curcumin analogue L48H37 in human osteosarcoma are still unknown; hence, we investigated whether L48H37 represses human osteosarcoma cells' biological behavior of migratory potential and invasive activities and attempted to delve into its underlying mechanisms. L48H37 up to 5 μM inhibited, without cytotoxicity, the motility, migration, and invasion of human osteosarcoma U2OS and MG-63 cells. In U2OS cells, the human protease array revealed an obvious decrease in urokinase plasminogen activator (uPA) expression after L48H37 treatment, and L48H37 actually reduced the level, protein and mRNA expression, and promoter activity of uPA dose-dependently. L48H37 decreased the phosphorylation of STAT3, JAK1, JAK2, and JAK3 in U2OS cells, but did not affect the phosphorylation of ERK, JNK, p38, and Akt. Using colivelin, an activator of STAT3, the L48H37-induced decrease in uPA and migratory potential could be countered as expected. Collectively, L48H37 represses the invasion and migration capabilities of U2OS and MG-63 cells by the suppression of uPA expression and the inhibition of JAK/STAT signaling. These results suggest that L48H37 may be a potential candidate for anti-metastatic treatment of human osteosarcoma.

Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Bone Neoplasms; Cell Movement; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 1; Neoplasm Invasiveness; Osteosarcoma; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator

Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity.. The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied.. The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR.. The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.

Topics: Alendronate; Animals; Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Hyaluronic Acid; Male; Mice, Nude; Micelles; Osteosarcoma; Particle Size; Polymers; Proton Magnetic Resonance Spectroscopy; Stearic Acids

Breast cancer (BCa) bone metastases (BMETs) drive osteolysis via a feed-forward loop involving tumoral secretion of osteolytic factors (e.g., PTHrP) induced by bone-matrix-derived growth factors (e.g., TGFβ). In prior experiments, turmeric-derived curcumin inhibited in vivo BMET progression and in vitro TGFβ/Smad-signaling in a TGFβ-stimulated PTHrP-dependent human xenograft BCa BMET model (MDA-SA cells). However, it is unclear whether curcumin or curcumin-glucuronide mediates in vivo protection since curcumin-glucuronide is the primary circulating metabolite in rodents and in humans. Thus, effects of curcumin vs. curcumin-glucuronide on Smad-dependent TGFβ signaling were compared in a series of BCa cell lines forming TGFβ-dependent BMET in murine models, and tissue-specific metabolism of curcumin in mice was examined by LC-MS. While curcumin inhibited TGFβ-receptor-mediated Smad2/3 phosphorylation in all BCa cells studied (human MDA-SA, MDA-1833, MDA-2287 and murine 4T1 cells), curcumin-glucuronide did not. Similarly, curcumin, but not curcumin-glucuronide, blocked TGFβ-stimulated secretion of PTHrP from MDA-SA and 4T1 cells. Because the predominant serum metabolite, curcumin-glucuronide, lacked bioactivity, we examined tissue-specific metabolism of curcumin in mice. Compared to serum and other organs, free curcumin (both absolute and percentage of total) was significantly increased in bone, which was also a rich source of enzymatic deglucuronidation activity. Thus, curcumin, and not curcumin-glucuronide, appears to inhibit bone-tropic BCa cell TGFβ-signaling and to undergo site-specific activation (deconjugation) within the bone microenvironment. These findings suggest that circulating curcumin-glucuronide may act as a prodrug that preferentially targets bone, a process that may contribute to the bone-protective effects of curcumin and other highly glucuronidated dietary polyphenols.

Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Curcumin; Female; Glucuronides; Humans; Mice; Mice, Inbred C57BL; Parathyroid Hormone-Related Protein; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Drug Screening Assays, Antitumor; Gene Expression; Humans; Inhibitory Concentration 50; Membrane Potential, Mitochondrial; Mitochondria; Osteosarcoma; Signal Transduction

Many cancers, such as human breast cancer and lung cancer, easily metastasize to bones, leading to the formation of secondary tumors in advanced stages. On the basis of the CD44-targeted effect of oHA and the bone-targeted effect of ALN, we prepared a reduction-responsive, CD44 receptor-targeting and bone-targeting nanomicelle, called CUR-loaded ALN-oHA-S-S-CUR micelles. In this study, we aimed to evaluate the antitumor activity and bone-targeting ability of CUR-loaded ALN-oHA-S-S-CUR micelles. The in vivo experiment results showed that a larger number of micelles was gathered in the bone metastatic tumor tissue and reduced the bone destruction. The CUR-loaded ALN-oHA-S-S-CUR micelles markedly inhibited the tumor growth. So the CUR-loaded ALN-oHA-S-S-CUR micelles constitute a promising drug delivery system for bone tumor therapy.

Topics: Alendronate; Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Curcumin; Drug Carriers; Drug Liberation; Female; Humans; Hyaluronan Receptors; Hyaluronic Acid; Hydrogen-Ion Concentration; Mice; Mice, Nude; Micelles; Oxidation-Reduction; Particle Size; Polymers; Treatment Outcome; Xenograft Model Antitumor Assays

Curcumin has demonstrated valuable therapeutic potential against a variety of human cancers including osteosarcoma. However, the molecular mechanisms underlying its anti-tumor effect remain to be poorly understood. By RNA sequence profiling, we found that curcumin significantly down-regulates the expression of estrogen-related receptor alpha (ERRα) in osteosarcoma cells. Overexpression of ERRα diminished curcumin-activated apoptotic cell death and scavenged curcumin-induced reactive oxygen species (ROS), while ERRα silencing sensitized osteosarcoma cells to curcumin, resulting in increased inhibition of cell proliferation. In addition, we found that curcumin suppressed the ERRα gene expression through upregulation of miR-125a. Data from this study revealed a novel mechanism for curcumin-mediated apoptotic cell death, which involves tumor cell killing via activating miR-125a/ERRα pathway. Our studies also provide further support for osteosarcoma therapy by targeting ERRα alone or in combination with curcumin. J. Cell. Biochem. 118: 74-81, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Apoptosis; Bone Neoplasms; Cell Line, Tumor; Curcumin; ERRalpha Estrogen-Related Receptor; Humans; MicroRNAs; Neoplasm Proteins; Osteosarcoma; Receptors, Estrogen; RNA, Neoplasm; Signal Transduction

The use of nutraceuticals is gaining in popularity in human and canine oncology with a relatively limited understanding of the effects in the vastly different tumor types seen in canine oncology. We have previously shown that turmeric root (TE) and rosemary leaf (RE) extracts can work synergistically to reduce neoplastic cell growth, but the mechanisms are poorly understood and require further elucidation.. The use of RE in combination with TE induces a synergistic response to induce apoptosis which is better than either extract alone. This appears to be related to a variable increased TE uptake in cells and activation of pathways involved in the apoptotic response.

Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Curcuma; Dog Diseases; Dogs; Female; Mammary Neoplasms, Animal; Mastocytoma; Osteosarcoma; Phytotherapy; Plant Extracts; Plant Leaves; Rosmarinus

Osteosarcoma (OS) is the most common type of malignant bone tumor. Despite aggressive multimodal treatments, including surgical resection, chemotherapy and adjunctive immunotherapies, patients with OS with high-grade malignancy have a poor five-year survival rate that has remained unchanged over the past two decades, highlighting the urgent requirement for novel therapeutic approaches. Signal transducers and activators of transcription 3 (STAT3) has been implicated as an oncogene and therapeutic target in a variety of neoplastic diseases. The aim of the present study was to determine whether inhibition of the janus kinase 2 (JAK2)/STAT3 pathway by FLLL32, a specific JAK2/STAT3 inhibitor, is able to provide a potential therapy for OS. FLLL32 inhibited OS cell growth in vitro and delayed OS growth in an OS xenograft nude mouse model. STAT3 knockdown by short hairpin RNA delayed OS formation in vivo. Thus, the JAK2/STAT3 pathway is important in OS formation. Efficacy of the FLLL32 pharmacological inhibitor in delaying OS growth suggests that targeting JAK2/STAT3 may be a potential therapeutic strategy for patients with OS.

Topics: Animals; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2; Mice; Osteosarcoma; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Osteosarcoma is the most frequent primary malignant form of bone cancer, comprising 30% of all bone cancer cases. The objective of this in vitro study was to develop a treatment against osteosarcoma with higher selectivity toward osteosarcoma cells and lower cytotoxicity toward normal healthy osteoblast cells. Curcumin (or diferuloylmethane) has been found to have antioxidant and anticancer effects by multiple cellular pathways. However, it has lower water solubility and a higher degradation rate in alkaline conditions. In this study, the amphiphilic peptide C18GR7RGDS was used as a curcumin carrier in aqueous solution. This peptide contains a hydrophobic aliphatic tail group leading to their self-assembly by hydrophobic interactions, as well as a hydrophilic head group composed of an arginine-rich and an arginine-glycine-aspartic acid structure. Through characterization by transmission electron microscopy, self-assembled structures of spherical amphiphilic nanoparticles (APNPs) with diameters of 10-20 nm in water and phosphate-buffered saline were observed, but this structure dissociated when the pH value was reduced to 4. Using a method of codissolution with acetic acid and dialysis tubing, the solubility of curcumin was enhanced and a homogeneous solution was formed in the presence of APNPs. Successful encapsulation of curcumin in APNPs was then confirmed by Fourier transform infrared and X-ray diffraction analyses. The cytotoxicity and cellular uptake of the APNP/curcumin complexes on both osteosarcoma and normal osteoblast cell lines were also evaluated by methyl-thiazolyl-tetrazolium assays and confocal fluorescence microscopy. The results showed that the curcumin-loaded APNPs had significant selective cytotoxicity against MG-63 osteosarcoma cells when compared with normal osteoblasts. We have demonstrated for the first time that APNPs can encapsulate hydrophobic curcumin in their hydrophobic cores, and curcumin-loaded APNPs could be an innovative treatment for the selective inhibition of osteosarcoma cells.

Topics: Antineoplastic Agents; Arginine; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Curcumin; Drug Carriers; Humans; Hydrophobic and Hydrophilic Interactions; Microscopy, Electron, Transmission; Nanospheres; Oligopeptides; Osteoblasts; Osteosarcoma; Solubility; Spectroscopy, Fourier Transform Infrared; X-Ray Diffraction

Curcumin is a polyphenol compound extracted from ginger plant, turmeric, commonly used in a variety of food coloring and flavoring additives. Curcumin has many effects such as anti-inflammatory, anti-tumor, antioxidant and anti-microbial effects. However, the mechanism underlying the anti-cancer effect of curcumin on human osteoclastoma (Giant cell tumor, GCT) cells remains unclear. The objectives of this study were to determine the efficacy of curcumin on proliferation and apoptosis of GCT cells and its related mechanisms. In our study, cell viability, cellular apoptosis and caspase-3 activity of GCT cells were analyzed using 3.3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry (FCM) assay and commercial kits, respectively. Next, MMP-9 gene expression quantity, NF-κB activity and JNK protein expression of GCT cells were tested with real-time polymerase chain reaction (RT-PCR), commercial kits and western blotting assay, respectively. Firstly, MMP-9, NF-κB and JNK inhibitors were added into GCT cells and which was researched the mechanism of curcumin on human GCT cells. In this study, the efficacy of curcumin reduced cell viability, induced cellular apoptosis and increased caspase-3 activity of GCT cells. Furthermore, curcumin inhibited the MMP-9 gene expression quantity and NF-κB activity, and activated JNK protein expression in GCT cells. Meanwhile, down-regulation of MMP-9 gene expression quantity and NF-κB activity could promote the anti-cancer effect of curcumin on cell viability of GCT cells. Interesting, down-regulation of JNK protein expression could also reversed the anti-cancer effect of curcumin on cell viability of GCT cells. Taken together, our results suggest that curcumin inhibits cell proliferation and promotes apoptosis in osteoclastoma cell through suppression of MMP-9 and NF-κB, and activation JNK signaling pathways.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Bone Neoplasms; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Giant Cell Tumor of Bone; Humans; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 9; NF-kappa B; Osteoclasts; Signal Transduction; Time Factors; Tumor Cells, Cultured

In this study, we screened the different human osteosarcoma cell line MG-63 miRNAs after the treatment of curcumin and explored the effects of curcumin on MG-63 cells and its mechanism.. Affemitrix miRNA chip was used to detect the changes of miRNA expression profile in MG-63 cells before and after curcumin treatment, and screen different expression of miRNAs. The target gene of miRNA was analyzed by bioinformatics. The expression levels of miRNA-138 target genes Smad4, NFκB p65 and cyclin D3 were detected. MTT and Transwell Cell invasion assays were used to observe the effects of curcumin on MG-63 cells.. Curcumin could significantly inhibit the proliferation of MG-63 cells and the expression levels of miRNA-138 target genes Smad4, NFκB p65 and cyclin D3 in MG-63 cells (P<0.05); overexpression of hsa-miR-138 down-regulated the expression levels of Smad4, NFκB p65 and cyclin D3 compared with the treatment of curcumin, while inhibition of hsa-miR-138 up-regulated the expression levels of Smad4, NFκB p65 and cyclin D3.. Curcumin could increase the expression of hsa-miR-138, hsa-miR-138 inhibited cell proliferation and invasive ability by inhibition of its target genes.

Topics: Antineoplastic Agents; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Oligonucleotide Array Sequence Analysis; Osteosarcoma; Real-Time Polymerase Chain Reaction; Transfection

The antitumor effects of curcumin have attracted widespread attention worldwide. One of its major functions is to induce the apoptosis of tumor cells, but the antitumor mechanism is currently unclear. In the present study, we found that cell mortality and curcumin concentration were dose dependent. Curcumin of low concentrations (10 μΜ) could reduce the level of reactive oxygen species (ROS) in tumor cells, while curcumin of high concentrations (80 μΜ) was able to significantly increase the content of ROS. In addition, Western blotting detection suggested that curcumin of high concentrations can induce the release of Cyto-C and the activation of Caspase-3, and that ROS scavenger NAC apparently inhibits apoptosis protein release and activation, consequently slowing the curcumin-induced apoptosis. Taken together, curcumin further activates the mitochondrial apoptotic pathway by inducing cells to generate ROS and ultimately promotes the apoptosis of tumor cells.

Topics: Apoptosis; Bone Neoplasms; Caspase 3; Cell Line, Tumor; Cell Proliferation; Curcumin; Cytochromes c; Humans; Osteosarcoma; Reactive Oxygen Species; Signal Transduction

Osteosarcoma is a primary bone malignancy with aggressive metastatic potential and poor prognosis rates. In our earlier work we have investigated the therapeutic potential of curcumin as an anti-invasive agent in osteosarcoma by its ability to regulate the Wnt/β-catenin signaling pathway. However, the clinical use of curcumin is limited owing to its low potency and poor pharmacokinetic profile. In this study, an attempt was made to achieve more potent Wnt inhibitory activity in osteosarcoma cells by carrying out synthetic chemical modifications of curcumin. We synthesized a total of five series consisting of 43 curcumin analogs and screened in HEK293T cells for inhibition of β-catenin transcriptional activity. Six promising analogs, which were 6.5- to 60-fold more potent than curcumin in inhibiting Wnt activity, were further assessed for their anti-invasive activity and Wnt inhibitory mechanisms. Western blot analysis showed disruption of β-catenin protein nuclear translocation following treatment with analogs 2f, 3c and 4f. Using transwell assays, we also found that these compounds were more potent than 1a (curcumin) in impeding the invasion of osteosarcoma cells, possibly through suppressing MMP-9 activity. Structure-activity-relationship studies revealed that Wnt inhibitory effects could be enhanced by shortening and restraining the flexibility of the 7-carbon linker moiety connecting the terminal aromatic rings of curcumin and substituting both rings with appropriate substituents. Our results demonstrate that the synthesized curcumin analogs are more potent Wnt inhibitors in osteosarcoma cell lines as compared to parental curcumin and are good lead compounds for further development. Future in vivo tests with these compounds will define their therapeutic potentials as promising drug candidates for clinical treatment of osteosarcoma.

Topics: Antineoplastic Agents; beta Catenin; Bone Neoplasms; Cell Line, Tumor; Curcumin; HEK293 Cells; Humans; Neoplasm Invasiveness; Osteosarcoma; Wnt Signaling Pathway

The aim of the present study was to investigate and compare the effects of diferuloylmethane (curcumin) and diphenyldifluoroketone (EF-24) on cell growth and apoptosis induction in human osteogenic sarcoma cells. This was examined by MTT assay, nuclear DAPI staining, caspase-activation assay, flow cytometry analysis and immunoblotting in Saos2 human osteogenic sarcoma cells. Curcumin and EF-24 inhibited the growth of Saos2 cells in a dose-dependent manner. The apparent potency of EF-24 was more than 3-fold higher that of curcumin. Treatment with curcumin or EF-24 resulted in nuclear condensation and fragmentation in the cells. The caspase-3/-7 activities were detected in living cells treated with curcumin or EF-24. Flow cytometry showed that the rate of apoptosis was increased by curcumin and EF-24 compared to the control. Curcumin and EF-24 promoted the proteolytic cleavages of procaspase-3/-7/-8/-9 with increases in the amount of cleaved caspase-3/-7/-8/-9. The curcumin- or EF-24-induced apoptosis in the Saos2 cells was mediated by the expression of Fas and activation of caspase-8, caspase-3 and poly(ADP-ribose) polymerase. Immunoblotting revealed the Bid and Bcl-2 proteins to be downregulated, and truncated-Bid, Bax and p53 proteins to be upregulated by curcumin and EF-24. Curcumin and EF-24 increased the Bax/Bcl-2 ratio significantly. These results suggest that the curcumin and EF-24 inhibit cell proliferation and induce apoptotic cell death in Saos2 human osteogenic sarcoma cells via both the mitochondria-mediated intrinsic pathway and the death receptor-mediated extrinsic pathway, and may have potential properties for anti-osteosarcoma drug discovery.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Benzylidene Compounds; BH3 Interacting Domain Death Agonist Protein; Bone Neoplasms; Caspase 3; Caspase 7; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Proliferation; Curcumin; Enzyme Activation; Fas-Associated Death Domain Protein; Humans; Osteosarcoma; Piperidones; Poly(ADP-ribose) Polymerases; Tumor Suppressor Protein p53

An attempt has been made to use curcumin (CUR) in combination with Etoposide (ETP) by encapsulating in nanoemulsion, as two tier approach i.e., to evaluate improvement in efficacy of ETP on prostate cancer cells (PC3 and DU145) and to assess their effect on cross-talk between osteoblast and tumor cells leading to metastatic cascade in bones. Nanoemulsion was developed and evaluated for size, charge, in-vitro drug release and anticancer activity, effect on cross talk between osteoblast and prostate cancer cells and pharmacokinetics in rats. The entrapment efficiency of both ETP and CUR in nanoemulsion was more than 98% while the globule size was less than 150 nm with zeta potential - 29.8 mV. The percent inhibition in case of ETP and ETP: CUR (1:3 w/w) was 55.92 ± 1.2 and 41.13 ± 2.4% (at 5 μM) respectively when tested in PC3 cells. DU-145 seemed to be less responsive in comparison to PC3 cells both in respect of ETP and their mixture (ETP+ CUR). Our data shows that CUR and ETP after encapsulation in nanoemulsion (F5) were effectively delivered intracellularly in PC3 cells and the cytotoxicity of F5 was enhanced by 1.5 fold as compared to ETP + CUR at 5 μM concentration. It has also been observed that mice calvarial osteoblasts cultured and incubated with PC-3 and DU-145 cells conditioned media induces inhibition of osteoblast differentiation event. While this inhibition was significantly reversed by F5 at 5 μM concentration over other treated groups, the pharmacokinetic profile of both ETP and CUR was also significantly improved when administered in nanoemulsion.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cell Communication; Cell Line, Tumor; Curcumin; Drug Combinations; Emulsions; Etoposide; Humans; Male; Mice; Nanocapsules; Osteoblasts; Prostatic Neoplasms; Rats, Sprague-Dawley; Treatment Outcome

Effects of curcuminoids on breast cancer cell secretion of the bone-resorptive peptide parathyroid hormone-related protein (PTHrP) and on lytic breast cancer bone metastasis were evaluated. In vitro, transforming growth factor (TGF)-β-stimulated PTHrP secretion was inhibited by curcuminoids (IC50 = 24 μM) in MDA-MB-231 human breast cancer cells independent of effects on cell growth inhibition. Effects on TGF-β signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-β signaling. In vivo, mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated ip every other day with curcuminoids (25 or 50 mg/kg) for 21 days. Osteolytic bone lesion area was reduced up to 51% (p < 0.01). Consistent with specific effects on bone osteolysis, osteoclast number at the bone-tumor interface was reduced up to 53% (p < 0.05), while tumor area within bone was unaltered. In a separate study, tumor mass in orthotopic mammary xenografts was also unaltered by treatment. These data suggest that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Curcumin; Disease Models, Animal; Female; Humans; Mice; Molecular Structure; Osteolysis; Parathyroid Hormone-Related Protein; Signal Transduction; Transforming Growth Factor beta

Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.

Topics: Animals; Anthraquinones; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcumin; Female; Humans; Interleukin-6; Mice; Mice, Nude; Osteosarcoma; Phosphorylation; STAT3 Transcription Factor; Sulfonamides; Tumor Burden; Xenograft Model Antitumor Assays

Delivery of therapeutic agents to bone is crucial in several diseases such as osteoporosis, Paget's disease, myeloproliferative diseases, multiple myeloma as well as skeletal metastasizing cancers. Prevention of cancer growth and lowering the cancer induced bone resorption is important in the treatment of bone metastasizing cancers. Keeping in mind the low diffusivity and availability of cell surface targets on cancer cells, we designed a targeted system to deliver chemotherapeutic agents to the bone microenvironment as an approach to tissue targeting using alendronate (Aln). We co-encapsulated curcumin and bortezomib in the PLGA nanoparticles to further enhance the therapeutic efficiency and overall clinical outcome. These multifunctional nanoparticles were characterized for particle size, morphology and drug encapsulation. The particles were spherical with smooth surface and had particle size of 235 ± 70.30 nm. We validated the bone targeting ability of these nanoparticles in vitro. Curcumin and bortezomib are known to have synergistic effect in inhibition of growth of cancer; however there was no synergism in the anti-osteoclastogenic activity of these agents. Surprisingly, curcumin by itself had significant inhibition of osteclastogenic activity. In vivo non-invasive bioimaging showed higher localization of Aln-coated nanoparticles to the bone compared to control groups, which was further confirmed by histological analysis. Aln-coated nanoparticles protected bone resorption and decreased the rate of tumor growth as compared to control groups in an intraosseous model of bone metastasis. Our data show efficient attachment of Aln on the surface of nanoparticles which could be used as a drug carrier for preferential delivery of multiple therapeutic agents to bone microenvironment.

Topics: Alendronate; Animals; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Boronic Acids; Bortezomib; Breast Neoplasms; Curcumin; Drug Carriers; Female; Humans; Lactic Acid; Mice; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Osteoporosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrazines

To investigate the reversion of P-gp mediated multidrug resistance of U-2OS/ADM cells with curcumin in vitro.. With doxorubicin as induction drugs, human osteosarcoma cell line U-2OS was induced object, multi-drug resistant of human osteosarcoma cell line model (U-2OS/ADM) were established by high-dose method, The before and after reversal efficacy of curcumin for U-2OS/ADM cells to chemotherapeutic drugs were measured by MTT assay. The effects of curcumin on Rh-123 uptake and efflux were analyzed by flow cytometer.. (1) MTT demonstrates curcumin (20 micromol/L) can increase the cytotoxicity of Adriamycin to U-2OS/ADM cells. (2) The result of FCM shows that Curcumin can increase the accumulation of Rh-123 and increase the cytotoxicity of Adriamycin to U-2OS/ADM cells in a dose-dependent manner.. The reversal mechanism of curcumin was blocked the function of P-gp in U-2OS/ADM cellular membrane.

Topics: Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Curcumin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Osteosarcoma

Curcumin is a naturally occurring phenolic compound shown to have a wide variety of antitumor activities; however, it does not attain sufficient blood levels to do so when ingested. Using structure-based design, a novel compound, FLLL32, was generated from curcumin. FLLL32 possesses superior biochemical properties and more specifically targets STAT3, a transcription factor important in tumor cell survival, proliferation, metastasis, and chemotherapy resistance. In our previous work, we found that several canine and human osteosarcoma (OSA) cell lines, but not normal osteoblasts, exhibit constitutive phosphorylation of STAT3. Compared to curcumin, we hypothesized that FLLL32 would be more efficient at inhibiting STAT3 function in OSA cells and that this would result in enhanced downregulation of STAT3 transcriptional targets and subsequent death of OSA cells.. Human and canine OSA cells were treated with vehicle, curcumin, or FLLL32 and the effects on proliferation (CyQUANT®), apoptosis (SensoLyte® Homogeneous AMC Caspase- 3/7 Assay kit, western blotting), STAT3 DNA binding (EMSA), and vascular endothelial growth factor (VEGF), survivin, and matrix metalloproteinase-2 (MMP2) expression (RT-PCR, western blotting) were measured. STAT3 expression was measured by RT-PCR, qRT- PCR, and western blotting.. Our data showed that FLLL32 decreased STAT3 DNA binding by EMSA. FLLL32 promoted loss of cell proliferation at lower concentrations than curcumin leading to caspase-3- dependent apoptosis, as evidenced by PARP cleavage and increased caspase 3/7 activity; this could be inhibited by treatment with the pan-caspase inhibitor Z-VAD-FMK. Treatment of OSA cells with FLLL32 decreased expression of survivin, VEGF, and MMP2 at both mRNA and protein levels with concurrent decreases in phosphorylated and total STAT3; this loss of total STAT3 occurred, in part, via the ubiquitin-proteasome pathway.. These data demonstrate that the novel curcumin analog FLLL32 has biologic activity against OSA cell lines through inhibition of STAT3 function and expression. Future work with FLLL32 will define the therapeutic potential of this compound in vivo.

Topics: Animals; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Curcumin; DNA; Dog Diseases; Dogs; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Humans; Osteosarcoma; Protein Binding; STAT3 Transcription Factor

Curcumin is a naturally occurring polyphenolic compound found in the turmeric, which is used as food additive in Indian cooking and as a therapeutic agent in traditional Indian medicine. Curcumin is currently under investigation as a chemotherapeutic and chemopreventive agent in adult cancer models at both pre-clinical and clinical levels. In this preliminary study, we show that curcumin is effective in causing cell cycle arrest, inducing apoptosis, and suppressing colony formation in the Ewing sarcoma cell line SK-NEP-1. Curcumin causes upregulation of cleaved caspase 3 and downregulation of phospho-Akt, producing apoptosis in Ewing sarcoma cells at an inhibitory concentration 50% (IC50) of approximately 4 μM. Our findings indicate a need for further evaluation of curcumin in chemotherapy and chemoprevention of Ewing sarcoma.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Bone Neoplasms; Cell Cycle; Cell Line, Tumor; Curcumin; Flow Cytometry; Humans; Proto-Oncogene Proteins c-akt; Sarcoma, Ewing

Curcumin is the lipid-soluble antioxidant compound obtained from the rhizome of Curcuma longa Linn, also known as turmeric. Curcumin targets multiple chemotherapeutic and inflammatory pathways and has demonstrated safety and tolerability in humans, supporting its potential as a therapeutic agent; however, the clinical literature lacks conclusive evidence supporting its use as a therapeutic agent due to its low bioavailability in humans. The purpose of this study was to quantify plasma levels of free curcumin after dosing of a solid lipid curcumin particle (SLCP) formulation versus unformulated curcumin in healthy volunteers and to determine its tolerability and dose-plasma concentration relationship in late-stage osteosarcoma patients. Doses of 2, 3, and 4 g of SLCP were evaluated in 11 patients with osteosarcoma. Plasma curcumin levels were measured using a validated high-performance liquid chromatography method. The limit of detection of the assay was 1 ng/mL of curcumin. In healthy subjects, the mean peak concentration of curcumin achieved from dosing 650 mg of SLCP was 22.43 ng/mL, whereas plasma curcumin from dosing an equal quantity of unformulated 95% curcuminoids extract was not detected. In both healthy individuals and osteosarcoma patients, high interindividual variability in pharmacokinetics and nonlinear dose dependency was observed, suggesting potentially complex absorption kinetics. Overall, good tolerability was noted in both healthy and osteosarcoma groups.

Topics: Adolescent; Adult; Antineoplastic Agents; Bone Neoplasms; Chemistry, Pharmaceutical; Child; Chromatography, High Pressure Liquid; Curcuma; Curcumin; Drug Tolerance; Female; Humans; Male; Osteosarcoma; Reference Values; Safety; Young Adult

The objective of this study was to investigate altered expressions of nuclear matrix proteins (NMPs) of human osteosarcoma (OS) MG-63 cells during curcumin-induced apoptosis of human OS MG-63 cells. MG-63 cells were cultured with curcumin (7.5 mg/L) for 72 hr. Morphological alterations of cells were captured using light microscopy and transmission electron microscopy, and cell cycle distribution was estimated by flow cytometry. NMPs were selectively extracted and subjected to two-dimensional gel electrophoresis (2-DE) analysis. Western blots were performed to determine changes in the expression levels of specific NMPs. The results demonstrated that typical characteristics of apoptosis were observed. Cellular chromatin agglutinated, cell nuclei condensed, and apoptotic bodies were formed after treatment with curcumin. The 2-DE results displayed 27 NMPs, 21 of which were identified to have change in expression levels significantly during apoptosis. The altered expressions of three of these NMPs (nucleophosmin, prohibitin, and vimentin) were further confirmed by immunoblotting. These findings indicated that the apoptosis of MG-63 cells was accompanied by the expression alteration of NMPs. Our results might help to reveal the relationship between NMPs and the regulation of gene expression in the process of apoptosis, as well as provide the basic concepts for future studies on the mechanisms of apoptosis and the therapy for bone diseases.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Cell Nucleus; Chromatin; Curcumin; Electrophoresis, Gel, Two-Dimensional; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Microscopy, Electron, Transmission; Nuclear Matrix-Associated Proteins; Nuclear Proteins; Nucleophosmin; Osteosarcoma; Prohibitins; Repressor Proteins; Vimentin

Curcumin is a major component of Curcuma longa rhizome and has been used as a traditional medicine for centuries. In this study, we showed that curcumin induced cell cycle arrest followed by antiproliferation and apoptosis in human osteosarcoma (HOS) cells.. Antiproliferative activity was measured with the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Nuclear fragmentation was observed with a fluorescence microscope. Flow cytometry was performed to observe cell cycle distribution and apoptotic body appearance. Changes in cell cycle regulatory and apoptosis-related proteins were investigated by Western blot analysis.. The IC(50) value of curcumin was approximately 4.0 microg/ml. Induction of apoptosis was evidenced by apoptotic body appearance and chromosomal DNA degradation. Flow-cytometric analysis indicated that curcumin induced successive G(1)/S and G(2)/M phase arrest followed by apoptosis in HOS cells. The G(1)/S and G(2)/S phase arrest was accompanied by down-regulation of cyclin D1, cdc2 and cyclin B1, respectively. Apoptosis was induced by capspase-3 activation and poly(ADP-ribosyl)polymerase (PARP) cleavage.. Our results demonstrated that curcumin caused death of HOS cells by blocking cells successively in G(1)/S and G(2)/M phases and activating the caspase-3 pathway.

Topics: Antineoplastic Agents; Apoptosis; Blotting, Western; Bone Neoplasms; Caspase 3; Cell Cycle; Cell Proliferation; Curcumin; Enzyme Activation; Flow Cytometry; Humans; Osteosarcoma; Poly(ADP-ribose) Polymerases; Tumor Cells, Cultured

 Curcumin, an active ingredient derived from the rhizome of the plant, Curcuma longa, has antioxidant, anti-inflammatory and anti-cancer activities. The aims of this study were to examine whether curcumin can induce apoptosis in an osteosarcoma cell line.. Curcumin-induced apoptosis in human osteosarcoma U2OS cells was investigated using morphological analysis, marked nuclear condensation and fragmentation of chromatin, which were observed by Hoechst 33258 staining and DNA ladder formation. The U2OS cells were treated with or without curcumin. Cell viability was assessed by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium (MTT) method. Cell-cycle, apoptosis and apoptosis-related proteins in U2OS cells were evaluated by flow cytometry and western blotting.. Curcumin showed growth inhibitory effects on U2OS cells in a dose-and time-dependent manner, inducing significant G1 arrest and apoptosis in U2OS cells. This curcumin-induced apoptosis in U2OS cells was accompanied by up-regulation of Bax, Bak, and p-Bad and down-regulation of Bcl-2, but no effect on the levels of Bcl-X(L) or Bad proteins was noted. Moreover, curcumin treatment resulted in a significant reduction of mitochondrial membrane potential and increase in the concentrations of mitochondrial cytochrome C and caspase-3.. Multiple molecular pathways are involved in curcumin-induced apoptosis of human U2OS cells. These include pro-and anti-apoptotic Bcl-2 family proteins, mitochondrial membrane potential, mitochondrial cytochrome C and caspase-3.

Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Cell Survival; Curcumin; DNA, Neoplasm; Flow Cytometry; Humans; Osteosarcoma; Up-Regulation

There is increasing evidence that the stringent selective pressure imposed by androgen ablation therapy on the residual prostate cancer cells may actually accelerate the development of the hormone refractory and bone metastatic phenotype. The propensity of prostate cancer to establish osseous metastases is very likely mediated by the osteomimetic properties of the prostate cancer cells. Prostate cancer cells acquire these "bone-like" properties in order to survive in the bony microenvironment. This process is facilitated by common growth factor trophisms between the bone stromal cells, osteoblasts, and the prostate cancer cells wherein a number of growth factors and their receptors are involved. Thus, a general inhibition of the tyrosine kinase signaling pathways may have a therapeutic advantage in interfering with the metastatic potential of these prostate cancer cells. This study focuses on the potential of curcumin, a plant based non-toxic tyrosine kinase inhibitor in interfering with the development of bone like properties of C4-2B, a highly metastatic derivative of LNCaP prostate cancer cell line.. C4-2B prostate cancer cells were analyzed for their constitutive expression and ligand inducible activation of growth factor receptors such as EGF-R and CSF1-R. Expression of bone-specific transcription factors such as Cbfa-1 and the production of PTHRP were followed. The ability of the C4-2B cells to mineralize under specific conditions was analyzed. The activation status of the transcription factor NF-kappa B was also followed.. Curcumin inhibited the ligand-stimulated autophosphorylation of EGF-R and CSF1-R that were crucially involved in the development of osteomimetic properties of C4-2B cells. When C4-2B cells were grown under promineralization conditions, curcumin prevented the formation of the mineralized nodules. It also inhibited the expression of the core-binding factor a-1 in C4-2B cells which was responsible for the expression of several bone-specific proteins. The IKK activity was severely impaired, showing marked NF-kappa B inhibition. The experiments indicate that curcumin can also interfere with the development of the osteoblast and the osteoclast-like properties by these prostate cancer cells.. The highly metastatic C4-2B prostate cancer cell line is already "programmed" to exhibit the bone-like properties that would at least in part explain its affinity to set up osseous metastases. Curcumin is able to interfere with the osteoblastic component as well as the osteoclastic component of this phenotype, by interfering with the growth factor receptor pathways and by inhibiting the NF-kappa B activation process. It is concluded that curcumin may inhibit the growth factor collaboration between the prostate cancer cells and the osteoblast/stromal cells, thus exhibiting a potential to prevent the establishment of bony metastases.

Topics: Antineoplastic Agents; Bone Neoplasms; Cell Communication; Cell Survival; Curcumin; ErbB Receptors; Humans; Male; Osteoblasts; Phenotype; Prostatic Neoplasms; Receptor, Macrophage Colony-Stimulating Factor; Tumor Cells, Cultured