Metallocompounds as anticancer agents against osteosarcoma.

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure-activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.

Promising Dual Anticancer and Antimetastatic Action by a Cu(II) Complex Derived from Acylhydrazone on Human Osteosarcoma Models.

Osteosarcoma cancers are becoming more common in children and young adults, and existing treatments have low efficacy and a very high mortality rate, making it pressing to search for new chemotherapies with high efficacy and high selectivity index. Copper complexes have shown promise in the treatment of osteosarcoma. Here, we report the synthesis, characterization, and anticancer activity of [Cu(N-N-Fur)(NO3)(H2O)] complex where N-N-Fur is (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide. The [Cu(N-N-Fur)(NO3)(H2O)] complex was characterized via X-ray diffraction and electron spin resonance (ESR), displaying a copper center in a nearly squared pyramid environment with the nitrate ligand acting as a fifth ligand in the coordination sphere. We observed that [Cu(N-N-Fur)(NO3)(H2O)] binds to DNA in an intercalative manner. Anticancer activity on the MG-63 cell line was evaluated in osteosarcoma monolayer (IC50 2D: 1.1 ± 0.1 µM) and spheroids (IC50 3D: 16.3 ± 3.1 µM). Selectivity assays using nontumoral fibroblast (L929 cell line) showed that [Cu(N-N-Fur)(NO3)(H2O)] has selectivity index value of 2.3 compared to cis-diamminedichloroplatinum(II) (CDDP) (SI = 0.3). Additionally, flow cytometry studies demonstrated that [Cu(N-N-Fur)(NO3)(H2O)] inhibits cell proliferation and conveys cells to apoptosis. Cell viability studies of MG-63 spheroids (IC50 = 16.3 ± 3.1 µM) showed that its IC50 value is 4 times lower than for CDDP (IC50 = 65 ± 6 µM). Besides, we found that cell death events mainly occurred in the center region of the spheroids, indicating efficient transport to the microtumor. Lastly, the complex showed dose-dependent reductions in spheroid cell migration from 7.5 to 20 µM, indicating both anticancer and antimetastatic effects.

Effects of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in patients with osteosarcoma and their influencing factors.

OBJECTIVE: The objective of this study was to investigate the impact of Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline) on cardiac function in osteosarcoma patients and analyze the factors influencing this effect. METHODS: A retrospective study was conducted on 165 osteosarcoma patients admitted to our hospital from January 2020 to December 2022. Based on the chemotherapy regimen, the patients were divided into two groups: the control group (n = 62) treated with Cisplatin and cyclophosphamide, and the observation group (n = 103) treated with Doxorubicin, Epirubicin, and Liposomal Doxorubicin (Anthracycline). The general records of both groups were analyzed, and left ventricular ejection fraction (LVEF) was evaluated through echocardiography before and after chemotherapy. Blood cTnT and CK-MB levels were measured using immunoluminescence. The incidence of adverse reactions during chemotherapy was also analyzed. Univariate analysis was performed to identify patients with cardiotoxic events, and multiple logistic regression analysis was done to study the effects of Doxorubicin, Epirubicin, Liposomal Doxorubicin, and their dosages on cardiotoxicity in patients. RESULTS: The general records between the two groups showed no significant differences (P > 0.05). However, at the fourth cycle of chemotherapy, the observation group exhibited a lower LVEF (P < 0.05), and a higher percentage of LVEF decrease compared to the control group (P < 0.05). Moreover, the observation group had higher levels of blood cTnT and CK-MB (P < 0.05). The incidence of cardiotoxicity in the observation group was also higher (P < 0.05), but no significant differences were seen in other adverse reaction rates (P > 0.05). The occurrence of cardiotoxicity was found to be related to the choice and dosage of chemotherapy drugs (P < 0.05), but not significantly correlated with age, sex, and mediastinal irradiation in patients (P > 0.05). Furthermore, the use of Doxorubicin, Epirubicin, and Liposomal Doxorubicin in chemotherapy, as well as an increase in their dosages, was found to elevate the risk of cardiotoxicity in osteosarcoma patients (P < 0.05). However, age, sex, and mediastinal radiation were not significantly associated with cardiotoxicity in osteosarcoma patients (P > 0.05). CONCLUSION: We demonstrated that Doxorubicin, Epirubicin, Liposomal Doxorubicin (Anthracycline), and other drugs adversely affected cardiac function in osteosarcoma patients, increasing the risk of cardiac toxicity. Therefore, close monitoring of cardiac function during chemotherapy is crucial, and timely adjustments to the chemotherapy regimen are necessary. In addition, rational control of drug selection and dosage is essential to minimize the occurrence of cardiac toxicity.

Inhibition of anlotinib-induced autophagy attenuates invasion and migration by regulating epithelial-mesenchymal transition and cytoskeletal rearrangement through ATG5 in human osteosarcoma cells.

The cure rates for osteosarcoma have remained unchanged in the past three decades, especially for patients with pulmonary metastasis. Thus, a new and effective treatment for metastatic osteosarcoma is urgently needed. Anlotinib has been reported to have antitumor effects on advanced osteosarcoma. However, both the effect of anlotinib on autophagy in osteosarcoma and the mechanism of anlotinib-mediated autophagy in pulmonary metastasis are unclear. The effect of anlotinib treatment on the metastasis of osteosarcoma was investigated by transwell assays, wound healing assays, and animal experiments. Related proteins were detected by western blotting after anlotinib treatment, ATG5 silencing, or ATG5 overexpression. Immunofluorescence staining and transmission electron microscopy were used to detect alterations in autophagy and the cytoskeleton. Anlotinib inhibited the migration and invasion of osteosarcoma cells but promoted autophagy and increased ATG5 expression. Furthermore, the decreases in invasion and migration induced by anlotinib treatment were enhanced by ATG5 silencing. In addition, Y-27632 inhibited cytoskeletal rearrangement, which was rescued by ATG5 overexpression. ATG5 overexpression enhanced epithelial-mesenchymal transition (EMT). Mechanistically, anlotinib-induced autophagy promoted migration and invasion by activating EMT and cytoskeletal rearrangement through ATG5 both in vitro and in vivo. Our results demonstrated that anlotinib can induce protective autophagy in osteosarcoma cells and that inhibition of anlotinib-induced autophagy enhanced the inhibitory effects of anlotinib on osteosarcoma metastasis. Thus, the therapeutic effect of anlotinib treatment can be improved by combination treatment with autophagy inhibitors, which provides a new direction for the treatment of metastatic osteosarcoma.

Micellar solution of [223Ra]RaCl2: Reaching renal excretion, potent efficacy in osteoblastic osteosarcoma in PDX model, biochemistry alterations and pharmacokinetics.

Despite the successful use of the radiopharmaceutical radium-223 dichloride ([223Ra]RaCl2) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [223Ra]RaCl2 and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [223Ra]RaCl2 in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [223Ra]RaCl2. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1-0.02) from 24 to 96 h after administration. In addition, the micellar [223Ra]RaCl2 exhibited a significantly higher uptake in left (%ID/g = 0.85-0.23) and right (%ID/g = 0.76-0.24) kidneys than in small (%ID/g = 0.43-0.06) and large intestines (%ID/g = 0.24-0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [223Ra]RaCl2. The micellar [223Ra]RaCl2 also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [223Ra]RaCl2 indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [223Ra]RaCl2, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose-response outcomes and organ/tissue dosimetry for clinical translation.

Menadione and protocatechuic acid: A drug combination with antitumor effects in murine osteosarcoma cells.

Osteosarcoma (OS) is a primary malignant bone tumor that has an abnormal expression of oncogenesis and tumor suppressors and causes dysregulation of various signaling pathways. Thus, novel therapeutic strategies for OS are needed to overcome the resistance of traditional treatments. This study evaluated the cytotoxic and anticancer effects of the association between menadione (MEN) and protocatechuic acid (PCA) in murine OS cells (UMR-106). The concentrations were 3.12 µM of isolated MEN, 500 µM of isolated PCA, and their associations. We performed cell viability assays, morphology modification analysis, cell migration by the wound-healing method, apoptosis by flow cytometry, reactive oxygen species (ROS) production, gene expression of NOX by RT-qPCR, and degradation of MMP-2 and 9 by zymography. Our results showed that the association of MEN+PCA was more effective in OS cells than the compounds alone. The association decreased cell viability, delayed cell migration, and decreased the expression of NOX-2 and ROS. In addition, the MEN+PCA association induced a slight increase in the apoptotic process. In summary, the association can enhance the compound's antitumor effects and establish a higher selectivity for tumor cells, possibly caused by significant mitochondrial damage and antioxidant properties.

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.

Pharmacogenetics of the Primary and Metastatic Osteosarcoma: Gene Expression Profile Associated with Outcome.

Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. In recent decades, OS treatment has reached a plateau and drug resistance is still a major challenge. Therefore, the present study aimed to analyze the expression of the genes related to pharmacogenetics in OS. The expression of 32 target genes in 80 paired specimens (pre-chemotherapeutic primary tumor, post-chemotherapeutic primary tumor and pulmonary metastasis) obtained from 33 patients diagnosed with OS were analyzed by the real-time PCR methodology. As the calibrators (control), five normal bone specimens were used. The present study identified associations between the OS outcome and the expression of the genes TOP2A, DHFR, MTHFR, BCL2L1, CASP3, FASLG, GSTM3, SOD1, ABCC1, ABCC2, ABCC3, ABCC5, ABCC6, ABCC10, ABCC11, ABCG2, RALBP1, SLC19A1, SLC22A1, ERCC1 and MSH2. In addition, the expression of the ABCC10, GGH, GSTM3 and SLC22A1 genes were associated with the disease event, and the metastasis specimens showed a high expression profile of ABCC1, ABCC3 and ABCC4 genes and a low expression of SLC22A1 and ABCC10 genes, which is possibly an important factor for resistance in OS metastasis. Therefore, our findings may, in the future, contribute to clinical management as prognostic factors as well as possible therapeutic targets.

Nano-hydroxyapatite radiolabeled with radium dichloride [223Ra] RaCl2 for bone cancer targeted alpha therapy: In vitro assay and radiation effect on the nanostructure.

The use of targeted alpha therapy (TAT) for bone cancer is increasing each year. Among the alpha radionuclides, radium [223Ra]Ra+2 is the first one approved for bone cancer metastasis therapy. The development of novel radiopharmaceutical based on [223Ra]Ra+2 is essential to continuously increase the arsenal of new TAT drugs. In this study we have developed, characterized, and in vitro evaluated [223Ra] Ra-nano-hydroxyapatite. The results showed that [223Ra] Ra-nano-hydroxyapatite has a dose-response relationship for osteosarcoma cells and a safety profile for human fibroblast cells, corroborating the application as a radiopharmaceutical.

Peri-osteosarcoma adipose computed tomography attenuation and volume for predicting chemotherapy response in pediatric patients.

BACKGROUND: The chemosensitivity of osteosarcoma patients to MTX is closely related to prognosis. There is currently a lack of advance prediction methods for MTX sensitivity. OBJECTIVE: We proposed novel peri-osteosarcoma fat parameters based on computed tomography (CT) to evaluate the chemotherapy response preoperatively and calculate the correlation between image characteristics and methotrexate (MTX) blood concentration and systemic inflammation. MATERIALS AND METHODS: Pediatric patients with osteosarcoma (OS) who were treated with high-dose MTX were retrospectively studied and grouped according to postoperative Huvos classification. Clinical data were collected and reviewed. Image characteristics including peri-osteosarcoma fat volume and fat attenuation index were measured using the threshold method based on CT images. Statistical significance, correlation and prediction performance were performed. RESULTS: Eighteen patients (good response (GR) group/poor response (PR) group: 10/8) was enrolled. MTX peak value at 6 h differed significantly between the two groups which was significantly higher in GR group (745.1 µmol/L vs 529.0 µmol/L p = 0.001). Peri-osteosarcoma fat attenuation index was significantly lower in GR group compared with that in PR group (- 104.90 vs. - 97.19, p < 0.0001). MTX blood concentration at 6 h negatively correlated with peri-osteosarcoma fat attenuation index (R = - 0.519, p = 0.027). In addition, 6 h MTX blood concentration (OR 0.974; 95% CI 0.951-0.998, p = 0.037) and FAI (OR 2.108; 95% CI 1.047-4.243, p = 0.037) were, respectively, independently related to good response to chemotherapy. The prediction performance on chemotherapy response of peri-osteosarcoma fat attenuation index and 6 h MTX blood concentration were both good with the comparable area under the ROC curve (0.950, 95% CI 0.856-1.000 and 0.963, 95% CI 0.878-1.00). CONCLUSIONS: Peri-osteosarcoma fat parameters based on CT were associated with the chemotherapy response and the MTX blood concentration, but not with the systemic inflammation. Combined with the requirement of current clinical practice, peri-osteosarcoma fat parameters may have the potential to be valuable image characteristics for monitoring chemotherapy response in OS pediatric patients.

Management of chemotherapy-induced febrile neutropenia and use of granulocyte colony-stimulating factor in patients with soft tissue or bone sarcoma.

INTRODUCTION: Febrile neutropenia, an oncological complication related to myelosuppressive chemotherapy, can lead to unplanned hospitalization, morbidity, mortality, and changes in the oncological therapeutic plan. The present study aimed (1) to determine the prevalence of chemotherapy-induced febrile neutropenia requiring hospitalization and the use of granulocyte colony-stimulating factor and (2) to evaluate its consequences for the oncological treatment of patients with soft tissue or bone sarcomas. METHODS: This is a cross-sectional and retrospective study (January 2018 to December 2019) carried out in a reference oncology hospital in the Brazilian public health system. Inpatients diagnosed with chemotherapy-induced febrile neutropenia, older than the age of 18 years, and treated with granulocyte colony-stimulating factor were included in the study. RESULTS: Twenty-nine chemotherapy-induced febrile neutropenia events were identified, involving 25 patients. Among the febrile neutropenia events, 90% were grade 4, and 59% occurred during palliative chemotherapy. Among patients with febrile neutropenia, 31% had arterial hypertension or/and diabetes mellitus comorbidities, 34% had infectious skin sites, such as compression ulcers and tumor wounds, and 31% had infections with defined etiologic agents. Treatment of hospitalized patients was performed with cefepime in combinations or alone (97%) and filgrastim. The outcomes related to chemotherapy-induced febrile neutropenia were chemotherapy dose reduction (31%), chemotherapy cycle delays (21%), chemotherapy treatment suspension (17%), deaths (7%), and other associated complications (10%). Granulocyte colony-stimulating factor prophylaxis was prescribed in 72.41% of febrile neutropenia events. The frequency of febrile neutropenia concerning total chemotherapy cycles was 2.15%. CONCLUSION: Even with granulocyte colony-stimulating factor prophylaxis, an overall prevalence of 2.15% of febrile neutropenia associated with hospitalization was observed, causing negative outcomes in chemotherapy treatment of patients.

Postoperative Analgesia and Palliative Care of Peng Block for Terminal Osteosarcoma.

Palliative care involves patients with a high incidence of chronic pain and inadequate treatment related to opioid abuse. In terminal patients, the side effects of opioids may result in lower quality of life due to their deleterious immunosuppression and gastrointestinal effects. In our routine clinical practice, we consider the ultrasound-guided PENG block as a palliative analgesic technique to improve end-of-life care to terminal patients.

Propranolol blocks osteosarcoma cell cycle progression, inhibits angiogenesis and slows xenograft growth in combination with cisplatin-based chemotherapy.

Osteosarcoma is still associated with limited response to standard-of-care therapy and alarmingly elevated mortality rates, especially in low- and middle-income countries. Despite multiple efforts to repurpose ß-blocker propranolol in oncology, its potential application in osteosarcoma management remains largely unexplored. Considering the unsatisfied clinical needs of this aggressive disease, we evaluated the antitumoral activity of propranolol using different in vitro and in vivo osteosarcoma preclinical models, alone or in addition to chemotherapy. Propranolol significantly impaired cellular growth in ß2-adrenergic receptor-expressing MG-63 and U-2OS cells, and was capable of blocking growth-stimulating effects triggered by catecholamines. siRNA-mediated ADRB2 knockdown in MG-63 cells was associated with decreased cell survival and a significant attenuation of PPN anti-osteosarcoma activity. Direct cytostatic effects of propranolol were independent of apoptosis induction and were associated with reduced mitosis, G0/G1 cell cycle arrest and a significant down-regulation of cell cycle regulator Cyclin D1. Moreover, colony formation, 3D spheroid growth, cell chemotaxis and capillary-like tube formation were drastically impaired after propranolol treatment. Interestingly, anti-migratory activity of ß-blocker was associated with altered actin cytoskeleton dynamics. In vivo, propranolol treatment (10 mg/kg/day i.p.) reduced the early angiogenic response triggered by MG-63 cells in nude mice. Synergistic effects were observed in vitro after combining propranolol with chemotherapeutic agent cisplatin. Sustained administration of propranolol (10 mg/kg/day i.p., five days a week), alone and especially in addition to low-dose metronomic cisplatin (2 mg/kg/day i.p., three times a week), markedly reduced xenograft progression. After histological analysis, propranolol and cisplatin combination resulted in low tumor mitotic index and increased tumor necrosis. ß-blockade using propranolol seems to be an achievable and cost-effective therapeutic approach to modulate osteosarcoma aggressiveness. Further translational studies of propranolol repurposing in osteosarcoma are warranted.

Response to neoadjuvant chemotherapy and survival of children and adolescents with high-grade osteosarcoma treated based on the EURAMOS-1 protocol.

BACKGROUND: High-grade osteosarcoma is the most common malignant bone tumor in children and adolescents. This study aimed to evaluate the histologic response to neoadjuvant chemotherapy and overall and event-free survival rates in patients < 21 years of age with a diagnosis of conventional osteosarcoma. METHODS: We conducted an analytical and observational study of a cohort of patients < 21 years old with a diagnosis of conventional osteosarcoma treated with the OS INC-2009 protocol (based on EURAMOS-1). Descriptive analysis was performed, and overall and event-free survival rates were calculated by the Kaplan-Meier method. RESULTS: Between April 2009 and October 2016, 84 patients with conventional osteosarcoma (mean age 13.5 ± 3.2 years) were admitted. Metastatic disease at diagnosis was observed in 36 patients (42.8%). Of the 41 patients who received neoadjuvant chemotherapy (50.6%), 15 (36.6%; confidence interval [95% CI]: 49.9-75.6) were classified as good responders and 26 (63%; 95% CI: 22.5-58.0) as poor responders. The 5-year overall and event-free survival rates in good responders were 88.8% (95% CI: 43.3-98.3) and 81.4% (95% CI: 43.5-95.0); in poor responders it was 66.5% (95% CI: 40.7-83.1) and 31.4% (95% CI: 13.8-50.7), respectively. CONCLUSIONS: Good responders' evaluation of histologic response to neoadjuvant chemotherapy showed improved overall and event-free survival rates. Specialized centers with multidisciplinary and comprehensive management are required to make the application of high-toxicity protocols feasible.

INTRODUCCIÓN: El osteosarcoma de alto grado es el tumor óseo maligno más común en niños y adolescentes. El objetivo de este trabajo fue evaluar la respuesta histológica a la quimioterapia neoadyuvante y la supervivencia global y libre de eventos en pacientes menores de 21 años con diagnóstico de osteosarcoma convencional. MÉTODOS: Se llevó a cabo un estudio observacional analítico de una cohorte de pacientes menores de 21 años con diagnóstico de osteosarcoma convencional tratados con el protocolo OS INC-2009 (basado en EURAMOS-1). Se realizó el análisis descriptivo y se calcularon la supervivencia global y la supervivencia libre de eventos por el método de Kaplan-Meier. RESULTADOS: Entre abril de 2009 y octubre de 2016 se analizaron 84 pacientes con osteosarcoma convencional, cuya edad promedio fue de 13.5 años (desviación estándar: ± 3.2). La enfermedad metastásica al diagnóstico se observó en 36 pacientes (42.8%). De los 41 (50.6%) pacientes que recibieron terapia neoadyuvante, 15 (36.6%; intervalo de confianza del 95% [IC95%]: 49.9-75.6) se clasificaron como buenos respondedores y 26 (63%; IC95%: 22.5-58.0) como malos respondedores. Las supervivencias global y libre de eventos a 5 años en los buenos respondedores fueron del 88.8% (IC95%: 43.3-98.3) y el 81.4% (IC95% 43.5-95.0), y en los malos respondedores fueron del 66.5% (IC95%: 40.7-83.1) y el 31.4% (IC95%: 13.8-50.7), respectivamente. CONCLUSIONES: La evaluación de la respuesta histológica a la quimioterapia neoadyuvante de los pacientes buenos respondedores muestra unas mejores supervivencias global y libre de eventos. Se requieren centros especializados con manejos multidisciplinarios e integrales para hacer factible la aplicación de protocolos con alta toxicidad.

Evaluation of Myrcia bella in murine osteosarcoma cells: Effect of the extract and enriched fractions of tannins and flavonoids.

Myrcia bella Cambess (Myrtaceae) is an important and common plant, native to the Brazilian Cerrado, with cytotoxicity, antimicrobial, and antidiabetic properties. Therefore, the effects of crude hydroalcoholic extract (CE) and fractions of ellagitannins (ELT) and flavonoids (FV) from Myrcia bella leaves were evaluated in a UMR-106 murine osteosarcoma cells and MC3T3 (normal cell). Cell viability and migration, production of reactive oxygen species (ROS) and matrix metalloproteinase (MMP) -2 and -9 activities were evaluated. In general, CE (80 µg/mL), ELT (160 µg/mL) and FV (64 µg/mL) reduced cell viability (p < 0.05). FV (64 µg/mL) was more effective in inhibition of cell migration, ROS production, and MMP-2 activity when compared to CE and ELT. Myrcia bella a rich source of phenolic compounds and its fraction of flavonoids have cytotoxic effects on osteosarcoma cells, preserving the viability of normal osteoblasts. Due to its antioxidant capacity, flavonoid may be a new therapeutic strategy for cancer.

Anti-tumour potential and selectivity of caffeic acid phenethyl ester in osteosarcoma cells.

Osteosarcoma is the most common type of bone cancer, and metastasis is widespread decreasing the survival rate. The search for new therapeutic strategies has increased for phytochemicals due to their potential as antioxidants and anticancer properties. Thus, we evaluated the caffeic acid phenethyl ester (CAPE) and caffeic acid's (CA) anticancer properties on UMR-106 murine osteosarcoma cells. The IC25 and IC50 were 1.3 and 2.7 µM for CAPE and 91.0 and 120.0 µM for CA, respectively. This study shows the potential anticancer properties of CAPE and highlights how a phenethyl ester component addition can improve the pharmacological potency in relation to its precursor CA. Our results showed that CAPE was more efficient and selective in reducing the viability of tumor cells compared to the control osteoblasts (MC3T3-E1) (p < 0.05). In addition, CAPE was 44-fold (IC25) and 70-fold (IC50) more cytotoxic than CA. CAPE also decreased ROS generation and cell migration. In summary, CAPE was more selective for tumor cells, preserving normal ones, suggesting its potential role as an anticancer drug.

The role of dietary polyphenols in osteosarcoma: A possible clue about the molecular mechanisms involved in a process that is just in its infancy.

Osteosarcoma (OS) is a primary malignant bone tumor mainly affecting children, teenagers and young adults, being associated with early metastasis and poor prognosis. The beneficial effects of polyphenols have been investigated in different areas, including their potential to fight OS. Polyphenols are believed to reduce morbidity and/or slow down the development of cancer. This review aimed to assess the effect of polyphenols in OS and investigate their molecular mechanisms. It was observed that the broad spectrum of health-promoting properties of plant polyphenols in OS occurs mainly due to modulation of reactive oxygen species, anti-inflammatory activity, anti-angiogenesis, apoptosis inducer, inhibition of invasion and metastasis. However, it is worth mentioning that although the promising effects of polyphenols in the fight against OS, most of the studies have been performed using in vitro and in vivo animal models. Therefore, studies in humans are needed to validate the effectiveness of polyphenols in OS treatment. PRACTICAL APPLICATIONS: Polyphenols are widely used for various diseases, however, until now, their real role in the treatment of osteosarcoma remains unknown. This review provides a broad spectrum of research conducted with polyphenols and their potential as adjuvant therapy in the treatment of osteosarcoma. However, prior to their clinical application for osteosarcoma treatment, there is a need to isolate and identify specific polyphenolic compounds with high antitumor activity, increase their oral bioavailability, and to investigate their interactions with chemotherapeutic drugs being used in clinical practice.

Diosmetin inhibits cell proliferation and promotes apoptosis through STAT3/c-Myc signaling pathway in human osteosarcoma cells.

BACKGROUND: Diosmetin is a bioflavonoid compound naturally abundant in citrus fruits. It is found to perform a variety of activities, while its antitumor property in osteosarcoma, a malignant tumor with unmet clinical treatment, remained unknown. METHODS: Colony formation assay, cell cycle analysis and apoptosis analysis were conducted respectively to observe the effect of diosmetin on cell proliferation and apoptosis in human osteosarcoma cells. Western blot and immunoprecipitation were used to detect the expression of apoptotic molecules and activation of STAT3/c-Myc pathway in Saos-2 and U2SO cells. RESULTS: Diosmetin significantly inhibited cell proliferation, induced cell cycle arrest at G2/M phase and promoted cell apoptosis in both Saos-2 and U2SO cells. Moreover, Diosmetin downregulated the expression of anti-apoptotic protein Bcl-xL while upregulated the levels of pro-apoptotic proteins including cleaved Caspase-3, cleaved-PARP and Bax. Furthermore, diosmetin dose-dependently inhibited STAT3 phosphorylation, reduced the expression of its downstream protein c-Myc and impeded the interaction between STAT3 molecules. CONCLUSIONS: These results suggest that diosmetin exerts anti-osteosarcoma effects by suppressing cell proliferation and inducing apoptosis via inhibiting the activation of STAT3/c-Myc signaling pathway, which provide the possibility for diosmetin to be a chemotherapeutic candidate for osteosarcoma.

Cytotoxicity of a Lipid-Rich Extract from Native Mexican Avocado Seed (Persea americana var. drymifolia) on Canine Osteosarcoma D-17 Cells and Synergistic Activity with Cytostatic Drugs.

Osteosarcoma is the most common malignant bone tumor in both children and dogs. It is an aggressive and metastatic cancer with a poor prognosis for long-term survival. The search for new anti-cancer drugs with fewer side effects has become an essential goal for cancer chemotherapy; in this sense, the bioactive compounds from avocado have proved their efficacy as cytotoxic molecules. The objective of this study was to determine the cytotoxic and antiproliferative effect of a lipid-rich extract (LEAS) from Mexican native avocado seed (Persea americana var. drymifolia) on canine osteosarcoma D-17 cell line. Also, the combined activity with cytostatic drugs was evaluated. LEAS was cytotoxic to D-17 cells in a concentration-dependent manner with an IC50 = 15.5 µg/mL. Besides, LEAS induced caspase-dependent cell apoptosis by the extrinsic and intrinsic pathways. Moreover, LEAS induced a significant loss of mitochondrial membrane potential and increased superoxide anion production and mitochondrial ROS. Also, LEAS induced the arrest of the cell cycle in the G0/G1 phase. Finally, LEAS improved the cytotoxic activity of cisplatin, carboplatin, and in less extension, doxorubicin against the canine osteosarcoma cell line through a synergistic effect. In conclusion, avocado could be a potential source of bioactive molecules in the searching treatments for osteosarcoma.

New drug candidates for osteosarcoma: Drug repurposing based on gene expression signature.

Osteosarcoma (OS) is an aggressive bone malignancy and the third most common cancer in adolescence. Since the late 1970s, OS therapy and prognosis had only modest improvements, making it appealing to explore new tools that could help ameliorate the treatment. We present a meta-analysis of the gene expression signature of primary OS, and propose small molecules that could reverse this signature. The meta-analysis was performed using GEO microarray series. We first compared gene expression from eleven primary OS against osteoblasts to obtain the differentially expressed genes (DEGs). We later filtered those DEGs by verifying which ones had a concordant direction of differential expression in a validation group of 82 OS samples versus 30 bone marrow mesenchymal stem cells (BM-MSC) samples. A final gene expression signature of 266 genes (98 up and 168 down regulated) was obtained. The L1000CDS2 engine was used for drug repurposing. The top molecules predicted to reverse the signature were afatinib (PubChem CID 10184653), BRD-K95196255 (PubChem CID 3242434), DG-041 (PubChem CID 11296282) and CA-074 Me (PubChem CID 23760717). Afatinib (Gilotrif™) is currently used for metastatic non-small-cell lung cancer with EGFR mutations, and in vitro evidence shows antineoplastic potential in OS cells. The other three molecules have reports of antineoplastic effects, but are not currently FDA-approved. Further studies are necessary to establish the potential of these drugs in OS treatment. We believe our results can be an important contribution for the investigation of new therapeutic genetic targets and for selecting new drugs to be tested for OS.