Antitumoral Potential of Artepillin C, a Compound Derived from Brazilian Propolis, against Breast Cancer Cell Lines.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer among women worldwide with limited treatment options. Artepillin C (3,5-diprenyl-4-hydroxycinnamic acid) is one of the main constituents of Brazilian propolis presenting different activities, including antitumoral effects against various types of cancer. OBJECTIVE: We evaluated the antitumoral potential and mechanisms of action of artepillin C against two distinct human breast cancer cell lines, MCF-7 and MDA-MB-231, to explore a new therapeutic candidate. METHODS: Cell viability was assessed by MTT assay and the long-term cytotoxicity was performed by clonogenic assay. The morphological changes were observed by light microscopy, analysis of cell death pathway by Annexin V FITC/propidium iodide (PI), lactate dehydrogenase (LDH) by colorimetry, DNA fragmentation by agarose gel and senescence by ß-galactosidase. Detection of total reactive oxygen species (ROS) by fluorescence microscopy and determination of mitochondrial transmembrane potential by flow cytometry were also performed. RESULTS: Artepillin C presented a strong and dose-time-dependent cytotoxic effect on MCF-7 and MDA-MB-231 cell lines, with cytotoxicity more evident in MCF-7. In both cancer cell lines, the clonogenic potential was significantly reduced and the morphology of the cells was changed. The treatment also induced death by necrosis and late apoptosis in MCF-7 and MDA-MB-231 and induced cell senescence in MCF-7. Also, artepillin C increased total ROS in both cancer cells and decreased mitochondrial membrane potential in MDA-MB-231 cells. CONCLUSION: Artepillin C presented antitumoral potential in two human breast cancer cell lines, MCF-7, and MDA-MB-231, suggesting a new promising option for the treatment and/or chemopreventive strategy for breast cancer.

The Essential Oil from Conyza bonariensis (L.) Cronquist (Asteraceae) Exerts an In Vitro Antimelanoma Effect by Inducing Apoptosis and Modulating the MAPKs, NF-κB, and PKB/AKT Signaling Pathways.

The characterization and cytotoxicity of the essential oil from Conyza bonariensis (L.) aerial parts (CBEO) were previously conducted. The major compound was (Z)-2-lachnophyllum ester (EZ), and CBEO exhibited significant ROS-dependent cytotoxicity in the melanoma cell line SK-MEL-28. Herein, we employed the Molegro Virtual Docker v.6.0.1 software to investigate the interactions between the EZ and Mitogen-Activated Protein Kinases (MAPKs), the Nuclear Factor kappa B (NF-κB), and the Protein Kinase B (PKB/AKT). Additionally, in vitro assays were performed in SK-MEL-28 cells to assess the effect of CBEO on the cell cycle, apoptosis, and these signaling pathways by flow cytometry and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using MAPKs inhibitors. CBEO induced a significant increase in the sub-G1 peak, as well as biochemical and morphological changes characteristic of apoptosis. The in-silico results indicated that EZ interacts with Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), p38α MAPK, NF-κB, and PKB/AKT. Moreover, CBEO modulated the ERK1/2, JNK, p38 MAPK, NF-κB, and PKB/AKT activities in SK-MEL-28 cells. Furthermore, CBEO's cytotoxicity against SK-MEL-28 cells was significantly altered in the presence of MAPKs inhibitors. These findings support the in vitro antimelanoma effect of CBEO through apoptosis induction, and the modulation of ERK, JNK, p38 MAPK, NF-κB, and PKB/AKT activities.

Biotechnological potential of essential oils from different chemotypes of Lippia alba(Mill.) N.E.Br. ex Britton & P. Wilson / Potencial biotecnológico de los aceites esenciales de diferentes quimiotipos de Lippia alba(Mill.) N.E.Br. ex Britton y P. Wilson

This study reports the biotechnological importance of seven Lippia albaspecimens collected in different places in Brazil, and evaluation of some activities as larvicidal against Aedes spp., antifungal against dermatophytes; cytotoxicity against SNB-19 (astrocytoma), HCT-116 (human colon) and PC-3 (human prostate) cancer cell lines, and inhibition of the enzyme acetylcholinesterase (AChE). The essential oils, whose extraction yield was about 1.24 w/w ± 0.9%, showed differences in their chemical composition and considered as chemotypes. The essential oils containing neral and geranial as main constituents showed better action against HCT-116 cell lines (IC50 value was 9.22 µg/mL), larvicidal activity against arbovirus vectors (LC50 value against A. aegypti was 1.59 µg/mL) and inhibition of AChE (halo inhibition zone was 1 cm). The essential oils containing mainly monoterpenoids showed better antifungal action with MIC values range from 0.15 to 1.25 mg/mL. This chemical and biological characterization may be useful for biotechnological applications.

Este estudio reporta la importancia biotecnológica de siete especímenes de Lippia alba recolectados en diferentes lugares de Brasil, y evaluación de algunas actividades como larvicida contra Aedes spp., Antifúngico contra dermatofitos; citotoxicidad contra líneas celulares de cáncer SNB-19 (astrocitoma), HCT-116 (colon humano) y PC-3 (próstata humana), e inhibición de la enzima acetilcolinesterasa (AChE). Los aceites esenciales, cuyo rendimiento de extracción fue de aproximadamente 1,24 p/p ± 0,9%, mostraron diferencias en su composición química y se consideraron quimiotipos. Los aceites esenciales que contienen neral y geranial como constituyentes principales mostraron una mejor acción contra las líneas celulares HCT-116 (el valor de CI50 fue de 9.22 µg/mL), actividad larvicida contra los vectores de arbovirus (el valor de LC50 contra A. aegypti fue de 1.59 µg/mL) e inhibición de AChE (la zona de inhibición del halo era de 1 cm). Los aceites esenciales que contienen principalmente monoterpenoides mostraron una mejor acción antifúngica con valores de CMI en el rango de 0.15 a 1.25 mg/mL. Esta caracterización química y biológica puede ser útil para aplicaciones biotecnológicas.

Polypodium leucotomos targets multiple aspects of oral carcinogenesis and it is a potential antitumor phytotherapy against tongue cancer growth.

Introduction: Oral cancer refers to malignant tumors, of which 90% are squamous cell carcinomas (OSCCs). These malignancies exhibit rapid progression, poor prognosis, and often mutilating therapeutical approaches. The determination of a prophylactic and/or therapeutic antitumor role of the polyphenolic extract Polypodium leucotomos(PL) would be relevant in developing new tools for prevention and treatment. Methods: We aimed to determine the antitumor effect of PL by treating OSCC cell lines with PL metabolites and evaluating its action during OSCC progression in vivo. Results: PL treatment successfully impaired cell cycling and proliferation, migration, and invasion, enhanced apoptosis, and modulated macrophage polarization associated with the tumoral immune-inflammatory response of tongue cancer cell lines (TSCC). PL treatment significantly decreased the expression of MMP1 (p < 0.01) and MMP2 (p < 0.001), and increased the expression of TIMP1 (p < 0.001) and TIMP2 (p < 0.0001) in these cells. The mesenchymal-epithelial transition phenotype was promoted in cells treated with PL, through upregulation of E-CAD (p < 0.001) and reduction of N-CAD (p < 0.05). PL restrained OSCC progression in vivo by inhibiting tumor volume growth and decreasing the number of severe dysplasia lesions and squamous cell carcinomas. Ki-67 was significantly higher expressed in tongue tissues of animals not treated with PL(p < 0.05), and a notable reduction in Bcl2 (p < 0.05) and Pcna (p < 0.05) cell proliferation-associated genes was found in dysplastic lesions and TSCCs of PL-treated mice. Finally, N-cad(Cdh2), Vim, and Twist were significantly reduced in tongue tissues treated with PL. Conclusion: PL significantly decreased OSCC carcinogenic processes in vitro and inhibited tumor progression in vivo. PL also appears to contribute to the modulation of immune-inflammatory oral tumor-associated responses. Taken together, these results suggest that PL plays an important antitumor role in processes associated with oral carcinogenesis and may be a potential phytotherapeutic target for the prevention and/or adjuvant treatment of TSCCs.

Antitumor Effect of Zwitterions of Imidazolium Derived from L-methionine in BALB/c Mice with Lymphoma L5178Y.

BACKGROUND: In the therapy of cancer, several treatments have been designed using nanomaterials, among which gold nanoparticles (AuNPs) have been featured as a promising antitumoral agent. Our research group has developed the synthesis of gold nanoparticles L-AuNPs and D-AuNPs stabilized with zwitterions of imidazolium (L-1 and D-1) derived from L-methionine and D-methionine. Because the stabilizer agent is chiral, we observed through circular dichroism that AuNPs also present chirality; such chirality as well as the fact that the stabilizing agent contains fragments of methionine and imidazolium that are commonly involved in biological processes, opens up the possibility that this system may have biological compatibility. Additionally, the presence of methionine in the stabilizing agent opens the application of this system as a possible antitumor agent because methionine is involved in methylation processes of molecules such as DNA. OBJECTIVE: The aim of this research is the evaluation of the antitumor activity of gold nanoparticles stabilized with zwitterions of imidazolium (L-AuNPs) derived from L-methionine in the model of BALB/c mice with lymphoma L5178Y. METHODS: Taking as a parameter cell density, the evaluation of the inhibitory effect of L-AuNPs was carried out with a series of in vivo tests in BALB/c type mice; three groups of five mice each were formed (Groups 1, 2 and 3); all mice were i.p. inoculated with the lymphoblast murine L5178Y. Group 1 consisted of mice without treatment. In the Groups 2 and 3 the mice were treated with L-AuNPs at 0.3 mg/Kg on days 1, 7 and 14 by orally and intraperitonally respectively. RESULTS: These results show low antitumor activity of these gold nanoparticles (L-NPsAu) but interestingly, the imidazolium stabilizing agent of gold nanoparticle (L-1) displayed promising antitumor activity. On the other hand, the enantiomer of L-1, (D-1) as well as asymmetric imidazole derivate from L-methionine (L-2), do not exhibit the same activity as L-1. CONCLUSION: The imidazolium stabilizing agent (L-1) displayed promising antitumor activity. Modifications in the structure of L-1 showed that, the stereochemistry (like D-1) and the presence of methionine fragments (like L-2) are determinants in the antitumor activity of this compound.

In Vivo Photodynamic Therapy With a Lipophilic Zinc(II) Phthalocyanine Inhibits Colorectal Cancer and Induces a Th1/CD8 Antitumor Immune Response.

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) is an antitumor procedure clinically approved for the treatment of different cancer types. Despite strong efforts and promising results in this field, PDT has not yet been approved by any regulatory authority for the treatment of colorectal cancer, one of the most prevalent gastrointestinal tumors. In the search of novel therapeutic strategies, we examined the in vivo effect of PDT with a lipophilic phthalocyanine (Pc9) encapsulated into polymeric poloxamine micelles (T1107) in a murine colon carcinoma model. STUDY DESIGN/MATERIALS AND METHODS: In vivo assays were performed with BALB/c mice challenged with CT26 cells. Pc9 tumor uptake was evaluated with an in vivo imaging system. Immunofluorescence, western blot, and flow cytometry assays were carried out to characterize the activation of apoptosis and an antitumor immune response. RESULTS: Pc9-T1107 effectively delayed tumor growth and prolonged mice survival, without generating systemic or tissue-specific toxicity. The induction of an apoptotic response was characterized by a decrease in the expression levels of Bcl-XL , Bcl-2, procaspase 3, full length Bid, a significant increment in the amount of active caspase-3 and the detection of PARP-1 cleavage. Infiltration of CD8+ CD107a+ T cells and higher levels of interferon-γ and tumor necrosis factor-α were also found in PDT-treated tumors. CONCLUSIONS: Pc9-T1107 PDT treatment reduced tumor growth, inducing an apoptotic cell death and activating an immune response. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Antitumor activity of new chemical compounds in triple negative mammary adenocarcinoma models.

AIM: According to the need for the development of new anticancer agents, we have synthetized novel bioactive compounds and aimed to determine their antitumor action. MATERIALS & METHODS: We describe in vitro studies evaluating the effect of 35 novel chemical compounds on two triple negative murine mammary adenocarcinoma tumors. RESULTS & CONCLUSION: Three compounds were selected because of their high antitumor activity and their low toxicity to normal cells. Their effect on tumor cells apoptosis, clonogenicity and migratory capacity, were determined. We found that the selected compounds showed inhibition of viability and clonogenic capacity, and promotion of apoptosis. They also decreased the migratory capacity of tumor cells. The results obtained suggest the likelihood of their future use as antitumor and/or antimetastatic agents.

Docetaxel-loaded solid lipid nanoparticles prevent tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells.

BACKGROUND: Metastasis causes the most breast cancer-related deaths in women. Here, we investigated the antitumor effect of solid lipid nanoparticles (SLN-DTX) when used in the treatment of metastatic breast tumors using 4T1-bearing BALB/c mice. RESULTS: Solid lipid nanoparticles (SLNs) were produced using the high-energy method. Compritol 888 ATO was selected as the lipid matrix, and Pluronic F127 and Span 80 as the surfactants to stabilize nanoparticle dispersion. The particles had high stability for at least 120 days. The SLNs' dispersion size was 128 nm, their polydispersity index (PDI) was 0.2, and they showed a negative zeta potential. SLNs had high docetaxel (DTX) entrapment efficiency (86%), 2% of drug loading and showed a controlled drug-release profile. The half-maximal inhibitory concentration (IC50) of SLN-DTX against 4T1 cells was more than 100 times lower than that of free DTX after 24 h treatment. In the cellular uptake test, SLN-DTX was taken into the cells significantly more than free DTX. The accumulation in the G2-M phase was significantly higher in cells treated with SLN-DTX (73.7%) than in cells treated with free DTX (23.0%), which induced subsequent apoptosis. TEM analysis revealed that SLN-DTX internalization is mediated by endocytosis, and fluorescence microscopy showed DTX induced microtubule damage. In vivo studies showed that SLN-DTX compared to free docetaxel exhibited higher antitumor efficacy by reducing tumor volume (p < 0.0001) and also prevented spontaneous lung metastasis in 4T1 tumor-bearing mice. Histological studies of lungs confirmed that treatment with SLN-DTX was able to prevent tumor. IL-6 serum levels, ki-67 and BCL-2 expression were analyzed and showed a remarkably strong reduction when used in a combined treatment. CONCLUSIONS: These results indicate that DTX-loaded SLNs may be a promising carrier to treat breast cancer and in metastasis prevention.

Anticancer Potential of Palladium(II) Complexes With Schiff Bases Derived from 4-Aminoacetophenone Against Melanoma In Vitro.

BACKGROUND/AIM: Melanoma represents a big challenge for clinical treatment. Besides being the most aggressive and the deadliest form of skin cancer, it is often refractory to commonly used anticancer drugs. Hence, developing new anti-cancer agents is crucial to improve refractory melanoma treatment. Studies using palladium(II) complexes have reported antitumor effects on cancer cells. In this study, we aimed to determine the cytotoxic effect of three novel synthesized Pd(II) complexes with Schiff bases derived from 4-aminoacetophenone on the MDA-MB-435 melanoma cell line. MATERIALS AND METHODS: Cells were treated with ligand and Pd(II) complexes. Cell viability, morphology and death induction upon treatment were examined. RESULTS: Novel synthesized Pd(II) complexes led to decreased viability of cells. They also induced morphological alterations and cell death, mainly in the C3 complex. CONCLUSION: The novel synthesized complexes have a significant cytotoxic effect on cell line MDA-MB-435, especially C3 and can be considered as an antitumor agent for further studies.

ß-Cyclodextrin complex improves the bioavailability and antitumor potential of cirsiliol, a flavone isolated from Leonotis nepetifolia (Lamiaceae).

Cirsiliol is a flavone found in many Lamiaceae species with high cytotoxic activity against tumor cell lines. Although cirsiliol is being used in cancer therapy, its pharmacological potential is limited by its low solubility and bioavailability. In this paper, a cirsiliol-ß-cyclodextrin inclusion complex was developed in order to increase its solubility and bioavailability. The formation of inclusion complex was proved by scanning electron microscopy, Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) and solubility increment was verified through the ultraviolet-visible (UV-Vis) method. The cytotoxic effect against tumor cells (PC3, HCT-116 and HL-60 human cell lines, and S-180 murine cell line) and the antitumor activity in mice bearing sarcoma S-180 were also investigated. The inclusion complex was obtained with 71.45% of total recovery and solubility 2.1 times higher compared to the compound in its free form. This increment in solubility was responsible by a tumor growth inhibition potentiation (1.5 times greater compared to compound in its free form). In addition, this study showed that cirsiliol and its inclusion complex in ß-cyclodextrin have strong antitumor potential at low doses without promoting side effects commonly observed for conventional drugs as doxorubicin.

Copper complex with sulfamethazine and 2,2'-bipyridine supported on mesoporous silica microspheres improves its antitumor action toward human osteosarcoma cells: cyto- and genotoxic effects.

Ideal drugs to cure cancer leave normal cells unharmed while selectively turning tumor cells unviable. Several copper complexes have been able to selectively slow down tumor proliferation. We hypothesized that Cu(smz)2(bipy)·H2O (1)-a copper-complex that has two ligands capable of interacting with DNA-would outperform Cu(smz)2(OH2)·2H2O (2), and also that supporting 1 on mesoporous silica spheres would decrease even further tumor cell viability in vitro. After exposing osteosarcoma cells (MG-63) and normal phenotype cells of bone origin (MC3T3-E1) to either complex, we studied their toxic effect and mechanisms of action. We determined cell viability (MTT assay) and quantified formation of reactive oxygen species (oxidation of DHR-123 to rhodamine). Moreover, we assessed genotoxicity from (i) formation of micronucleus (MN assay) and (ii) damage of DNA (Comet assay). After the exposure of 1 supported on silica spheres, we tested cell viability. Our results confirm our hypotheses: inhibition of tumor cells follows: supported 1 > dissolved 1 > 2. Future work that enhances the load of the complex exclusively in mesopores may improve the ability of 1 to further inhibit tumor cell viability.

Bacterial Therapy of Cancer: Promises, Limitations, and Insights for Future Directions.

Spontaneous tumors regression has been associated with microbial infection for 100s of years and inspired the use of bacteria for anticancer therapy. Dr. William B. Coley (1862-1936), a bone- sarcoma surgeon, was a pioneer in treating his patients with both live bacterial-based and mixture of heat-killed bacteria known as "Coley's toxins." Unfortunately, Coley was forced to stop his work which interrupted this field for about half a century. Currently, several species of bacteria are being developed against cancer. The bacterial species, their genetic background and their infectious behavior within the tumor microenvironment are thought to be relevant factors in determining their anti-tumor effectiveness in vivo. In this perspective article we will update the most promising results achieved using bacterial therapy (alone or combined with other strategies) in clinically-relevant animal models of cancer and critically discuss the impact of the bacterial variants, route of administration and mechanisms of bacteria-cancer-cell interaction. We will also discuss strategies to apply this information using modern mouse models, molecular biology, genetics and imaging for future bacterial therapy of cancer patients.

Antitumor effectiveness of a combined therapy with a new cucurbitacin B derivative and paclitaxel on a human lung cancer xenograft model.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.

l-Glutamine supplementation promotes an improved energetic balance in Walker-256 tumor-bearing rats.

We evaluated the effects of supplementation with oral l-glutamine in Walker-256 tumor-bearing rats. A total of 32 male Wistar rats aged 54 days were randomly divided into four groups: rats without Walker-256 tumor, that is, control rats (C group); control rats supplemented with l-glutamine (CG group); Walker-256 tumor rats without l-glutamine supplementation (WT group); and WT rats supplemented with l-glutamine (WTG group). l-Glutamine was incorporated into standard food at a proportion of 2 g/100 g (2%). After 10 days of the experimental period, the jejunum and duodenum were removed and processed. Protein expression levels of key enzymes of gluconeogenesis, that is, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, were analyzed by western blot and immunohistochemical techniques. In addition, plasma corticosterone, glucose, insulin, and urea levels were evaluated. The WTG group showed significantly increased plasma glucose and insulin levels ( p < 0.05); however, plasma corticosterone and urea remained unchanged. Moreover, the WTG group showed increased immunoreactive staining for jejunal phosphoenolpyruvate carboxykinase and increased expression of duodenal glucose-6-phosphatase. Furthermore, the WTG group presented with less intense cancer cachexia and slower tumor growth. These results could be attributed, at least partly, to increased intestinal gluconeogenesis and insulinemia, and better glycemia maintenance during fasting in Walker-256 tumor rats on a diet supplemented with l-glutamine.

Pomegranate seed oil nanoemulsions with selective antiglioma activity: optimization and evaluation of cytotoxicity, genotoxicity and oxidative effects on mononuclear cells.

CONTEXT: Glioma is a malignant brain tumor with rapid proliferation, infiltrative growth, poor prognosis and it is chemoresistent. Pomegranate seed oil (PSO) has antioxidant, anti-inflammatory and antitumor properties. This study showed the optimization of PSO nanoemulsions (NEs) as an alternative for glioma treatment. OBJECTIVE: The study aimed to evaluate PSO NEs cytotoxicity on human blood cells and antiglioma effects against C6 cells. MATERIALS AND METHODS: NEs were prepared by the spontaneous emulsification method, using PSO at 1.5 and 3.0%, and were evaluated regarding their physical stability and antioxidant activity. Toxicity evaluations in human blood cells were performed in terms of cell viability, genotoxicity, lipid peroxidation, protein carbonylation, catalase activity and hemolysis at 0.1, 0.25 and 0.5 mg/mL PSO, after a 72-h incubation period. In vitro antitumor effect was determined against glioma cells after 24 and 48 h, and astrocytes were used as a non-transformed cell model. RESULTS: Formulations presented droplet size below 250 nm, low polydispersity index, negative zeta potential and pH in the acid range. NEs and PSO had scavenging capacity around 30% and promoted a proliferative effect in mononuclear cells, increasing about 50% cell viability. No genotoxic and oxidative damage was observed in lipid peroxidation, protein carbonylation and catalase activity evaluations for NEs. Hemolysis study showed a hemolytic effect at high concentrations. Moreover, formulations reduced only tumor cell viability to 47%, approximately. DISCUSSION AND CONCLUSION: Formulations are adequate and safe for intravenous administration. Besides, in vitro antitumor activity indicates that NEs are promising for glioma treatment.

Effects of Ultrasonic Disintegrates from Epimastigote Biomass of Trypanosoma cruzi Albarrada Strain (Mexico) on the Development of L5178Y Solid Malignant Transplanted Tumors in Male BALB/c Mice.

We studied in vivo antitumor effect of epimastigote form detritus of Trypanosoma cruzi, Mexican Albarrada strain, on L5178Y malignant tumor in BALB/c mice. The antitumor effect of ultrasonic detritus of the parasite was confirmed by shrinkage of the tumor and changed size of its symplastic necroses.

Antitumor and cytotoxic properties of a humanized antibody specific for the GM3(Neu5Gc) ganglioside.

Gangliosides are sialic acid-bearing glycosphingolipids expressed on all mammalian cell membranes, and participate in several cellular processes. During malignant transformation their expression changes, both at the quantitative and qualitative levels. Of particular interest is the overexpression by tumor cells of Neu5Gc-gangliosides, which are absent, or detected in trace amounts, in human normal cells. The GM3(Neu5Gc) ganglioside in particular has been detected in many human tumors, and it is considered one of the few tumor specific antigen. We previously demonstrated that a humanized antibody specific for this molecule, named 14F7hT, retained the binding and cytotoxic properties of the mouse antibody. In this work, we confirm that 14F7hT exerts a non-apoptotic cell death mechanism in vitro and shows its potent in vivo antitumor activity on a solid mouse myeloma model. Also, we demonstrate, in contrast to the murine counterpart, the capacity of this antibody to induce antibody-dependent cell-mediated cytotoxicity using human effector cells, which increases its potential for the treatment of GM3(Neu5Gc)-expressing human tumors.

Ketoprofen-loaded pomegranate seed oil nanoemulsion stabilized by pullulan: Selective antiglioma formulation for intravenous administration.

This study aimed to prepare pomegranate seed oil nanoemulsions containing ketoprofen using pullulan as a polymeric stabilizer, and to evaluate antitumor activity against in vitro glioma cells. Formulations were prepared by the spontaneous emulsification method and different concentrations of pullulan were tested. Nanoemulsions presented adequate droplet size, polydispersity index, zeta potential, pH, ketoprofen content and encapsulation efficiency. Nanoemulsions were able to delay the photodegradation profile of ketoprofen under UVC radiation, regardless of the concentration of pullulan. In vitro release study indicates that nanoemulsions were able to release approximately 95.0% of ketoprofen in 5h. Free ketoprofen and formulations were considered hemocompatible at 1 µg/mL, in a hemolysis study, for intravenous administration. In addition, a formulation containing the highest concentration of pullulan was tested against C6 cell line and demonstrated significant activity, and did not reduce fibroblasts viability. Thus, pullulan can be considered an interesting excipient to prepare nanostructured systems and nanoemulsion formulations can be considered promising alternatives for the treatment of glioma.

Encapsulation of cisplatin in long-circulating and pH-sensitive liposomes improves its antitumor effect and reduces acute toxicity.

Cisplatin (CDDP) is one of the most effective and potent anticancer drugs used as first-line chemotherapy against several solid tumors. However, the severe side effects and its tendency to provoke chemoresistance often limit CDDP therapy. To avoid these inconveniences, the present study's research group developed long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP). The present study aimed to evaluate the antitumor effect and toxicity of SpHL-CDDP, as compared with that of free CDDP, and long-circulating and non- pH-sensitive liposomes containing CDDP (NSpHL-CDDP), after their intravenous administration in solid Ehrlich tumor-bearing mice. Antitumor activity was evaluated by analysis of tumor volume and growth inhibition ratio, serum vascular endothelial growth factor (VEGF) levels, and histomorphometric and immunohistochemical studies. Body weight variation and the histological examination of bone marrow and kidneys were used as toxicity indicators. A significant reduction in the tumor volume and a higher tumor growth inhibition ratio was observed after SpHL-CDDP treatment, compared with free CDDP and NSpHL-CDDP treatments. In addition, complete remission of the tumor was detected in 18.2% of the mice treated with SpHL- CDDP (16 mg/kg). As such, the administration of SpHL-CDDP, as compared with free CDDP and NSpHL-CDDP, led to a decrease in the area of necrosis and in the percentage of positive CDC 47 tumor cells. A significant reduction in the VEGF serum level was also observed after SpHL-CDDP treatment, as compared with free-CDDP treatment. SpHL-CDDP administered in a two-fold higher dose than that of free CDDP presented a loss in body weight and changes in the hematopoietic tissue morphology, which proved to be similar to that of free CDDP. No changes could be verified in the renal tissue after any formulations containing CDDP had been administered. These findings showed that SpHL-CDDP allowed for the administration of higher doses of CDDP, significantly improving its antitumor effect.

Preliminary evaluation of antitumor effect and induction apoptosis in PC-3 cells of extract from Patrinia heterophylla

Patrinia heterophylla Bunge, Caprifoliaceae, is a traditional Chinese medicine that has been used for cancer therapy. In our study, a panel of human cancer cells was treated with extract of Patrinia heterophylla Bunge. (PHEB), MTT study showed that PC-3 Human prostate adenocarcinoma was the most responsive (IC50 9.21±0.32 µg/mL) one to cell growth inhibition, the further study also demonstrated that PHEB could inhibit the proliferation of PC-3 based on a concentration-and time-dependent manner. The transplanted model of sarcoma 180 (S180) and hepatoma 22 (H22) was established in mice, the study demonstrated that i.p. administration of 20, 40, 60 mg/kg PHEB exhibited a significant inhibitory effect on the growth of transplantation tumor, with inhibition rate 23.9, 48.4 and 53.6 percent on S180 and 21.0, 46.3 and 57.2 percent on H22, respectively. To investigate the molecular mechanism of PHEB in PC-3, the morphological changes of apoptosis were observed by fluorescent microscopy, apoptosis rate was analyzed by flow cytometry (FCM). Morphological characterizations such as apoptotic bodies and membrane blebs were shown by microscopy. The increase of an early apoptotic population was observed in a dose-dependent manner. These results suggest that PHEB has anti-tumor effects and its mechanism is attributed partially to apoptosis induced.