INCREASING ANTITUMOR EFFECTS OF CHEMORADIOTHERAPY BY DRUG EFFLUX INHIBITION WITH ENCAPSULATED ANTI-RLIP-76

2011 ◽  
Vol 21 (01n02) ◽  
pp. 39-46 ◽  
Author(s):  
S. HARADA ◽  
S. EHARA ◽  
K. ISHII ◽  
H. YAMAZAKI ◽  
S. MATSUYAMA ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Antitumor Effect ◽  
Tumor Tissue ◽  
Chemotherapeutic Agent ◽  
Drug Efflux ◽  
Antitumor Effects ◽  
X Ray ◽  
Tumor Irradiation ◽  
Efflux Inhibition

Microencapsulated anti-RLIP76 was tested in vivo using C 3 He / J mice to determine the increasing of antitumor effects by chemotherapeutic agent efflux inhibition during chemoradiotherapy. Microcapsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2, and 0.3 mmol carboplatin onto a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2. Microcapsules were subcutaneously injected into MM46 tumors previously inoculated into the left hind legs of C 3 He / J mice. Subsequent radiotherapy consisted of tumor irradiation with 10 Gy or 20 Gy 60 Co . The antitumor effects of microcapsules were tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and mortality. Carboplatin levels were monitored using particle-induced X-ray emission (PIXE) and a micro-PIXE camera. Anti-RLIP76 inhibited the efflux of carboplatin from tumor tissue, which led to an increase in the concentration of carboplatin. Higher carboplatin concentration significantly increased the combined antitumor effect of radiation and chemotherapy. A significant decrease in adverse effects was also observed with microencapsulated anti-RLIP76.

IMPROVED RADIOSENSITIVE MICROCAPSULES USING H2O2

2010 ◽  
Vol 20 (01n02) ◽  
pp. 29-36 ◽  
Author(s):  
SATOSHI HARADA ◽  
SHIGERU EHARA ◽  
K. ISHII ◽  
H. YAMAZAKI ◽  
S. MATSUYAMA ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Antitumor Effect ◽  
Liquid Core ◽  
Antitumor Effects ◽  
Treated Area ◽  
Tumor Irradiation ◽  
Radiation Induced ◽  
Effects Of Radiation ◽  
Capsule Size

The radiation-induced releasing of the liquid-core of the microcapsules was improved using H 2 O 2, which produced O 2 generation of H 2 O 2 after irradiation. Further, we tested whether these microcapsules enhanced the antitumor effects and decreased the adverse effects in vivo in C3He / J mice. The capsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2, and 0.3 mmol of carboplatin on a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2. The microcapsules were subcutaneously injected into MM46 tumors that had been inoculated in the left hind legs of C3He / J mice. The radiotherapy comprised tumor irradiation with 10 Gy or 20 Gy 60 Co . The antitumor effect of the microcapsules was tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and death. The size of the capsule size was 23 ± 2.4 µ m ɸ and that of the liquid core, 20.2 ± 2.2 µ m ɸ. The injected microcapsules localized drugs around the tumor. The production of O 2 by radiation increased the release of carboplatin from the microcapsules. The antitumor effects of radiation, carboplatin, and released oxygen were synergistic. Localization of the carboplatin decreased its adverse effects. However, the H 2 O 2 caused ulceration of the skin in the treated area. The use of our microcapsules enhanced the antitumor effects and decreased the adverse effects of carboplatin. However, the skin-ulceration caused by H 2 O 2 must be considered before these microcapsules can be used clinically.

scholarly journals {Ru(CO)x}-Core complexes with benzimidazole ligands: synthesis, X-ray structure and evaluation of anticancer activity in vivo

2017 ◽  
Vol 46 (9) ◽  
pp. 3025-3040 ◽  
Author(s):  
Gabriella Tamasi ◽  
Antonello Merlino ◽  
Federica Scaletti ◽  
Petra Heffeter ◽  
Anton A. Legin ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Anticancer Activity ◽  
Antitumor Effects ◽  
X Ray ◽  
Murine Colon

fac-[RuII(CO)3Cl2(MBI)] and -[RuII(CO)3Cl2(DMBI)] are CO-releasing materials able to link histidines of proteins, and the latter showed antitumor effects in murine colon cancer.

scholarly journals Antitumor Effect of a Novel Spiro-Acridine Compound is Associated with Up-Regulation of Th1-Type Responses and Antiangiogenic Action

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 29 ◽  
Author(s):  
Daiana K. Frade Silva ◽  
Sâmia S. Duarte ◽  
Thaís M. H. Lisboa ◽  
Rafael C. Ferreira ◽  
Ana Luíza de O. Lopes ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Antitumor Effect ◽  
Inflammatory Responses ◽  
Lethal Dose ◽  
Ehrlich Ascites Carcinoma ◽  
Antitumor Effects ◽  
Th2 Immune Response

Tumor cells have specific features, including angiogenesis induction, cell cycle dysregulation, and immune destruction evasion. By inducing a T helper type 2 (Th2) immune response, tumor cells may favor immune tolerance within the tumor, which allows progression of cancer growth. Drugs with potential antitumor activity are the spiro-acridines, which is a promising new class of acridine compounds. Herein, the novel spiro-acridine (E)-5′-oxo-1′-((3,4,5-trimethoxybenzylidene)amino)-1′,5′-dihydro-10H-spiro[acridine-9,2′-pyrrole]-4′-carbonitrile (AMTAC-17) was synthesized and tested for antitumor effects. Toxicity evaluation was performed in mice after acute treatment (2000 mg/kg, intraperitoneally, i.p.). The Ehrlich ascites carcinoma model was used to investigate the antitumor activity of AMTAC-17 (12.5, 25, or 50 mg/kg, i.p.) after seven days of treatment. Effects on the cell cycle, angiogenesis, and inflammatory responses were investigated. LD50 (lethal dose 50%) was estimated to be higher than 5000 mg/kg. AMTAC-17 reduced the Ehrlich tumor’s total viable cancer cells count and peritumoral micro-vessels density, and induced an increase in the sub-G1 peak. Additionally, there was an increase of Th1 cytokine profile levels (IL-1β, TNF-α, and IL-12). In conclusion, the spiro-acridine compound AMTAC-17 presents low toxicity, and its in vivo antitumor effect involves modulation of the immune system to a cytotoxic Th1 profile and a reduction of tumor angiogenesis.

scholarly journals Fruticuline A, a chemically-defined diterpene, exerts antineoplastic effects in vitro and in vivo by multiple mechanisms

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Claudia Rita Corso ◽  
Maria Carolina Stipp ◽  
Débora Rasec Radulski ◽  
Marihá Mariott ◽  
Luisa Mota da Silva ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Molecular Mechanisms ◽  
Tumor Tissue ◽  
Human Cancer ◽  
Biological Properties ◽  
Ehrlich Carcinoma ◽  
Antitumor Effects ◽  
Mcf 7

Abstract Natural products have been recognized as important bioactive compounds on the basis of their wide biological properties. Here we investigated the antitumor effect and molecular mechanisms of the diterpene Fruticuline A (fruti) from Salvia lachnostachys, in human cancer cell lineages and Solid Ehrlich Carcinoma in mice. Fruti reduced MCF-7 and HepG2 proliferation by the reduction of Cyclin D1 levels and decreased NF-κB gene levels in both cell types. Furthermore, fruti also induced apoptosis in HepG2 cells, reduced Bcl-2 gene expression and induced necroptosis by increasing Ripk in MCF-7 cells. In mice, fruti prevented tumor development and reduced Cyclin D1, Bcl-2 and Rela gene levels, and reduced the p-NF-κB/NF-κB ratio in tumor tissue. Furthermore, fruti induced necrosis and apoptosis, increased N-acetyl-β-D-glucosaminidase and TNF-α levels and reduced IL-10 and Vegf levels in tumor tissue. Collectively, fruti exerts antitumor effects through the inhibition of the NF-κB pathway, reducing Cyclin D1 and Bcl-2 levels. In vitro the apoptosis and necroptosis pathways are involved in the cellular death, whereas in vivo, cells undergo necrosis by increased tumor inflammation and reduction of angiogenesis. Thus, fruticuline A acts in tumor cells by multiple mechanisms and represents a promising molecule for drug development in cancer treatment.

scholarly journals Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing

2021 ◽  
Vol 11 ◽  
Author(s):  
Chan Gyu Lee ◽  
TaeEun Kim ◽  
Sungyoul Hong ◽  
Jongwan Chu ◽  
Ju Eun Kang ◽  
...  
Keyword(s):  
Tumor Targeting ◽  
Antitumor Effect ◽  
Immune Cell ◽  
Tumor Growth Inhibition ◽  
Type I ◽  
Biophysical Properties ◽  
Her2 Positive ◽  
Antitumor Effects ◽  
Direct Cell

Type I interferon (IFN) has been approved as an anticancer agent to treat some malignancies. However, IFNs have a short in vivo half-life, systemic toxicity, and poor biophysical properties, which prevent it from being widely used for cancer therapy. This study aimed to construct recombinant IFN-β-1a mutein immunocytokines that comprise a human epidermal growth factor receptor 2 (HER2)-targeting antibody and IFN-β muteins with an additional glycosylation, which can overcome the limitation of the cytokine itself. Hence, the molecular design aims to 1) enhance productivity and biophysical properties by adding secondary glycosylation in IFN-β, 2) increase the therapeutic index of IFN-β therapy by preferential retention at the tumor by possessing high affinity for HER2-expressing cancer cells, and 3) improve the pharmacokinetics and, thus, the convenience of IFN-β administration. The yield of trastuzumab-IFN-β mutein was higher than that of trastuzumab-wild-type IFN-β in the mammalian cell culture system. Trastuzumab-IFN-β mutein showed similar IFN activity and HER2-targeting ability equivalent to that of IFN-β mutein and trastuzumab, respectively. Trastuzumab-IFN-β mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-β mutein alone. Trastuzumab-IFN-β mutein and IFN-β mutein displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-β mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Tumor-targeting effect of trastuzumab-IFN-β mutein was analyzed using in vivo fluorescence imaging. The accumulation of trastuzumab-IFN-β mutein was observed in HER2-positive tumors rather than other tissues except the liver. To evaluate the both direct tumor growth inhibition effect and indirect immune cell-mediated antitumor effect, we tested the effect of trastuzumab-IFN-β mutein in HER2-positive cancer xenograft models using nude mice or humanized mice. Trastuzumab-IFN-β mutein could significantly enhance tumor regression when compared with trastuzumab or IFN-β mutein. In addition, an increase in tumor-infiltrating lymphocytes was observed in the trastuzumab-IFN-β mutein-treated group, implying that the tumor-targeting IFN-β may have an enhanced antitumor effect through increased immune response. Therefore, targeting IFN-β with an anti-HER2 monoclonal antibody makes the immunocytokine more potent than either agent alone. These novel findings suggest that trastuzumab-IFN-β mutein merits clinical evaluation as a new candidate of anticancer therapeutics.

scholarly journals Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Tetsuya Yamada ◽  
Shohei Tsuji ◽  
Shinsuke Nakamura ◽  
Yusuke Egashira ◽  
Masamitsu Shimazawa ◽  
...  
Keyword(s):  
Cell Lines ◽  
Dna Methyltransferase ◽  
Antitumor Effect ◽  
Metabotropic Glutamate Receptor ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase

OBJECTIVEGlutamatergic signaling significantly promotes proliferation, migration, and invasion in glioblastoma (GBM). Riluzole, a metabotropic glutamate receptor 1 inhibitor, reportedly suppresses GBM growth. However, the effects of combining riluzole with the primary GBM chemotherapeutic agent, temozolomide (TMZ), are unknown. This study aimed to investigate the efficacy of combinatorial therapy with TMZ/riluzole for GBM in vitro and in vivo.METHODSThree GBM cell lines, T98G (human; O6-methylguanine DNA methyltransferase [MGMT] positive), U87MG (human; MGMT negative), and GL261 (murine; MGMT positive), were treated with TMZ, riluzole, or a combination of both. The authors performed cell viability assays, followed by isobologram analysis, to evaluate the effects of combinatorial treatment for each GBM cell line. They tested the effect of riluzole on MGMT, a DNA repair enzyme causing chemoresistance to TMZ, through quantitative real-time reverse transcription polymerase chain reaction in T98G cells. Furthermore, they evaluated the efficacy of combinatorial TMZ/riluzole treatment in an orthotopic mouse allograft model of MGMT-positive GBM using C57BL/6 J mice and GL261 cells.RESULTSRiluzole displayed significant time- and dose-dependent growth-inhibitory effects on all GBM cell lines assessed independently. Riluzole enhanced the antitumor effect of TMZ synergistically in MGMT-positive but not in MGMT-negative GBM cell lines. Riluzole singularly suppressed MGMT expression, and it significantly suppressed TMZ-induced MGMT upregulation (p < 0.01). Furthermore, combinatorial TMZ/riluzole treatment significantly suppressed tumor growth in the intracranial MGMT-positive GBM model (p < 0.05).CONCLUSIONSRiluzole attenuates TMZ-induced MGMT upregulation and enhances the antitumor effect of TMZ in MGMT-positive GBMs. Therefore, combinatorial TMZ/riluzole treatment is a potentially promising novel therapeutic regimen for MGMT-positive GBMs.

scholarly journals Antitumor Effects of Systemic DNAse I and Proteases in an In Vivo Model

2016 ◽  
Vol 15 (4) ◽  
pp. NP35-NP43 ◽  
Author(s):  
Catalina Trejo-Becerril ◽  
Enrique Pérez-Cardenas ◽  
Blanca Gutiérrez-Díaz ◽  
Desiree De La Cruz-Sigüenza ◽  
Lucía Taja-Chayeb ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Antitumor Effect ◽  
Dnase I ◽  
In Vivo Model ◽  
Circulating Dna ◽  
Healthy Individuals ◽  
Antitumor Effects ◽  
Immunodeficient Mice

Background. Cell-free DNA circulates in cancer patients and induces in vivo cell transformation and cancer progression in susceptible cells. Based on this, we hypothesized that depletion of circulating DNA with DNAse I and a protease mix could have antitumor effects. Study design. The study aimed to demonstrate that DNAse I and a protease mix can degrade in vitro DNA and proteins from the serum of healthy individuals and cancer patients, and in vivo in serum of Wistar rats,. Moreover, the antitumor effect of the systemically administered enzyme mix treatmentwas evaluated in nude mice subcutaneously grafted with the human colon cancer cell line SW480. Results. The serum DNA of cancer patients or healthy individuals was almost completely degraded in vitro by the enzymatic treatment, but no degradation was found with the enzymes given separately. The intravenous administration of the enzymes led to significant decreases in DNA and proteins from rat serum. No antitumor effect was observed in immunodeficient mice treated with the enzymes given separately. In contrast, the animals that received both enzymes exhibited a marked growth inhibition of tumors, 40% of them having pathological complete response. Conclusion. This study demonstrated that systemic treatment with DNAse I and a protease mix in rats decreases DNA and proteins from serum and that this treatment has antitumor effects. Our results support the hypothesis that circulating DNA could have a role in tumor progression, which can be offset by depleting it. Further studies are needed to prove this concept.

scholarly journals Th1-Biased Immunomodulation and In Vivo Antitumor Effect of a Novel Piperine Analogue

2018 ◽  
Vol 19 (9) ◽  
pp. 2594 ◽  
Author(s):  
Jephesson Santos ◽  
Monalisa Brito ◽  
Rafael Ferreira ◽  
Ana Moura ◽  
Tatyanna Sousa ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Antitumor Effect ◽  
Lethal Dose ◽  
Ehrlich Ascites Carcinoma ◽  
Cytokine Profile ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Antitumor Effects

Natural products have an important role as prototypes in the synthesis of new anticancer drugs. Piperine is an alkaloid amide with antitumor activity and significant toxicity. Then, the N-(p-nitrophenyl)acetamide piperinoate (HE-02) was synthesized, and tested for toxicological and antitumor effects. The toxicity was evaluated in vitro (on RAW 264.7 cells and mice erythrocytes) and in vivo (acute toxicity in mice). The Ehrlich ascites carcinoma model was used to evaluate the antitumor activity of HE-02 (6.25, 12.5 or 25 mg/kg, intraperitoneally, i.p.), as well as toxicity. HE-02 induced only 5.01% of hemolysis, and reduced the viability of RAW 264.7 cells by 49.75% at 1000 µg/mL. LD50 (lethal dose 50%) was estimated at around 2000 mg/kg (i.p.). HE-02 reduced Ehrlich tumor cell viability and peritumoral microvessels density. There was an increase of Th1 helper T lymphocytes cytokine profile levels (IL-1β, TNF-α, IL-12) and a decrease of Th2 cytokine profile (IL-4, IL-10). Moreover, an increase was observed on reactive oxygen species and nitric oxide production. Weak in vivo toxicological effects were recorded. Our data provide evidence that the piperine analogue HE-02 present low toxicity, and its antitumor effect involves modulation of immune system to a cytotoxic Th1 profile.

scholarly journals The FGFR Family Inhibitor AZD4547 Exerts an Antitumor Effect in Ovarian Cancer Cells

2021 ◽  
Vol 22 (19) ◽  
pp. 10817
Author(s):  
Yu Ran Na ◽  
Jin Young Kim ◽  
Chang Ho Song ◽  
Mikyung Kim ◽  
Yen Thi Do ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Antitumor Effect ◽  
Potent Inhibitor ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Antitumor Effects ◽  
Ovarian Cancer Stem Cells ◽  
Antiangiogenic Effect

The dysregulation of fibroblast growth factor (FGF) signaling has been implicated in tumorigenesis, tumor progression, angiogenesis, and chemoresistance. The small-molecule AZD4547 is a potent inhibitor of FGF receptors. This study was performed to investigate the antitumor effects and determine the mechanistic details of AZD4547 in ovarian cancer cells. AZD4547 markedly inhibited the proliferation and increased the apoptosis of ovarian cancer cells. AZD4547 also suppressed the migration and invasion of ovarian cancer cells under nontoxic conditions. Furthermore, it attenuated the formation of spheroids and the self-renewal capacities of ovarian cancer stem cells and exerted an antiangiogenic effect. It also suppressed in vivo tumor growth in mice. Collectively, this study demonstrated the antitumor effect of AZD4547 in ovarian cancer cells and suggests that it is a promising agent for ovarian cancer therapy.

scholarly journals Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects

2022 ◽  
Vol 23 (2) ◽  
pp. 730
Author(s):  
Marina Filimonova ◽  
Anna Shitova ◽  
Olga Soldatova ◽  
Ljudmila Shevchenko ◽  
Alina Saburova ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Antitumor Activity ◽  
Anticancer Agents ◽  
Antitumor Effect ◽  
Toxic Effects ◽  
Ehrlich Carcinoma ◽  
Inhibiting Activity ◽  
Antitumor Effects ◽  
Nos Inhibitor

We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents.

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