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.

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 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.

Doxorubicin nanomedicine based on ginsenoside Rg1 with alleviated cardiotoxicity and enhanced antitumor activity

Nanomedicine ◽  
2021 ◽  
Vol 16 (29) ◽  
pp. 2587-2604
Author(s):  
Chaoqi Li ◽  
Xiangbo Gou ◽  
Hui Gao
Keyword(s):  
Antitumor Activity ◽  
Protective Effect ◽  
Tumor Targeting ◽  
Antitumor Effect ◽  
Ginsenoside Rg1 ◽  
Antitumor Effects ◽  
Tumor Bearing ◽  
Targeting Ability

Aim: The authors aimed to develop Dox@Rg1 nanoparticles with decreased cardiotoxicity to expand their application in cancer. Materials & methods: Dox@Rg1 nanoparticles were developed by encapsulating doxorubicin (Dox) in a self-assembled Rg1. The antitumor effect of the nanoparticles was estimated using 4T1 tumor-bearing mice and the protective effect on the heart was investigated in vitro and in vivo. Results: Different from Dox, the Dox@Rg1 nanoparticles induced increased cytotoxicity to tumor cells, which was decreased in cardiomyocytes by the inhibition of apoptosis. The study in vivo revealed that the Dox@Rg1 nanoparticles presented a perfect tumor-targeting ability and improved antitumor effects. Conclusion: Dox@Rg1 nanoparticles could enhance the antitumor effects and decrease the cardiotoxicity of Dox.

Репрограммированые in vitro на М3 фенотип макрофаги останавливают рост солидной карциномы in vivo

2018 ◽  
pp. 41-46
Author(s):  
А.А. Раецкая ◽  
С.В. Калиш ◽  
С.В. Лямина ◽  
Е.В. Малышева ◽  
О.П. Буданова ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Antitumor Effect ◽  
Tumor Development ◽  
Significant Inhibition ◽  
The Body ◽  
Ehrlich Carcinoma ◽  
Solid Carcinoma ◽  
Ec Cells

Цель исследования. Доказательство гипотезы, что репрограммированные in vitro на М3 фенотип макрофаги при введении в организм будут существенно ограничивать развитие солидной карциномы in vivo . Методика. Рост солидной опухоли инициировали у мышей in vivo путем подкожной инъекции клеток карциномы Эрлиха (КЭ). Инъекцию макрофагов с нативным М0 фенотипом и с репрограммированным M3 фенотипом проводили в область формирования солидной КЭ. Репрограммирование проводили с помощью низких доз сыворотки, блокаторов факторов транскрипции STAT3/6 и SMAD3 и липополисахарида. Использовали две схемы введения макрофагов: раннее и позднее. При раннем введении макрофаги вводили на 1-е, 5-е, 10-е и 15-е сут. после инъекции клеток КЭ путем обкалывания макрофагами с четырех сторон область развития опухоли. При позднем введении, макрофаги вводили на 10-е, 15-е, 20-е и 25-е сут. Через 15 и 30 сут. после введения клеток КЭ солидную опухоль иссекали и измеряли ее объем. Эффект введения макрофагов оценивали качественно по визуальной и пальпаторной характеристикам солидной опухоли и количественно по изменению ее объема по сравнению с группой без введения макрофагов (контроль). Результаты. Установлено, что M3 макрофаги при раннем введении от начала развития опухоли оказывают выраженный антиопухолевый эффект in vivo , который был существенно более выражен, чем при позднем введении макрофагов. Заключение. Установлено, что введение репрограммированных макрофагов M3 ограничивает развитие солидной карциномы в экспериментах in vivo . Противоопухолевый эффект более выражен при раннем введении М3 макрофагов. Обнаруженные в работе факты делают перспективным разработку клинической версии биотехнологии ограничения роста опухоли, путем предварительного программирования антиопухолевого врожденного иммунного ответа «в пробирке». Aim. To verify a hypothesis that macrophages reprogrammed in vitro to the M3 phenotype and injected into the body substantially restrict the development of solid carcinoma in vivo . Methods. Growth of a solid tumor was initiated in mice in vivo with a subcutaneous injection of Ehrlich carcinoma (EC) cells. Macrophages with a native M0 phenotype or reprogrammed towards the M3 phenotype were injected into the region of developing solid EC. Reprogramming was performed using low doses of serum, STAT3/6 and SMAD3 transcription factor blockers, and lipopolysaccharide. Two schemes of macrophage administration were used: early and late. With the early administration, macrophages were injected on days 1, 5, 10, and 15 following the injection of EC cells at four sides of the tumor development area. With the late administration, macrophages were injected on days 10, 15, 20, and 25. At 15 and 30 days after the EC cell injection, the solid tumor was excised and its volume was measured. The effect of macrophage administration was assessed both qualitatively by visual and palpation characteristics of solid tumor and quantitatively by changes in the tumor volume compared with the group without the macrophage treatment. Results. M3 macrophages administered early after the onset of tumor development exerted a pronounced antitumor effect in vivo , which was significantly greater than the antitumor effect of the late administration of M3 macrophages. Conclusion. The observed significant inhibition of in vivo growth of solid carcinoma by M3 macrophages makes promising the development of a clinical version of the biotechnology for restriction of tumor growth by in vitro pre-programming of the antitumor, innate immune response.

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

Raspberry pulp polysaccharides inhibit tumor growth via immunopotentiation and enhance docetaxel chemotherapy against malignant melanoma in vivo

2015 ◽  
Vol 6 (9) ◽  
pp. 3022-3034 ◽  
Author(s):  
Yong-Jing Yang ◽  
Han-Mei Xu ◽  
You-Rui Suo
Keyword(s):  
Malignant Melanoma ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Inhibit Tumor Growth ◽  
Docetaxel Chemotherapy

Raspberry pulp polysaccharides exhibit antitumor activity in vivo against malignant melanoma through immunopotentiation and enhance the antitumor effect of docetaxel.

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.

In Vivo Evaluation of Immunomodulating Effects of Lenalidomide (L) on Tumor Cell Microenvironment as a Possible Underlying Mechanism of the Antitumor Effects Observed in Patients (pts) with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2975-2975 ◽  
Author(s):  
Asher Alban Chanan-Khan ◽  
Swaminathan Padmanabhan ◽  
Kena C. Miller ◽  
Paula Pera ◽  
Laurie DiMiceli ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Study ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Cell ◽  
Underlying Mechanism ◽  
Antitumor Effects ◽  
Absolute Increase

Abstract Introduction: L is a more potent analogue of thalidomide with antitumor activity reported in MDS and multiple myeloma. Clinical anti-leukemic activity of L is reported for the first time by our group in pts with CLL. The underlying mechanism of its antitumor activity remains undetermined. We investigated the effect of L on the tumor microenvironment and studied the modulation of soluble cytokines and immune cells (T and NK cells) in pts receiving L. Patients and Methods: CLL pts enrolled on the clinical study with L were eligible. Pre and post (day 7) samples were obtained for evaluation of changes in serum cytokine and immune cell environment. Malignant cells were also obtained to investigate the in vitro antitumor activity of L prior to initiating treatment on clinical trial. Results: With Anexin V staining for evaluation of apoptosis induction, in vitro testing of pts samples (n=10) showed only a modest increase in apoptosis at 200mg of L - levels clinically not achievable. Yet same pts treated with L on clinical study showed significant antitumor response, suggesting the mechanism to be possibly related to modulation of the tumor microenvironment. In evaluation of the tumor cytokine microenvironment (n= 10) we noted significant L induced increase in IL-10 (n=6), IL-8 (n=8), IP-10 (n=10), IL-8 (n=8), TNF-alpha (n=4) and decrease in PDGF (n=5) and RANTES (n=5). While evaluation of the immune cell repertoire we observed an absolute increase in T-cell as well as NK-cell after treatment with L. Conclusion: Our in vitro evaluation does not suggest a direct apoptotic effect of L on the malignant CLL cells and thus support the hypothesis that the anti-leukemic effect noted in the clinical trial (reported separately) is most likely from in vivo modulation of the tumor microenvironment as is demonstrated from changes in the cytokine milieu and the cellular immune response. Collectively these changes may be responsible for the immune modulating properties of L and the resultant anti-CLL activity in pts.

Preclinical evaluation of SC0245, a small molecule inhibitor of ATR kinase.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15642-e15642
Author(s):  
Jian Wang ◽  
Qi Li ◽  
Yuanfeng Xia ◽  
Chi-Chung Chan ◽  
Xusheng Yuan ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Mouse Models ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
Small Molecule Inhibitor ◽  
Inhibiting Activity ◽  
Molecule Inhibitor ◽  
Phosphoinositide 3 Kinase ◽  
Atr Kinase

e15642 Background: The ataxia telangiectasia and Rad3-related (ATR) kinase is a member of the phosphoinositide 3-kinase related kinase (PIKK) family. ATR plays an important role in maintaining genome integrity during DNA replication through the activation of Chk1, and regulation of the DNA damage response (DDR). Replication stress (RS) is a major source of genomic instability in cancer, and targeting the RS-response kinase ATR has emerged as a promising antitumor approach. The purpose of this study was to investigate the antitumor activity of SC0245, a small molecule inhibitor of ATR kinase, in preclinical models of ATM pathway or ARID1A deficient solid tumors. Methods: The kinase inhibiting activity of SC0245 was determined using the ATR/ATRIP(h) complex assays. The cellular anti-proliferative activity was evaluated with tumor cells which was ATM pathway or ARID1A deficient. The in vivo antitumor activity of SC0245 was evaluated in ATM pathway or ARID1A deficient cell-derived xenograft (CDX) mouse models of gastric cancer (SNU-601) and colorectal adenocarcinoma (LoVo). Results: SC0245 displayed potent kinase inhibiting activity for ATR/ATRIP complex with IC50 14 nM, and had outstanding selectivity in the 104 onco-kinase panels. SC0245 significantly inhibited cell proliferation in ATM pathway or ARID1A deficient LoVo cells with IC50 0.163 μM, SNU-601 cells with IC50 0.218 μM. SC0245 showed excellent pharmacokinetics (PK) features with oral bioavailability ( > 80%) in mouse, rat and dog. Moreover, in the SNU601 and LoVo CDX mouse models, SC0245 oral administration significantly inhibited tumor growth, with better efficacy than AZD6738. Conclusions: SC0245, a novel potent ATR kinase inhibitor, has marked antitumor efficacy in the ATM pathway or ARID1A deficient solid tumor animal models, and has outstanding PK properties. SC0245 represents a promising clinical candidate for treating solid cancers, such as gastric and colorectal cancers.

Antitumor Activities of Extracts and Compounds from Water Decoctions of Taxus cuspidata

2010 ◽  
Vol 38 (06) ◽  
pp. 1107-1114 ◽  
Author(s):  
Shougang Jiang ◽  
Yu Zhang ◽  
Yuangang Zu ◽  
Zhuo Wang ◽  
Yujie Fu
Keyword(s):  
Antitumor Activity ◽  
Water Soluble ◽  
Taxus Cuspidata ◽  
Antitumor Activities ◽  
Antitumor Effects ◽  
Anticancer Properties ◽  
Specific Host ◽  
First Time

Water decoctions from the leaves of Taxus cuspidata are used in traditional Chinese medicine to treat cancer, suggesting that water soluble constituents from these leaves may possess anticancer properties. Interestingly, hydrophilic paclitaxel derivatives, as opposed to paclitaxel itself, can be detected by high pressure liquid chromatography in water decoctions from these leaves. The remainder extracts, which are free of paclitaxel and hydrophilic paclitaxel derivatives, from the T. cuspidata leaves were investigated for antitumor activity in vivo and in vitro for the first time in this study. EE80B, 7-xylosyl-10-deacetylpaclitaxel and 7-xylosyl-10-deacetylpaclitaxel C displayed the most antitumor activity in vivo. However, in vitro studies with tumor cell lines showed that EE80B had a significantly smaller antitumor effect than paclitaxel. We hypothesize that water decoctions from T. cuspidata leaves exhibit antitumor effects in vivo, which may be aided by the activation of specific host mechanisms (e.g. stimulation of antitumor immunity) which are not present in vitro.

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