Autocrine tumor growth regulation and tumor-associated hypoglycemia in murine melanoma B16 in vivo

Introduction of α-cyano α,β-unsaturated carbonyl moiety into natural cyclic compounds markedly improves their bioactivities, including inhibitory potential against tumor growth and metastasis. Previously, we showed that cyano enone-bearing derivatives of 18βH-glycyrrhetinic (GA) and deoxycholic acids displayed marked cytotoxicity in different tumor cell lines. Moreover, GA derivative soloxolone methyl (SM) was found to induce ER stress and apoptosis in tumor cells in vitro and inhibit growth of carcinoma Krebs-2 in vivo. In this work, we studied the effects of these compounds used in non-toxic dosage on the processes associated with metastatic potential of tumor cells. Performed screening revealed SM as a hit compound, which inhibits motility of murine melanoma B16 and human lung adenocarcinoma A549 cells and significantly suppresses colony formation of A549 cells. Further study showed that SM effectively blocked transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition (EMT) of A549 cells: namely, inhibited TGF-β-stimulated motility and invasion of tumor cells as well as loss of their epithelial characteristics, such as, an acquisition of spindle-like phenotype, up- and down-regulation of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin, zona occludens-1 (ZO-1)) markers, respectively. Network pharmacology analysis with subsequent verification by molecular modeling revealed that matrix metalloproteinases MMP-2/-9 and c-Jun N-terminal protein kinase 1 (JNK1) can be considered as hypothetical primary targets of SM, mediating its marked anti-EMT activity. The inhibitory effect of SM on EMT revealed in vitro was further confirmed in a metastatic model of murine B16 melanoma: SM was found to effectively block metastatic dissemination of melanoma B16 cells in vivo, increase expression of E-cadherin and suppress expression of MMP-9 in lung metastatic foci. Altogether, our data provided valuable information for a better understanding of the antitumor activity of cyano enone-bearing semisynthetic compounds and revealed SM as a promising anti-metastatic drug candidate.

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Effect of release-active anti-interferon-gamma antibodies on the course of the tumor process in in vivo experimental models

Nauchno-prakticheskii zhurnal «Patogenez» ◽

10.25557/2310-0435.2018.03.132-134 ◽

2018 ◽

pp. 132-134

Author(s):

Т.Г. Разина ◽

И.А. Эртузун ◽

Е.Н. Амосова ◽

С.Г. Крылова ◽

Е.П. Зуева ◽

...

Keyword(s):

Tumor Growth ◽

Interferon Gamma ◽

Conformational Changes ◽

Hematogenous Metastasis ◽

Walker 256 Carcinosarcoma ◽

Melanoma B16 ◽

Enhanced Production ◽

Walker 256 ◽

Stimulation Of

Интерферон-гамма (ИФН) играет важную роль в иммунных механизмах сдерживания опухолевого процесса, однако в определенных условиях может оказывать проопухолевое действие. Релиз-активные антитела (РА АТ) к ИФН изменяют конформацию молекулы этого цитокина, облегчают его связывание с рецептором и усиливают продукцию эндогенного ИФН. Цель настоящего исследования состояла в изучении влияния РА АТ к ИФН на имеющийся опухолевый процесс на моделях меланомы и карциносаркомы. Методика. Было изучено влияние препарата на течение опухолевого процесса в моделях меланомы В-16 у мышей и карциносаркомы Уокера 256 у крыс. Результаты. У мышей с меланомой В-16, чувствительной к ИФН, тестируемый препарат не стимулировал рост и метастазирование опухоли. В модели карциносаркомы Уокера 256 у крыс РА АТ к ИФН также не влияли на размер опухоли, однако значительно ингибировали гематогенное метастазирование. Заключение. В настоящем исследовании не было выявлено стимулирования опухолевого процесса и метастазирования препаратом РА АТ к ИФН. Interferon-gamma (IFN) plays an important role in antitumor immunity; however, in some circumstances, it may also favor tumor immune evasion. Released-active (RA) anti-IFN antibodies (Abs) are able to induce conformational changes in the IFN molecule and to facilitate its receptor binding, which results in enhanced production of this cytokine. The aim of the present study was to evaluate the effect of RA anti-IFN Abs on the tumor growth in models of melanoma and carcinosarcoma. Methods. The ability of anti-IFN RA Abs to influence the tumor growth was evaluated in the models of melanoma B16 in mice and Walker 256 carcinosarcoma in rats. Results. The exposure of mice with IFN-sensitive melanoma B16 to the tested drug did not result in stimulation of tumor growth and metastasis. RA anti-IFN Abs also did not affect the tumor size in the rat model of Walker 256 carcinosarcoma but significantly inhibited the hematogenous metastasis. Conclusion. In the present study, no stimulation of the tumor process and metastasis by RA anti-IFN Abs were found.

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A New Synthetic Spiroketal: Studies on Antitumor Activity on Murine Melanoma Model In Vivo and Mechanism of Action In Vitro

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190131141400 ◽

2019 ◽

Vol 19 (4) ◽

pp. 567-578

Author(s):

Maria P. Fuggetta ◽

Pietro Spanu ◽

Fausta Ulgheri ◽

Francesco Deligia ◽

Paola Carta ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Antitumor Effect ◽

Antitumor Efficacy ◽

Murine Melanoma ◽

Melanoma Model ◽

High Antitumor Activity ◽

Dose Dependent

Background:In a previous study, we synthesised a new spiroketal derivative, inspired to natural products, that has shown high antiproliferative activity, potent telomerase inhibition and proapoptotic activity on several human cell lines.Objective:This work focused on the study of in vivo antitumor effect of this synthetic spiroketal on a murine melanoma model. In order to shed additional light on the origin of the antitumor effect, in vitro studies were performed.Methods:Spiroketal was administered to B16F10 melanoma mice at a dose of 5 mg/Kg body weight via intraperitoneum at alternate days for 15 days. Tumor volume measures were made every 2 days starting after 12 days from cells injection. The effects of the spiroketal on tumor growth inhibition, apoptosis induction, and cell cycle modification were investigated in vitro on B16 cells. HIF1α gene expression, the inhibition of cells migration and the changes induced in cytoskeleton conformation were evaluated.Results:Spiroketal displayed proapoptotic activity and high antitumor activity in B16 cells with nanomolar IC50. Moreover it has shown to inhibit cell migration, to strongly reduce the HIF1α expression and to induce strongly deterioration of cytoskeleton structure. A potent dose-dependent antitumor efficacy in syngenic B16/C57BL/6J murine model of melanoma was observed with the suppression of tumor growth by an average of 90% at a dose of 5 mg/kg.Conclusion:The synthesized spiroketal shows high antitumor activity in the B16 cells in vitro at nM concentration and a dose-dependent antitumor efficacy in syngenic B16/C57BL/6J mice. The results suggest that this natural product inspired spiroketal may have a potential application in melanoma therapy.

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Antitumor effect of a pyrazolone-based-complex [Cu(PMPP-SAL)(EtOH)] against murine melanoma B16 cell in vitro and in vivo

Acta Pharmaceutica ◽

10.2478/acph-2020-0040 ◽

2020 ◽

Vol 70 (4) ◽

pp. 561-575

Author(s):

Ayipairi Abula ◽

Jing Zhao ◽

Guancheng Xu ◽

Yijie Li ◽

Surong Sun

Keyword(s):

Growth Factor ◽

Antitumor Effect ◽

Therapeutic Potential ◽

Control Group ◽

Murine Melanoma ◽

Melanoma B16 ◽

Induction Of Apoptosis ◽

Endothelial Growth Factor

AbstractPyrazolone-based derivative metal complexes were reported to have cytotoxicity in some tumor cells. In this study, the antitumor effect of [Cu(PMPP-SAL)(EtOH)] (PMPP-SAL = N-(1-phenyl-3-methyl-4-propenylidene-5-pyrazolone)- salicylidene hydrazide anion) in murine melanoma B16 cells in vitro and in vivo was investigated. The results showed that [Cu(PMPP-SAL)(EtOH)] inhibited the survival of B16 cells in vitro, and the IC50 value was superior to cisplatin (DDP) (p < 0.001). B16 cell apoptosis was significantly higher in comparison to the control group (DMSO) (p < 0.01), and cell cycle arrest occurred at the G0/G1 phase. When challenged C57 BL/6J mice were treated with [Cu(PMPPSAL)(EtOH)], a smaller volume of B16 solid tumors were reported than the control group (p < 0.01), with lower positive expression indices of CD 34, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (p < 0.01). Moreover, the tumor growth was suppressed in mice due to the induction of apoptosis, as detected by the TUNEL assay (p < 0.001). In summary, [Cu(PMPP-SAL)(EtOH)] effectively inhibited the growth of B16 cells in vitro and in vivo due to the induction of apoptosis and the inhibition of intra-tumoral angiogenesis, demonstrating its therapeutic potential in melanoma treatment.

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Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

Melatonin Research ◽

10.32794/mr11250042 ◽

2019 ◽

Vol 2 (4) ◽

pp. 83-98 ◽

Cited By ~ 2

Author(s):

André De Lima Mota ◽

Bruna Vitorasso Jardim-Perassi ◽

Tialfi Bergamin De Castro ◽

Jucimara Colombo ◽

Nathália Martins Sonehara ◽

...

Keyword(s):

Breast Cancer ◽

Glucose Metabolism ◽

Tumor Growth ◽

Tumor Cells ◽

Carbonic Anhydrases ◽

In Vivo Models ◽

Ca Ix ◽

Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression.

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