scholarly journals MORPHOLOGICAL FEATURES OF DOXORUBICIN-RESISTANT WALKER 256 CARCINOSARCOMA AND RESPONSE OF MAST CELLS

2018 ◽  
Vol 40 (1) ◽  
pp. 42-47
Author(s):  
N V Boroday ◽  
V F Chekhun
Keyword(s):  
Drug Resistance ◽  
Mast Cells ◽  
Staining Intensity ◽  
Morphological Features ◽  
Histamine Content ◽  
Original Strain ◽  
Walker 256 Carcinosarcoma ◽  
Development Of Resistance ◽  
Walker 256

Background: The mechanisms of drug resistance of cancer have not been yet elucidated in details. Recently, the role of mast cells (MCs) in the development of drug resistance has been brought in the limelight. The aim of the study was to examine the morphological features of doxorubicin (DOX)-resistant Walker 256 carcinosarcoma and to assess the response of MCs and histamine content in these cells in relation to the development of resistance to DOX as well as in DOX-resistant tumors. Materials and Methods: The DOX resistance was induced by serial passages of Walker 256 carcinosarcoma in rats in the setting of DOX treatment in vivo. MCs in tumors were detected in the sections by staining with Toluidine Blue O. Histamine content in MCs stained with solution of Water Blue-Orcein was assessed by Astaldi semiquantitative method taking into account different staining intensity. Results: Formation of DOX resistance in the course of serial passages of Walker 256 carcinosarcoma was accompanied by the increase in the number of MCs in tumors and histamine content. Nevertheless, in tumors with phenotype of complete DOX resistance the number of histamine-containing MCs decreased to the same level as in tumors of the original strain that are DOX-sensitive. Conclusion: MCs are involved in formation of DOX resistance in Walker 256 carcinosarcoma.

Synthese, in vivo- und in vitro-Untersuchungen zur tumorhemmenden Wirkung von cis-Dichloro-dipeptidester-platin(II)-Komplexen / Synthesis, in vivo and in vitro Studies on the Antineoplastic Effect of cis-Dichloro-dipeptide Ester Platinum(II) Complexes

1976 ◽  
Vol 31 (6) ◽  
pp. 832-845 ◽  
Author(s):  
Wolfgang Beck ◽  
Bernhard Purucker ◽  
Michael Girnth ◽  
Helmut Schönenberger ◽  
Horst Seidenberger ◽  
...  
Keyword(s):  
Protein Biosynthesis ◽  
Sarcoma 180 ◽  
Protecting Group ◽  
Yoshida Sarcoma ◽  
Walker 256 Carcinosarcoma ◽  
E Coli ◽  
Antineoplastic Effect ◽  
Walker 256

cis-Dichlorodipeptide esterplatinum complexesCl2Pt(MetGlyOEt),Cl2Pt(EthionylGlyOEt), Cl2Pt(GlyGlyOEt)2 and Cl2Pt(GlySerOEt)2 are prepared from the α-amino acid complexes by peptide synthesis using platinum as an amino protecting group. cis-Cl2Pt(GlyGlyOEt)2 and cis-Cl2Pt(GlySerOEt)2 have been prepared also directly from K2PtCl4 and the dipeptidesters. cis-Cl2Pt(GlyGlyOEt)2 (2 a) and cis-Cl2Pt(NH3)2 (5) lead to a prefered inhibition of the DNA-synthesis of sarcoma 180, Yoshida-sarcoma and Walker-256-carcinosarcoma in vitro; RNA- and protein biosynthesis are influenced to a much lower degree. 2a and 5 cause filamentous growth in Escherichia coli B. The DNA polymerase deficient strain of E. coli, p 3478 pol A-, is more inhibited by 2 a and 5 than the non deficient strain W 3110 pol A+. Tumor growth of di-2-chloro-ethylmethylamine (HN2) resistant sarcoma 180 and of Yoshida sarcoma is weakly inhibited, whereas Walker-256-carcinosarcoma is markedly inhibited; however 2a and 5 show similar inhibition of the same tumor.

scholarly journals Antileishmanial Aminopyrazoles: Studies into Mechanisms and Stability of Experimental Drug Resistance

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
M. Van den Kerkhof ◽  
D. Mabille ◽  
S. Hendrickx ◽  
P. Leprohon ◽  
C. E. Mowbray ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Copy Number ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Copy Number Variations ◽  
Content Type ◽  
Development Of Resistance ◽  
Efflux Pump Inhibitors

ABSTRACT Current antileishmanial treatment is hampered by limitations, such as drug toxicity and the risk of treatment failure, which may be related to parasitic drug resistance. Given the urgent need for novel drugs, the Drugs for Neglected Diseases initiative (DNDi) has undertaken a drug discovery program, which has resulted in the identification of aminopyrazoles, a highly promising antileishmanial chemical series. Multiple experiments have been performed to anticipate the propensity for resistance development. Resistance selection was performed by successive exposure of Leishmania infantum promastigotes (in vitro) and intracellular amastigotes (both in vitro and in golden Syrian hamsters). The stability of the resistant phenotypes was assessed after passage in mice and Lutzomyia longipalpis sandflies. Whole-genome sequencing (WGS) was performed to identify mutated genes, copy number variations (CNVs), and somy changes. The potential role of efflux pumps (the MDR and MRP efflux pumps) in the development of resistance was assessed by coincubation of aminopyrazoles with specific efflux pump inhibitors (verapamil, cyclosporine, and probenecid). Repeated drug exposure of amastigotes did not result in the emergence of drug resistance either in vitro or in vivo. Selection at the promastigote stage, however, was able to select for parasites with reduced susceptibility (resistance index, 5.8 to 24.5). This phenotype proved to be unstable after in vivo passage in mice and sandflies, suggesting that nonfixed alterations are responsible for the elevated resistance. In line with this, single nucleotide polymorphisms and indels identified by whole-genome sequencing could not be directly linked to the decreased drug susceptibility. Copy number variations were absent, whereas somy changes were detected, which may have accounted for the transient acquisition of resistance. Finally, aminopyrazole activity was not influenced by the MDR and MRP efflux pump inhibitors tested. The selection performed does not suggest the rapid development of resistance against aminopyrazoles in the field. Karyotype changes may confer elevated levels of resistance, but these do not seem to be stable in the vertebrate and invertebrate hosts. MDR/MRP efflux pumps are not likely to significantly impact the activity of the aminopyrazole leads.

scholarly journals METABOLIC CHANGES DURING DEVELOPMENT OF WALKER-256 CARCINOSARCOMA RESISTANCE TO DOXORUBICIN

2015 ◽  
Vol 37 (1) ◽  
pp. 19-22 ◽  
Author(s):  
I N Todor ◽  
N Yu Lukianova ◽  
Yu V Shvets ◽  
Yu V Lozovska ◽  
V F Chekhun
Keyword(s):  
Drug Resistance ◽  
Oxidative Phosphorylation ◽  
Blood Serum ◽  
Tumor Tissue ◽  
Metabolic Changes ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Glucose Content ◽  
Walker 256 Carcinosarcoma ◽  
Walker 256 ◽  
Resistance To Doxorubicin

Aim: To study indices of energy metabolism, content of K+ and Mg++ both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. Methods: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains — by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. Results: It has been determined that development of drug resistance causes the decrease of K+, Mg++, glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor’s loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH. Conclusion: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance.

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

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.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

Imidazolidinyl urea activates mast cells via MRGPRX2 to induce non-histaminergic allergy

2021 ◽  
Author(s):  
Jiapan Gao ◽  
Delu Che ◽  
Xueshan Du ◽  
Yi Zheng ◽  
Huiling Jing ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Mast Cells ◽  
Pharmaceutical Products ◽  
Drug Induced ◽  
Inflammatory Infiltration ◽  
Local Inflammatory Response ◽  
Allergic Contact ◽  
G Protein Coupled

Abstract Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

scholarly journals Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 210-223 ◽  
Author(s):  
Eun Ji Gang ◽  
Hye Na Kim ◽  
Yao-Te Hsieh ◽  
Yongsheng Ruan ◽  
Heather A. Ogana ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

scholarly journals Cisplatin loaded multiwalled carbon nanotubes reverse drug resistance in NSCLC by inhibiting EMT

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuxin Qi ◽  
Wenping Yang ◽  
Shuang Liu ◽  
Fanjie Han ◽  
Haibin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Carbon Nanotubes ◽  
Drug Resistance ◽  
Western Blot ◽  
Multiwalled Carbon Nanotubes ◽  
Cell Lines ◽  
Nude Mice ◽  
Expression Level ◽  
Multiwalled Carbon

Abstract Background Lung cancer is one of the important health threats worldwide, of which 5-year survival rate is less than 15%. Non-small-cell lung cancer (NSCLC) accounts for about 80% of all lung cancer with high metastasis and mortality. Methods Cisplatin loaded multiwalled carbon nanotubes (Pt-MWNTS) were synthesized and used to evaluate the anticancer effect in our study. The NSCLC cell lines A549 (cisplatin sensitive) and A549/DDP (cisplatin resistant) were used in our in vitro assays. MTT was used to determine Cancer cells viability and invasion were measured by MTT assay and Transwell assay, respectively. Apoptosis and epithelial-mesenchymal transition related marker proteins were measured by western blot. The in vivo anti-cancer effect of Pt-MWNTs were performed in male BALB/c nude mice (4-week old). Results Pt-MWNTS were synthesized and characterized by X-ray diffraction, Raman, FT-IR spectroscopy and scan electron microscopy. No significant cytotoxicity of MWNTS was detected in both A549/DDP and A549 cell lines. However, Pt-MWNTS showed a stronger inhibition effect on cell growth than free cisplatin, especially on A549/DDP. We found Pt-MWNTS showed higher intracellular accumulation of cisplatin in A549/DDP cells than free cisplatin and resulted in enhanced the percent of apoptotic cells. Western blot showed that application of Pt-MWNTS can significantly upregulate the expression level of Bax, Bim, Bid, Caspase-3 and Caspase-9 while downregulate the expression level of Bcl-2, compared with free cisplatin. Moreover, the expression level of mesenchymal markers like Vimentin and N-cadherin was more efficiently reduced by Pt-MWNTS treatment in A549/DDP cells than free cisplatin. In vivo study in nude mice proved that Pt-MWNTS more effectively inhibited tumorigenesis compared with cisplatin, although both of them had no significant effect on body weight. Conclusion Pt-MWNT reverses the drug resistance in the A549/DDP cell line, underlying its possibility of treating NSCLC with cisplatin resistance.

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