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Article ; Online: RARα mediates all-trans-retinoic acid-induced VEGF-C, VEGF-D, and VEGFR3 expression in lung cancer cells.

Kalitin, Nikolay N / Karamysheva, Aida F

2016 Volume 40, Issue 4, Page(s) 456–464

Abstract: The regulation of vascular endothelial growth factors C (VEGF-C) and D (VEGF-D), and their receptor VEGFR3 gene and protein expression by all-trans-retinoic acid (atRA) in A549 lung cancer cells, was investigated. We showed that atRA treatment increased ... ...

Abstract	The regulation of vascular endothelial growth factors C (VEGF-C) and D (VEGF-D), and their receptor VEGFR3 gene and protein expression by all-trans-retinoic acid (atRA) in A549 lung cancer cells, was investigated. We showed that atRA treatment increased VEGF-C, VEGF-D, and VEGFR3 protein and mRNA contents in dose-dependent manner. atRA-mediated increase of both ligands and receptor expression correlated with the elevated level of retinoic acid receptor α (RARα) expression, while the level of another atRA receptor, peroxisome proliferator-activated receptor β/δ (PPARβ/δ), was decreased. We demonstrated that the classical counterpart of RARα, retinoid X receptor α (RXRα), was down-regulated in both cytoplasm and nucleus of A549 cells upon atRA addition. On the contrary, the nuclear quantity of another possible RARα counterpart, transcription factor Sp1, was increased after atRA treatment.
MeSH term(s)	Cell Line, Tumor ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Microscopy, Fluorescence ; RNA Interference ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Real-Time Polymerase Chain Reaction ; Retinoic Acid Receptor alpha/antagonists & inhibitors ; Retinoic Acid Receptor alpha/genetics ; Retinoic Acid Receptor alpha/metabolism ; Signal Transduction/drug effects ; Sp1 Transcription Factor/genetics ; Sp1 Transcription Factor/metabolism ; Tretinoin/pharmacology ; Vascular Endothelial Growth Factor C/genetics ; Vascular Endothelial Growth Factor C/metabolism ; Vascular Endothelial Growth Factor D/genetics ; Vascular Endothelial Growth Factor D/metabolism ; Vascular Endothelial Growth Factor Receptor-3/genetics ; Vascular Endothelial Growth Factor Receptor-3/metabolism
Chemical Substances	RNA, Messenger ; RNA, Small Interfering ; Retinoic Acid Receptor alpha ; Sp1 Transcription Factor ; Vascular Endothelial Growth Factor C ; Vascular Endothelial Growth Factor D ; Tretinoin (5688UTC01R) ; FLT4 protein, human (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-3 (EC 2.7.10.1)
Language	English
Publishing date	2016-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1143453-3
ISSN	1095-8355 ; 1065-6995
ISSN (online)	1095-8355
ISSN	1065-6995
DOI	10.1002/cbin.10587
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Article: Mechanisms of angiogenesis.

Karamysheva, A F

Biochemistry. Biokhimiia

2008 Volume 73, Issue 7, Page(s) 751–762

Abstract: Tissue activity of angiogenesis depends on the balance of many stimulating or inhibiting factors. The key signaling system that regulates proliferation and migration of endothelial cells forming the basis of any vessel are vascular endothelium growth ... ...

Abstract	Tissue activity of angiogenesis depends on the balance of many stimulating or inhibiting factors. The key signaling system that regulates proliferation and migration of endothelial cells forming the basis of any vessel are vascular endothelium growth factors (VEGF) and their receptors. The VEGF-dependent signaling system is necessary for formation of the embryonic vascular system. Neoangiogenesis during tumor growth is also associated with activation of this signaling system. The biological significance of the effect of such system on the cells depends on the content in tissue of various factors of the VEGF family and their receptors, while in the case of VEGFA it is defined by the ratio of different isoforms of this growth factor. A number of other signaling systems are also involved in regulation of the main steps of vessel formation. The signaling system Dll4/Notch regulates selection of endothelial cells for beginning of angiogenic expansion by endowing particular properties to endothelial cells leading in this process. An important step in vessel stabilization and maturation is vascular wall formation. Signaling system PDGFB/PDGFRbeta as well as angiopoietins Ang1, Ang2, and their receptor Tie2 are involved in recruiting mural cells (pericytes and smooth muscle cells). Identification of key molecules involved in the regulation of angiogenesis may provide new possibilities for development of drugs suitable for inhibition of angiogenesis or its stimulation in various pathologies.
MeSH term(s)	Angiopoietins/metabolism ; Animals ; Capillaries/growth & development ; Endothelium, Vascular/cytology ; Humans ; Mice ; Neoplasms/blood supply ; Neovascularization, Pathologic/etiology ; Neovascularization, Pathologic/metabolism ; Neovascularization, Physiologic ; Neuropilins/metabolism ; Receptors, TIE/metabolism ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Vascular Endothelial Growth Factor A/physiology
Chemical Substances	Angiopoietins ; Neuropilins ; Vascular Endothelial Growth Factor A ; Receptors, TIE (EC 2.7.10.1) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	2008-06-11
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1109-5
ISSN	1608-3040 ; 0006-2979 ; 0320-9717
ISSN (online)	1608-3040
ISSN	0006-2979 ; 0320-9717
DOI	10.1134/s0006297908070031
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Article: Analiz ékspressii genov VEGF-A/VEGFR1/VEGFR2 u patsientov s mielodisplasticheskim sindromom.

Kalitin, N N / Dudina, G A / Semochkin, S V / Karamysheva, A F

Terapevticheskii arkhiv

2017 Volume 89, Issue 7, Page(s) 39–44

Abstract: Aim: To assess the significance of gene expression of the vascular endothelial growth factor-A (VEGF-A) and its interacting receptors VEGFR1 and VEGFR2 as potential diagnostic and prognostic molecular markers in patients with myelodysplastic syndrome ( ... ...

Title translation	Analysis of VEGF-A/VEGFR1/VEGFR2 gene expression in patients with myelodysplastic syndrome.
Abstract	Aim: To assess the significance of gene expression of the vascular endothelial growth factor-A (VEGF-A) and its interacting receptors VEGFR1 and VEGFR2 as potential diagnostic and prognostic molecular markers in patients with myelodysplastic syndrome (MDS). Material and methods: A real time polymerase chain reaction (RT-PCR) assay was used to investigate the gene expression of VEGF-A, VEGFR1, and VEGFR2 in the mononuclear cell fractions obtained from 24 patients with MDS. Results: The expression of the 3 genes was identified in all the patients examined. There was the highest expression level of the VEGF-A gene (p<0.0001), whereas the expression of the VEGFR1 gene was higher than that of the VEGFR2 gene (p<0.001). The expression of the VEGF-A gene proved to be higher in patients at a higher risk of acute leukemia and positively correlated with the expression levels of the VEGFR1 gene (p<0.05) rather than that of the VEGFR2 gene. At the same time, patients with higher VEGFR1 gene expression had significantly lower overall survival rates (r=-0.5; p<0.05). Patients with intermediate-2 or high-risk acute leukemia showed an increase in the average expression levels of VEGF-A and VEGFR1 and a reduction in VEGFR2 expression. Conclusion: This investigation revealed correlations between the number of blast cells in patients with MDS and the expression levels of the VEGF-A gene and between the overall survival of patients with MDS and the expression levels of the VEGFR1 gene rather than those of the VEGF-A and VEGFR2 genes.
Language	Russian
Publishing date	2017
Publishing country	Russia (Federation)
Document type	English Abstract ; Journal Article
ZDB-ID	40718-5
ISSN	2309-5342 ; 0040-3660
ISSN (online)	2309-5342
ISSN	0040-3660
DOI	10.17116/terarkh201789739-44
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Article ; Online: Epoxidized linseed oil as a plasticizer for All-Cellulose Composites based on cellulose acetate butyrate and micronized pulp fibers

Valente, Bruno F.A. / Karamysheva, Anna / Silvestre, Armando J.D. / Neto, Carlos Pascoal / Vilela, Carla / Freire, Carmen S.R.

Industrial Crops & Products. 2023 Oct., v. 202 p.116980-

2023

Abstract: All-Cellulose Composites (ACCs) with cellulose derivatives have been neglected in the composite industry due to their high brittleness, low impact strength, and flowability. Epoxidized vegetable oils are well-known plasticizers for several polymers and ... ...

Abstract	All-Cellulose Composites (ACCs) with cellulose derivatives have been neglected in the composite industry due to their high brittleness, low impact strength, and flowability. Epoxidized vegetable oils are well-known plasticizers for several polymers and composites but have never been exploited on the production of ACCs. The present work investigates the potential of an epoxidized linseed oil (ELO) as a cost-effective additive to enhance the properties and processability of ACCs made with cellulose acetate butyrate (CAB) and micronized Eucalyptus pulp fibers. The thermo-mechanical characterization of the composites, obtained by melt-mixing, revealed that ELO significantly decreases the glass transition temperature (Tg) of the obtained composites without compromising their thermal stability. Moreover, an 84-fold improvement was achieved on the melt flow rate (MFR) with 30 wt% ELO, and growing amounts of this additive caused an augment on the elongation and flexural strains at break. High loads of ELO resulted also on a substantial improvement of the impact strength, with values raising from 5.3 ± 0.9 kJ.m⁻² up to 29.5 ± 1.7 kJ.m⁻². Furthermore, this eco-friendly plasticizer also led to higher water uptake values, as well as higher biodegradation rates than the non-plasticized ACCs. Therefore, these results evince a remarkable improvement on the ACCs processability, performance, and biodegradation upon addition of a bio-based and cost-effective plasticizer.
Keywords	Eucalyptus ; biodegradation ; brittleness ; butyrates ; cellulose ; cellulose acetate ; cost effectiveness ; glass transition temperature ; impact strength ; industry ; linseed oil ; plasticizers ; pulp ; thermal stability ; vegetables ; water uptake ; Biocomposites ; Impact behaviour ; Mechanical properties ; Thermal properties ; Plasticizer
Language	English
Dates of publication	2023-10
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	1132158-1
ISSN	1872-633X ; 0926-6690
ISSN (online)	1872-633X
ISSN	0926-6690
DOI	10.1016/j.indcrop.2023.116980
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Article ; Online: Biobased ternary films of thermoplastic starch, bacterial nanocellulose and gallic acid for active food packaging

Almeida, Tania / Karamysheva, Anna / Valente, Bruno F.A. / Silva, José M. / Braz, Márcia / Almeida, Adelaide / Silvestre, Armando J.D. / Vilela, Carla / Freire, Carmen S.R.

Food Hydrocolloids. 2023 Nov., v. 144 p.108934-

2023

Abstract: The use of active packaging technologies and biopolymeric materials are among the emerging trends for implementation of sustainability in the food packaging industry. Thus, herein, bioactive transparent nanocomposite films of thermoplastic starch (TPS) ... ...

Abstract	The use of active packaging technologies and biopolymeric materials are among the emerging trends for implementation of sustainability in the food packaging industry. Thus, herein, bioactive transparent nanocomposite films of thermoplastic starch (TPS) reinforced with bacterial nanocellulose (BNC) (1%, 5% and 10% w/w, relative to starch) and enriched with gallic acid (GA) (1 and 1.5% w/w, relative to starch) were prepared by the solvent casting method. The addition of BNC (≥5% w/w) and GA (1 and 1.5% w/w) enhanced both the mechanical properties (Young's Modulus: 1.2–2.0 GPa vs. 1.0 GPa for TPS; tensile strength: 23–39 MPa vs. 20 MPa for TPS) and the water resistance (moisture absorption and solubility in water) of the nanocomposites. All films are thermally stable up to 125 °C. It was also found that the addition of GA imparted the hydrocolloid TPS-BNC nanocomposites with UV-blocking properties and antioxidant activity (DPPH scavenging activity above 80%). In addition, the film with 10% w/w of BNC nanofibers and 1% w/w of GA had good oxygen barrier properties with a coefficient of permeability of 0.91 ± 0.12 cm³ μm m⁻² d⁻¹ kPa⁻¹ and antibacterial activity against the gram-positive Staphylococcus aureus (reduction of about 4.5 log₁₀ colony forming units (CFU) mL⁻¹ after 48 h). This is the first time that antibacterial activity is reported for TPS-BNC nanocomposites. The film with 10% w/w of BNC nanofibers and 1% w/w of GA was further demonstrated to have the ability of delaying the browning and weight loss of packaged fresh cut apple stored at +4 °C for 7 days. All these outcomes are of great relevance for the packaging sector, thus attesting the potential of the developed TPS-BNC-GA nanocomposites as sustainable and eco-friendly film materials for active food packaging.
Keywords	Staphylococcus aureus ; absorption ; antibacterial properties ; antioxidant activity ; apples ; cellulose ; gallic acid ; hydrocolloids ; industry ; modulus of elasticity ; nanocomposites ; nanofibers ; oxygen ; permeability ; solubility ; solvents ; starch ; tensile strength ; thermal stability ; thermoplastics ; weight loss ; Thermoplastic starch ; Bacterial nanocellulose ; Antioxidant and antibacterial activities ; Oxygen barrier properties ; Active food packaging
Language	English
Dates of publication	2023-11
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	742742-6
ISSN	1873-7137 ; 0268-005X
ISSN (online)	1873-7137
ISSN	0268-005X
DOI	10.1016/j.foodhyd.2023.108934
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Article ; Online: Vascular endothelial growth factor receptor 3 is a novel marker differing CD138-positive and CD138-negative multiple myeloma cells.

Kostjukova, Maria N / Tupitsyn, Nikolai N / Karamysheva, Aida F

British journal of haematology

2017 Volume 181, Issue 6, Page(s) 840–843

MeSH term(s)	Biomarkers, Tumor/biosynthesis ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Neoplasm Proteins/biosynthesis ; Syndecan-1 ; Vascular Endothelial Growth Factor Receptor-3/biosynthesis
Chemical Substances	Biomarkers, Tumor ; Neoplasm Proteins ; SDC1 protein, human ; Syndecan-1 ; FLT4 protein, human (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-3 (EC 2.7.10.1)
Language	English
Publishing date	2017-05-16
Publishing country	England
Document type	Letter
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.14706
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Article ; Online: Assessment of the Chemosensitivity of Uveal Melanoma Cells Ex Vivo.

Saakyan, S V / Tsygankov, А Yu / Moiseeva, N I / Karamysheva, А F / Garri, D D

Bulletin of experimental biology and medicine

2020 Volume 170, Issue 1, Page(s) 142–147

Abstract: The study was designed to create a primary cell culture of uveal melanoma and to evaluate its resistance to chemotherapy. Of the obtained 20 samples of uveal melanoma, the primary cultures with proliferation sufficient for MTT test were derived in only 7 ...

Abstract	The study was designed to create a primary cell culture of uveal melanoma and to evaluate its resistance to chemotherapy. Of the obtained 20 samples of uveal melanoma, the primary cultures with proliferation sufficient for MTT test were derived in only 7 cases. However, even these cultures were unable to survive more than 4 passages; the cells accumulated melanin and underwent apoptosis. Retinol palmitate and nepafenac produced no cytotoxic effect on uveal melanoma cells. Of 5 cultures treated with sodium valproate (Convulex), no pronounced cytotoxic effect was observed in one culture (UM4); in 2 cultures, 50% cells died in the presence of the lowest drug concentration of 1.88 mg/ml; and in 2 cultures, the same effect was achieved at drug concentrations 7-10 mg/ml. The cytotoxic effect of treosulfan was evaluated in only 4 cultures of uveal melanoma: the drug exhibited pronounced antitumor activity on all cultures, in 2 cases, it was effective at a concentration of 0.16 mg/ml. Gemcitabine in a concentration of 2.5 mg/ml produced a pronounced cytotoxic effect in 4 out of 7 cultures (death of 70-80% cells) and induced death of ~45% cells in the remaining 3 cultures. Mitoxantrone had ambiguous effect: in 2 of 5 cultures, the drug in high concentrations stimulated the growth of tumor cells, but in 3 cultures, the drug even in minimum concentrations induced death of 70-80% cells.
MeSH term(s)	Adult ; Aged ; Antineoplastic Agents/pharmacology ; Benzeneacetamides/pharmacology ; Busulfan/analogs & derivatives ; Busulfan/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Choroid Neoplasms/drug therapy ; Choroid Neoplasms/pathology ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Diterpenes/pharmacology ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Female ; Humans ; Male ; Melanoma/drug therapy ; Melanoma/pathology ; Middle Aged ; Phenylacetates/pharmacology ; Primary Cell Culture ; Retinyl Esters/pharmacology ; Tumor Cells, Cultured ; Uveal Neoplasms/drug therapy ; Uveal Neoplasms/pathology ; Valproic Acid/pharmacology
Chemical Substances	Antineoplastic Agents ; Benzeneacetamides ; Diterpenes ; Phenylacetates ; Retinyl Esters ; nepafenac (0J9L7J6V8C) ; Deoxycytidine (0W860991D6) ; retinol palmitate (1D1K0N0VVC) ; Valproic Acid (614OI1Z5WI) ; gemcitabine (B76N6SBZ8R) ; treosulfan (CO61ER3EPI) ; Busulfan (G1LN9045DK)
Language	English
Publishing date	2020-11-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	390407-6
ISSN	1573-8221 ; 0007-4888 ; 0365-9615
ISSN (online)	1573-8221
ISSN	0007-4888 ; 0365-9615
DOI	10.1007/s10517-020-05020-3
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Article: [Some molecular and genetic properties of progenitor cells in sarcomas induced with foreign body].

Morozova, O V / Karamysheva, A F / Moizhess, T G

Ontogenez

2015 Volume 46, Issue 2, Page(s) 94–101

Abstract: One of the important questions in understanding the mechanisms of carcinogenesis induced with foreign body (or plastic carcinogenesis), is a question about normal progenitor cells in sarcomas (FB sarcomas) appearing in close proximity to the plastic ... ...

Abstract	One of the important questions in understanding the mechanisms of carcinogenesis induced with foreign body (or plastic carcinogenesis), is a question about normal progenitor cells in sarcomas (FB sarcomas) appearing in close proximity to the plastic plate implanted under the skin of an experimental animal. There is an assumption in literature that progenitor cells in FB sarcomas originate from vascular endothelium cells feeding a connective tissue capsule that forms around foreign body. In our research, we studied mRNA expression of one of the endothelial cell markers--receptor VEGFR2/FIk1--and growth factor VEGF-A, which interacts with it, in precancerous cells of FB sarcomas in mice. In examined cells, mRNA expression of VEGF-A was found while mRNA expression of VEGFR2/FIk1 was absent. In light of this and formerly established properties of progenitor cells in FB sarcomas, possibilities of the origin of these sarcomas from endothelial cells, pericytes, and pluripotent mesenchymal stem cells are being discussed.
MeSH term(s)	Animals ; Biomarkers ; Cells, Cultured ; Endothelial Cells/pathology ; Gene Expression Regulation ; Male ; Mice, Inbred CBA ; Polyvinyls/adverse effects ; Precancerous Conditions ; Prostheses and Implants/adverse effects ; Sarcoma/etiology ; Sarcoma/genetics ; Sarcoma/pathology ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor Receptor-2/genetics
Chemical Substances	Biomarkers ; Polyvinyls ; Vascular Endothelial Growth Factor A ; vascular endothelial growth factor A, mouse ; polyvinylidene fluoride (24937-79-9) ; Kdr protein, mouse (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1)
Language	Russian
Publishing date	2015-03
Publishing country	Russia (Federation)
Document type	Journal Article
ZDB-ID	207373-0
ISSN	0475-1450
ISSN	0475-1450
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Article ; Online: Triterpenoids with modified A-ring as modulators of P-gp-dependent drug-resistance in cancer cells.

Rybalkina, Ekaterina Yu / Moiseeva, Natalia I / Karamysheva, Aida F / Eroshenko, Daria V / Konysheva, Anastasia V / Nazarov, Alexei V / Grishko, Victoria V

Chemico-biological interactions

2021 Volume 348, Page(s) 109645

Abstract: Semi-synthetic A-cycle modified triterpenic derivatives with A-cycle condensed with a heterocyclic fragment (compound 1) and fragmented A-ring (compound 2) were tested for cytotoxicity against several tumor cell cultures and doxorubicin (Dox)-resistant ... ...

Abstract	Semi-synthetic A-cycle modified triterpenic derivatives with A-cycle condensed with a heterocyclic fragment (compound 1) and fragmented A-ring (compound 2) were tested for cytotoxicity against several tumor cell cultures and doxorubicin (Dox)-resistant cell lines. The equal cytotoxicity of the tested compounds to the parental tumor cell lines (HBL-100, K562) and their resistant subclones (HBL-100/Dox, K562/i-S9) was revealed. The overexpression of ABCB1 (MDR1) gene and P-glycoprotein (P-gp) was confirmed for both resistant subclones of tumor cells. Compounds 1 and 2 were shown to inhibit the ABC-transporter gene expression (MDR1, MRP, MVP, and BCRP) and the transport of well-known P-gp substrate Rhodamine 123 from resistant cells. The docking of triterpenoids 1 and 2 into the drug binding site of P-gp revealed a similarity between the conformation of the tested triterpenoids and that of classical inhibitor verapamil, thus assuming these compounds to be more likely the inhibitors than the substrates of P-gp. Any tested triterpenic derivatives, when combined at non-toxic concentrations with doxorubicin, improved cytotoxic effect of the therapeutic drug against resistant subclones of tumor cells.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Humans ; Structure-Activity Relationship ; Triterpenes/chemistry ; Triterpenes/pharmacology
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Antineoplastic Agents ; Triterpenes
Language	English
Publishing date	2021-09-10
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2021.109645
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Article ; Online: A novel glycosylated indolocarbazole derivative LCS1269 effectively inhibits growth of human cancer cells in vitro and in vivo through driving of both apoptosis and senescence by inducing of DNA damage and modulating of AKT/mTOR/S6K and ERK pathways.

Kalitin, Nikolay N / Ektova, Lidia V / Kostritsa, Natalia S / Sivirinova, Anastasia S / Kostarev, Alexander V / Smirnova, Galina B / Borisova, Yulia A / Golubeva, Irina S / Ermolaeva, Elisaveta V / Vergun, Maria A / Babaeva, Maria A / Lushnikova, Anna A / Karamysheva, Aida F

Chemico-biological interactions

2022 Volume 364, Page(s) 110056

Abstract: In recent decades, indolocarbazole glycosides containing sugar moieties have attracted attention due to their diverse anti-tumor activities. In the present study, a series of new indolo [2,3-a]pyrrolo [3,4-c]carbazole derivatives were synthesized for the ...

Abstract	In recent decades, indolocarbazole glycosides containing sugar moieties have attracted attention due to their diverse anti-tumor activities. In the present study, a series of new indolo [2,3-a]pyrrolo [3,4-c]carbazole derivatives were synthesized for the first time. First of all, we have shown that compound 6e (LCS1269) had the most pronounced effect on inhibiting tumor growth in the transferable solid and non-solid murine tumors as compared with other synthesized indolocarbazole derivatives. The results of the in vivo nude mice xenoraft study also confirmed that LCS1269 treatment strongly suppressed the growth of human colon cancer SW620 xenografts. It is important to note that the antiproliferative activity of LCS1269 against three human cancer cell lines (MCF-7, HCT-116 and A549) was considerably higher than that against the non-tumor cell lines (immortalized breast cells and normal embryonic fibroblasts). Furthermore, the treatment of MCF-7, HCT-116 and A549 cells with LCS1269 caused the statistically significant inhibition of anchorage-dependent and anchorage-independent colony formation. We further revealed that LCS1269 treatment of investigated human cancer cells resulted in the DNA damage and G2/M cell cycle arrest followed by the decrease of mitochondrial membrane potential with subsequent initiation of intrinsic apoptosis and the triggering of senescence via p53-dependent mechanisms. In addition, our western blotting findings and molecular docking data suppose that LCS1269 could at least partially attenuate cancer cells growth by modulation of AKT/mTOR/S6K and ERK signaling pathways. Therefore, we concluded that LCS1269 might be the promising compound for implementation and probable use in the clinical practice.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Carbazoles/pharmacology ; Cell Line, Tumor ; Cell Proliferation ; DNA Damage ; Glycosides/pharmacology ; Humans ; MAP Kinase Signaling System ; Mice ; Mice, Nude ; Molecular Docking Simulation ; Neoplasms ; Proto-Oncogene Proteins c-akt/metabolism ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	Antineoplastic Agents ; Carbazoles ; Glycosides ; LCS1269 ; MTOR protein, human (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-07-21
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2022.110056
Database	MEDical Literature Analysis and Retrieval System OnLINE

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