scholarly journals MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

2019 ◽  
Author(s):  
Pietro Delfino ◽  
Christian Neander ◽  
Dea Filippini ◽  
Sabrina L. D’Agosto ◽  
Caterina Vicentini ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Map Kinase ◽  
Ductal Adenocarcinoma ◽  
Oncogenic Signaling ◽  
Kinase Activation ◽  
Immune Contexture ◽  
Inflammatory Macrophages

ABSTRACTThe RAF/MEK/ERK (MAP Kinase) pathway is the index oncogenic signaling towards which many compounds have been developed and tested for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). Here, we explored the immunological changes induced by targeted MEK1/2 inhibition (MEKi) using trametinib in preclinical mouse models of PDA. We evaluated the dynamic changes in the immune contexture of mouse PDA upon MEKi using a multidimensional approach (mRNA analyses, flow cytometry, and immunophenotyping). Effect of MEKi on the viability and metabolism of macrophages was investigated in vitro. We showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype (squamous/basal-like/quasimesenchymal), while short term MEKi treatment in mouse PDA induced subtype switching. Integrative mRNA expression and immunophenotypic analyses showed that MEKi reshapes the immune landscape of PDA by depleting rather than reprogramming macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early in the course of in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Tumor-associated macrophages were consistently reported to interfere with gemcitabine uptake by PDA cells. Here, our in vivo studies show a superior antitumor activity upon combination of MEKi and gemcitabine using a sequential rather than simultaneous dosing protocol. Our results show that MEK inhibition induces a dramatic remodeling of the tumor microenvironment of mouse PDA through depletion of macrophages, which substantially improves the antitumor activity of gemcitabine.

Characterization of MAP kinase and PKC isoform and effect of ACE inhibition in hypertrophy in vivo

1999 ◽  
Vol 277 (5) ◽  
pp. H1808-H1816 ◽  
Author(s):  
L. Kim ◽  
T. Lee ◽  
J. Fu ◽  
M. E. Ritchie
Keyword(s):  
Map Kinase ◽  
Gene Activation ◽  
Pressure Overload ◽  
Ace Inhibition ◽  
Binding Activity ◽  
Sham Operation ◽  
Kinase Activation ◽  
Mitogen Activated Protein

Protein kinase C (PKC) and mitogen-activated protein (MAP) kinase activation appear important in conferring hypertrophy in vitro. However, the response of PKC and MAP kinase to stimuli known to induce hypertrophy in vivo has not been determined. We recently demonstrated that pressure-overload hypertrophy induced a transiently transfected gene driven by an hypertrophy responsive enhancer (HRE) through a marked increase in binding activity of its interacting nuclear factor (HRF). These data suggested that the HRE/HRF could serve as a target for evaluating the signal transduction events responsible for hypertrophy in vivo. Accordingly, we characterized MAP kinase and PKC isoform activation, injected HRE driven reporter gene expression, and HRF binding activity in rat hearts subjected to ascending aortic clipping or sham operation in the presence of the angiotensin-converting enzyme (ACE) inhibitor fosinopril, hydralazine, or no treatment. Analyses showed that PKC-ε and MAP kinase were acutely activated following ascending aortic ligature and that fosinopril significantly inhibited but did not completely abrogate PKC-ε and MAP kinase activation. However, fosinopril completely prevented pressure overload-mediated induction of HRE containing constructs and obviated increased HRF binding activity. These results suggest a direct relationship between ACE activity and HRE/HRF-mediated gene activation and imply that PKC-ε and MAP kinase may be involved in transducing this signal.

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.

p85α Regulatory Subunit of Class IA PI-3Kinase Regulates Osteoclast Function(s) and Bone Mass.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2223-2223
Author(s):  
Veerendra Munugalavadla ◽  
Emily Sims ◽  
David A. Ingram ◽  
Alexander Robling ◽  
Reuben Kapur
Keyword(s):  
Bone Mass ◽  
Map Kinase ◽  
Intracellular Signaling ◽  
New Drugs ◽  
Regulatory Subunit ◽  
Regulatory Subunits ◽  
Kinase Activation ◽  
Osteoclast Function

Abstract Osteoclasts (OCs) play an indispensable role in regulating bone remodeling. In adults, a significant number of skeletal diseases have been linked to abnormal osteoclast function(s), including rheumatoid arthritis, periodontal disease, multiple myeloma, and metastatic cancers. Although, a clear picture of the critical players that regulate osteoclastogenesis and bone resorption has begun to emerge; further studies detailing the intracellular signaling pathways is necessary for the rationale development of new drugs for the treatment of bone disorders involving OCs. While recent studies utilizing pharmacologic inhibitors of PI-3Kinase have suggested a role for this pathway in osteoclastogenesis, these inhibitors interfere with the function of all classes of PI-3Kinase and result in extensive in vivo toxicity. Therefore, to therapeutically manipulate PI-3Kinase signaling cascade in osteoclasts, additional data evaluating the specific role of individual PI-3Kinase isoforms is necessary. Class IA PI-3Kinase are heterodimeric kinases consisting of a regulatory subunit and a catalytic subunit. Five different proteins, namely p85α, p55α, p50α, p85β, and p55γ, have been identified to date as the regulatory subunits. The p85α, p55α, and p50α proteins are derived from the same gene locus by alternative splicing mechanism. In contrast, distinct genes encode the p85β and p55γ subunits. Utilizing mice deficient in the expression of p85α subunit, we have recently shown that p85α subunit of PI-3Kinase plays an important role in regulating growth and actin based functions in bone marrow (BM) derived macrophages. Here, we demonstrate that OCs express multiple regulatory subunits of class IA PI-3Kinase, including p85α, p85β, p50α and p55α. Deficiency of p85α in OCs alone results in a significant increase in bone mass and bone density (% bone volume [BV]/trabecular volume [TV]: WT 6.7±0.01 vs p85α−/− 14±0.01*, *p<0.01). Histologic sections of p85α −/− bones reveal markedly increased cortical and trabecular mass. Despite their increased bone mass, mutant mice contain significantly greater numbers of OCs in vivo compared to wildtype controls (WT 45.6 vs p85α −/− 118*, *p<0.01). Thus, although OCs appear in p85α −/− mice, nonetheless, the bones of these mice become osteosclerotic, suggesting that osteoclasts lacking p85α may be defective. Consistent with this notion, p85α −/− BM derived OCs show reduced growth and differentiation in response to M-CSF and RANKL stimulation in vitro. Impaired differentiation due to p85α deficiency is manifested in the form of a significant reduction in TRAP positive multinucleated OCs (WT: 23.6±4 vs p85α −/−: 11.7±5*, n=3, *p<0.01), which is associated with a significant reduction in the activation of Akt and ERK MAP kinase. The transcription factor microphthalmia (MITF) is required for multinucleation of OCs. Mutations in MITF result in severe osteopetrosis. Recent studies have suggested that M-CSF induced ERK MAP kinase activation regulates MITFs function during multinucleation, therefore, we examined the expression of MITF in p85α −/− OCs. A 80% reduction in the expression of MITF was observed in p85α −/− OCs compared to controls. Remarkably, the defects in p85α deficient OCs were observed in spite of the continuous expression of p85β, p50α and p55α subunits, suggesting that p85α functions with specificity in regulating OC functions in vivo, in part by modulating the expression of MITF. Thus, p85α is a potential new target for antiosteoporosis therapy.

MAP Kinase Activation Is Essential for the Development of Acute Leukemia by MLL Fusion Protein and FLT3 Tyrosine Kinase Mutation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2067-2067
Author(s):  
Ryoichi Ono ◽  
Hidetoshi Kumgai ◽  
Hideaki Nakajima ◽  
Yukio Tonozuka ◽  
Ai Hishiya ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Acute Leukemia ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Oncogenic Potential ◽  
Kinase Activation

Abstract MLL (mixed lineage leukemia)-fusion-mediated acute leukemia in infants has frequently been found to have FLT3 overexpression or tyrosine kinase domain (TKD) mutation. We have recently developed both in vitro and in vivo leukemogenesis models where MLL fusion proteins cooperate with another FLT3 mutant, internal tandem duplication (ITD). However, little has been clear about molecular mechanism of the cooperativity between MLL fusion protein and FLT3 mutants, not only FLT3-ITD but also FLT3-TKD. The present study demonstrates that MLL-SEPT6 fusion protein associated with infantile acute leukemia cooperates in vitro with FLT3-TKD mainly through activated MAP kinase pathway, while MLL-SEPT6 cooperates with FLT3-ITD mainly through activated STAT5 pathway. We first found that the interleukin (IL) -3 dependent murine hematopoietic cell line immortalized by MLL-SEPT6, named HF6, was transformed to grow without IL-3 by forced expression of FLT3 mutants which activated MAP kinase and STAT5, as shown in IL-3 dependent murine pro-B Ba/F3 cells. A dominant negative mutant of STAT5A suppressed the proliferation of the HF6 cells transformed by FLT3-ITD more effectively than that by FLT3-TKD, similarly to the transformed Ba/F3 cells. However, unlike the transformed Ba/F3 cells, the proliferation of transformed HF6 cells was suppressed with an MEK inhibitor more effectively in the HF6 cells transformed by FLT3-TKD than by FLT3-ITD. These results suggested that, in the transformation of HF6 cells, MAP kinase activation is more critical for FLT3-TKD than STAT5, while STAT5 activation is more critical for FLT3-ITD than MAP kinase. Furthermore, HF6 cells became IL-3 independent by direct activation of Raf-MAP kinase, while Ba/F3 cells did not. In contrast, a constitutively active mutant of STAT5 enabled, not HF6, but Ba/F3 cells to grow without IL-3, thus suggesting the essential role of activation of the Raf-MAP kinase cascade in the growth of the cells expressing MLL fusion protein. We next examined the oncogenic potential of MLL-SEPT6 and either of the FLT3 mutants by leukemogenesis assays in vivo using bone marrow transplantation. Interestingly, FLT3-TKD cooperated with MLL-SEPT6 in vivo to induce acute leukemia in mice rapidly (26±5.5 days), similarly to FLT3-ITD (27±5.1 days), although the individual oncogenic potential of FLT3-TKD leading to T-cell lymphoma (119±11 days), was much weaker than that of FLT3-ITD leading to myeloproliferative disease (56±16 days). Taken together, these results suggest that MLL fusion protein can induce human acute leukemia in concert with MAP kinase activation through secondary genetic events including FLT3-TKD mutation or other mechanisms which activate MAP kinase.

scholarly journals 716 NL-201 induces inflammation in a 'cold' tumor microenvironment through upregulation of MHC-I, expansion of the TCR repertoire, and potent antitumor activity when combined with PD-1 inhibition

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A745-A745
Author(s):  
Christie Mortales ◽  
Benjamin Dutzar ◽  
Jerry Chen ◽  
Alex Chen ◽  
Justin Huard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Gene Expression Analysis ◽  
Granzyme B ◽  
Mhc I ◽  
B16f10 Cells ◽  
Tcr Repertoire

BackgroundNL-201 is a potent, selective, and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors that is being developed as an immunotherapy for cancer. Downregulation of MHC class I (MHC-I) expression by tumors is a well-known mechanism of immune escape, and IFNγ is known to upregulate MHC-I. Here, we investigated whether NL-201 monotherapy can convert a 'cold' tumor microenvironment (TME) to an immunologically 'hot' TME through IFNγ-mediated MHC-I expression. This effect could expand the TCR repertoire for increased antitumor response and improve anti-PD-1 combination therapy.MethodsFor in vitro assays, mouse splenocytes were cultured with Neo-2/15 to assess effector cell function, as well as co-cultured with B16F10 cells to assess IFNγ-induced MHC-I and PD-L1 expression. B16F10 tumors were established in C57BL/6 mice and dosed with NL-201, anti-PD-1, or both to assess in vivo efficacy. B16F10 tumors were excised and dissociated for phenotyping of tumor-infiltrating lymphocytes (TILs) using flow cytometry. For gene expression analysis, RNA and genomic DNA were extracted from tumors and submitted for NanoString Pancancer Immune Profiling and Adaptive ImmunoSEQ analysis, respectively.ResultsIn vitro, Neo-2/15 induced greater CD8+ T cell and NK cell proliferation, as well as granzyme B production and IFNγ-dependent MHC-I upregulation on B16F10 tumor cells, compared to IL-2 or IL-15. In 'cold' B16F10 syngeneic tumors, NL-201 monotherapy reduced tumor growth and induced MHC-I, IFNγ, and granzyme B upregulation. Gene expression analysis of NL-201–treated tumors demonstrated increased TCR repertoire diversity and inflammatory signature at the tumor. In addition, PD-L1 was significantly upregulated on B16F10 cells. While the B16F10 tumors exhibited resistance to anti-PD-1 monotherapy, combination treatment with NL-201 significantly improved anti-PD-1 activity. This may explain the potent anti-tumor activity of NL-201 with anti-PD-1 combination therapy.ConclusionsNL-201 induces potent inflammatory effects on effector cells and is able to turn 'cold' TMEs 'hot'. We demonstrate that NL-201 strongly upregulated MHC-I expression in vitro and in vivo via an IFNγ-dependent pathway. Increased antigen presentation drives TCR diversity while augmenting the inflammatory signature at the tumor. This adaptive response also upregulates PD-L1 expression and results in impressive antitumor activity when NL-201 and PD-1 inhibitors are co-administered. The demonstration that NL-201 can convert 'cold' tumors to immunologically 'hot' tumors may provide a novel therapeutic option for patients unresponsive to current standard of care checkpoint inhibitors. A Phase 1 study of NL-201 in patients with advanced solid tumors is currently underway (NCT04659629).Ethics ApprovalAll experiments were approved by the Institutional Animal Care and Use Committee of Bloodworks Northwest and performed under protocol 5360-03.

scholarly journals Most clinical anti-EGFR antibodies do not neutralize both wtEGFR and EGFRvIII activation in glioma

2019 ◽  
Vol 21 (8) ◽  
pp. 1016-1027 ◽  
Author(s):  
Sameer A Greenall ◽  
Mathew McKenzie ◽  
Ekatarina Seminova ◽  
Olan Dolezal ◽  
Lesley Pearce ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Receptor Activation ◽  
Oncogenic Signaling ◽  
Antibody Treatment ◽  
In Vitro Proliferation ◽  
Receptor Complexes ◽  
In Vivo Antitumor Activity ◽  
Domain Iii

Abstract Background Although epidermal growth factor receptor (EGFR) and its truncated, autoactive mutant EGFR variant (v)III are bona fide drivers of tumorigenesis in some gliomas, therapeutic antibodies developed to neutralize this axis have not improved patient survival in a limited number of trials. Previous studies using cells transduced to exogenously express EGFRvIII may have compromised mechanistic studies of anti-EGFR therapeutics. Therefore, we re-assessed the activity of clinical EGFR antibodies in patient-derived gliomaspheres that endogenously express EGFRvIII. Methods The antitumor efficacy of antibodies was assessed using in vitro proliferation assays and intracranial orthografts. Receptor activation status, antibody engagement, oncogenic signaling, and mechanism of action after antibody treatment were analyzed by immunoprecipitation and western blotting. Tracking of antibody receptor complexes was conducted using immunofluorescence. Results The EGFR domain III–targeting antibodies cetuximab, necitumumab, nimotuzumab, and matuzumab did not neutralize EGFRvIII activation. Chimeric monoclonal antibody 806 (ch806) neutralized EGFRvIII, but not wild-type (wt)EGFR activation. Panitumumab was the only antibody that neutralized both EGFRvIII and wtEGFR, leading to reduction of p-S6 signaling and superior in vitro and in vivo antitumor activity. Mechanistically, panitumumab induced recycling of receptor but not degradation as previously described. Panitumumab, via its unique avidity, stably cross-linked EGFRvIII to prevent its activation, while ch806 induced a marked reduction in the active EGFRvIII disulphide-bonded dimer. Conclusions We discovered a previously unknown major resistance mechanism in glioma in that most EGFR domain III–targeting antibodies do not neutralize EGFRvIII. The superior in vitro and in vivo antitumor activity of panitumumab supports further clinical testing of this antibody against EGFRvIII-stratified glioma.

scholarly journals The Pancreatic Tumor Microenvironment Buffers Redox Imbalance Imposed by Disrupted Mitochondrial Metabolism

2020 ◽  
Author(s):  
Samuel A. Kerk ◽  
Lin Lin ◽  
Amy L. Myers ◽  
Brandon Chen ◽  
Peter Sajjakulnukit ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cellular Proliferation ◽  
Redox Homeostasis ◽  
Treatment Strategies ◽  
Monocarboxylate Transporter ◽  
Ductal Adenocarcinoma ◽  
Monocarboxylate Transporter 1 ◽  
Redox Imbalance

ABSTRACTThe tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) restricts vascularization and consequently nutrient and oxygen access and drug delivery. Concurrently, recent work also demonstrates that the TME directly provides metabolites that facilitate cancer cell survival, growth, and therapeutic resistance. Redox imbalance is another restraint on cellular proliferation, yet it is unknow how the TME contributes to the maintenance redox homeostasis in PDA cells. Here, we demonstrate that the loss of mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2), a component in the malate-aspartate shuttle (MAS), disturbs redox homeostasis and halts proliferation of PDA cells in vitro. Surprisingly, we found GOT2 knockdown has no effect on in vivo tumor growth. We demonstrate that this discrepancy is explained by heterocellular pyruvate exchange from the TME, including from cancer associated fibroblasts (CAF). More broadly, pyruvate similarly confers resistance to inhibitors of mitochondrial respiration. Blocking pyruvate uptake through genetic or pharmacologic inhibition of monocarboxylate transporter 1 (MCT1) abrogated pyruvate-mediated restoration of redox homeostasis. In sum, this work describes a potential resistance mechanism mediated by metabolic crosstalk within the pancreatic TME. These findings have important implications for metabolic treatment strategies since several mitochondrial inhibitors are currently in clinical trials for PDA and other cancers.

scholarly journals Stromal cues regulate the pancreatic cancer epigenome and metabolome

2017 ◽  
Vol 114 (5) ◽  
pp. 1129-1134 ◽  
Author(s):  
Mara H. Sherman ◽  
Ruth T. Yu ◽  
Tiffany W. Tseng ◽  
Cristovao M. Sousa ◽  
Sihao Liu ◽  
...  
Keyword(s):  
Ductal Adenocarcinoma ◽  
Oncogenic Signaling ◽  
Potential Therapeutic Target ◽  
Key Driver ◽  
Accelerated Growth ◽  
Induced Changes ◽  
Insight Into

A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling—a hallmark and key driver of PDAC—is contingent on stromal inputs. Mechanistically, stroma-activated cancer cells show widespread increases in histone acetylation at transcriptionally enhanced genes, implicating the PDAC epigenome as a presumptive point of convergence between these pathways and a potential therapeutic target. Notably, inhibition of the bromodomain and extraterminal (BET) family of epigenetic readers, and of Bromodomain-containing protein 2 (BRD2) in particular, blocks stroma-inducible transcriptional regulation in vitro and tumor progression in vivo. Our work suggests the existence of a molecular “AND-gate” such that tumor activation is the consequence of mutant Kras and stromal cues, providing insight into the role of the tumor microenvironment in the origin and treatment of Ras-driven tumors.

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.

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