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Cancer cachexia, the unintentional loss of lean mass, contributes to functional dependency, poor treatment outcomes, and decreased survival. Although its pathogenicity is multifactorial, metabolic dysfunction remains a hallmark of cachexia. However, significant knowledge gaps exist in understanding the role of skeletal muscle lipid metabolism and dynamics in this condition. We examined skeletal muscle metabolic dysfunction, intramyocellular lipid droplet (LD) content, LD morphology and subcellular distribution, and LD-mitochondrial interactions using the Lewis lung carcinoma (LLC) murine model of cachexia. C57/BL6 male mice (n = 20) were implanted with LLC cells (106) in the right flank or underwent PBS sham injections. Skeletal muscle was excised for transmission electron microscopy (TEM; soleus), oil red O/lipid staining [tibialis anterior (TA)], and protein (gastrocnemius). LLC mice had a greater number (232%; P = 0.006) and size (130%; P = 0.023) of intramyocellular LDs further supported by increased oil-red O positive (87%; P = 0.0109) and "very high" oil-red O positive (178%; P = 0.0002) fibers compared with controls and this was inversely correlated with fiber size (R2 = 0.5294; P < 0.0001). Morphological analyses of LDs show increased elongation and complexity [aspect ratio: intermyofibrillar (IMF) = 9%, P = 0.046) with decreases in circularity [circularity: subsarcolemmal (SS) = 6%, P = 0.042] or roundness (roundness: whole = 10%, P = 0.033; IMF = 8%, P = 0.038) as well as decreased LD-mitochondria touch (−15%; P = 0.006), contact length (−38%; P = 0.036), and relative contact (86%; P = 0.004). Furthermore, dysregulation in lipid metabolism (adiponectin, CPT1b) and LD-associated proteins, perilipin-2 and perilipin-5, in cachectic muscle (P < 0.05) were observed. Collectively, we provide evidence that skeletal muscle myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in a preclinical model of cancer cachexia. NEW & NOTEWORTHY: We sought to advance our understanding of skeletal muscle lipid metabolism and dynamics in cancer cachexia. Cachexia increased the number and size of intramyocellular lipid droplets (LDs). Furthermore, decreases in LD-mitochondrial touch, contact length, and relative contact along with increased LD shape complexity with decreases in circularity and roundness. Dysregulation in lipid metabolism and LD-associated proteins was also documented. Collectively, we show that myosteatosis, altered LD morphology, and decreased LD-mitochondrial interactions occur in cancer cachexia. [ABSTRACT FROM AUTHOR]

Objective: to study the antitumor effects of organic lithium salt (lithium ascorbate) in different doses in comparison with inorganic lithium salt (carbonate).Material and methods. Two series of experiments were carried out on the effect of lithium preparations on the dynamics of transplantable Lewis lung carcinoma (LLC) growth and metastasis in F1 mice (CBA × C57Bl/6j). In the first series, a comparative study of the effects of different lithium ascorbate doses (1 and 10 mg/kg/day based on elemental lithium) was performed, and in the second series, a comparison was made of the effects of lithium ascorbate and carbonate when used at the same dose (5 mg/kg/day).Results. Significant antitumor effects were found for lithium ascorbate lower doses (1 and 5 mg/kg/day). A statistically significant antitumor effect of lithium ascorbate was observed from Day 10 throughout the entire observation period (tumor growth inhibition index (TGII) 30–40%). The antitumor effect of lithium carbonate in this experiment was less pronounced and stable (TGII 20–30%). No antimetastatic effect was observed with both preparations.Conclusion. Subchronic intragastric administration of lithium ascorbate and carbonate to tumor-bearing animals at a daily dose of 5 mg/kg, an antitumor effect is observed, manifested by LLC growth inhibition. Effective and safe antitumor doses of lithium ascorbate are in the range of 1–5 mg/kg.

Abstract Background The interplay between Toxoplasma gondii infection and tumor development is intriguing and not yet fully understood. Some studies showed that T. gondii reversed tumor immune suppression, while some reported the opposite, stating that T. gondii infection promoted tumor growth. Methods We created three mouse models to investigate the interplay between T. gondii and tumor. Model I aimed to study the effect of tumor growth on T. gondii infection by measuring cyst number and size. Models II and III were used to investigate the effect of different stages of T. gondii infection on tumor development via flow cytometry and bioluminescent imaging. Mouse strains (Kunming, BALB/c, and C57BL/6J) with varying susceptibilities to tumors were used in the study. Results The size and number of brain cysts in the tumor-infected group were significantly higher, indicating that tumor presence promotes T. gondii growth in the brain. Acute T. gondii infection, before or after tumor cell introduction, decreased tumor growth manifested by reduced bioluminescent signal and tumor size and weight. In the tumor microenvironment, CD4+ and CD8+ T cell number, including their subpopulations (cytotoxic CD8+ T cells and Th1 cells) had a time-dependent increase in the group with acute T. gondii infection compared with the group without infection. However, in the peripheral blood, the increase of T cells, including cytotoxic CD8+ T cells and Th1 cells, persisted 25 days after Lewis lung carcinoma (LLC) cell injection in the group with acute T. gondii. Chronic T. gondii infection enhanced tumor growth as reflected by increase in tumor size and weight. The LLC group with chronic T. gondii infection exhibited decreased percentages of cytotoxic CD8+ T cells and Th1 cells 25 days post-LLC injection as compared with the LLC group without T. gondii infection. At week 4 post-LLC injection, chronic T. gondii infection increased tumor formation rate [odds ratio (OR) 1.71] in both KM and BALB/c mice. Conclusions Our research elucidates the dynamics between T. gondii infection and tumorigenesis. Tumor-induced immune suppression promoted T. gondii replication in the brain. Acute and chronic T. gondii infection had opposing effects on tumor development. Graphical Abstract

Understanding tumor–host immune interactions and the mechanisms of lung cancer response to immunotherapy is crucial. Current preclinical models used to study this often fall short of capturing the complexities of human lung cancer and lead to inconclusive results. To bridge the gap, we introduce two new murine monoclonal lung cancer cell lines for use in immunocompetent orthotopic models. We demonstrate how our cell lines exhibit immunohistochemical protein expression (TTF-1, NapA, PD-L1) and common driver mutations (KRAS, p53, and p110α) seen in human lung adenocarcinoma patients, and how our orthotopic models respond to combination immunotherapy in vivo in a way that closely mirrors current clinical outcomes. These new lung adenocarcinoma cell lines provide an invaluable, clinically relevant platform for investigating the intricate dynamics between tumor and the immune system, and thus potentially contributes to a deeper understanding of immunotherapeutic approaches to lung cancer treatment. [ABSTRACT FROM AUTHOR]

The antitumor and antimetastatic activity of dopamine D2 receptor antagonists spiperone was studied in C57BL/6 mice in a model of combined pathology (emphysema and lung cancer). Emphysema was induced by administration of LPS and cigarette smoke extract. Lung cancer was induced by injection of Lewis lung carcinoma cells into the lung. It has been shown that under conditions of combined lung pathology, spiperone prevents inflammatory infiltration and emphysematous expansion of the lungs and reduces the size of the primary tumor node, the number of metastases, and the area of the lungs affected by metastases. Spiperone reduces the number of cancer stem cells (CSCs) in the lungs and blood of mice with combined pathology. CSCs isolated from the lungs and blood of mice with combined pathology treated with spiperone had a significantly lower potential to form a tumorosphere in vitro than CSCs from untreated mice with emphysema and lung carcinoma. Thus, blockade of dopamine D2 receptors is a promising approach for correcting combined lung pathology and can be used in the development of a method for treating lung cancer in patients with emphysema. [ABSTRACT FROM AUTHOR]

Background: The interplay between Toxoplasma gondii infection and tumor development is intriguing and not yet fully understood. Some studies showed that T. gondii reversed tumor immune suppression, while some reported the opposite, stating that T. gondii infection promoted tumor growth. Methods: We created three mouse models to investigate the interplay between T. gondii and tumor. Model I aimed to study the effect of tumor growth on T. gondii infection by measuring cyst number and size. Models II and III were used to investigate the effect of different stages of T. gondii infection on tumor development via flow cytometry and bioluminescent imaging. Mouse strains (Kunming, BALB/c, and C57BL/6J) with varying susceptibilities to tumors were used in the study. Results: The size and number of brain cysts in the tumor-infected group were significantly higher, indicating that tumor presence promotes T. gondii growth in the brain. Acute T. gondii infection, before or after tumor cell introduction, decreased tumor growth manifested by reduced bioluminescent signal and tumor size and weight. In the tumor microenvironment, CD4+ and CD8+ T cell number, including their subpopulations (cytotoxic CD8+ T cells and Th1 cells) had a time-dependent increase in the group with acute T. gondii infection compared with the group without infection. However, in the peripheral blood, the increase of T cells, including cytotoxic CD8+ T cells and Th1 cells, persisted 25 days after Lewis lung carcinoma (LLC) cell injection in the group with acute T. gondii. Chronic T. gondii infection enhanced tumor growth as reflected by increase in tumor size and weight. The LLC group with chronic T. gondii infection exhibited decreased percentages of cytotoxic CD8+ T cells and Th1 cells 25 days post-LLC injection as compared with the LLC group without T. gondii infection. At week 4 post-LLC injection, chronic T. gondii infection increased tumor formation rate [odds ratio (OR) 1.71] in both KM and BALB/c mice. Conclusions: Our research elucidates the dynamics between T. gondii infection and tumorigenesis. Tumor-induced immune suppression promoted T. gondii replication in the brain. Acute and chronic T. gondii infection had opposing effects on tumor development. [ABSTRACT FROM AUTHOR]

PDT using PSs based on polycationic derivatives of synthetic bacteriochlorin against Lewis lung carcinoma provides effective inhibition of tumor growth with an increase in the lifespan and survival of mice in the group. PDT with polycationic photosensitizers destroys CSCs and tumor neovascularization, and activates the desmoplastic reaction. These results open up new opportunities for increasing the effectiveness of treatment and reducing the incidence of relapses and metastases after PDT. [ABSTRACT FROM AUTHOR]

Abstract Background Metastatic disease is a major and difficult-to-treat complication of lung cancer. Considering insufficient effectiveness of existing therapies and taking into account the current problem of lung cancer chemoresistance, it is necessary to continue the development of new treatments. Methods Previously, we have demonstrated the antitumor effects of reprogrammed CD8+ T-cells (rCD8+ T-cells) from the spleen in mice with orthotopic lung carcinoma. Reprogramming was conducted by inhibiting the MAPK/ERK signalling pathway through MEKi and the immune checkpoint PD-1/PD-L1. Concurrently, CD8+ T-cells were trained in Lewis lung carcinoma (LLC) cells. We suggested that rCD8+ T-cells isolated from the spleen might impede the development of metastatic disease. Results The present study has indicated that the reprogramming procedure enhances the survival and cytotoxicity of splenic CD8+ T-cells in LLC culture. In an LLC model of spontaneous metastasis, splenic rCD8 + T-cell therapy augmented the numbers of CD8+ T-cells and CD4+ T-cells in the lungs of mice. These changes can account for the partial reduction of tumors in the lungs and the mitigation of metastatic activity. Conclusions Our proposed reprogramming method enhances the antitumor activity of CD8+ T-cells isolated from the spleen and could be valuable in formulating an approach to treating metastatic disease in patients with lung cancer.

The remarkable efficacy of cancer immunotherapy has been established in several tumor types. Of the various immunotherapies, PD-1/PD-L1 inhibitors are most extensively used in the treatment of many cancers in clinics. These inhibitors restore the suppressed antitumor immune response and inhibit tumor progression by blocking the PD-1/PD-L1 signaling. However, the low response rate is a major limitation in the clinical application of PD-1/PD-L1 inhibitors. Therefore, combination strategies that enhance the response rate are the need of the hour. In this investigation, PT-100 (also referred to as Talabostat, Val-boroPro, and BXCL701), an orally administered and nonselective dipeptidyl peptidase inhibitor, not only augmented the effectiveness of anti-PD-1 therapy but also significantly improved T immune cell infiltration and reversed the immunosuppressive tumor microenvironment. The combination of PT-100 and anti-PD-1 antibody increased the number of CD4+ and CD8+ T cells. Moreover, the mRNA expression of T cell-associated molecules was elevated in the tumor microenvironment. The results further suggested that PT-100 dramatically reduced the ratio of tumor-associated macrophages. These findings provide a promising combination strategy for immunotherapy in lung cancer. [ABSTRACT FROM AUTHOR]

The application of a biocompatible polymer nanocarrier can provide target delivery to tumor tissues, improved pharmacokinetics, controlled drug release, etc. Therefore, the proposed strategy was to use the water-soluble star-like copolymers with a Dextran core and Poly(N-isopropylacrylamide) grafts (D-g-PNIPAM) for conjugation with the widely used chemotherapy drugs in oncology–Cisplatin (Cis-Pt) and Doxorubicin (Dox). The molecular characteristics of the copolymer were received using size-exclusion chromatography. The physicochemical characterization of the D-g-PNIPAM-Cis-Pt (or Dox) nanosystem was conducted using dynamic light scattering and FTIR spectroscopy. Using traditional biochemical methods, a comparative analysis of the enhancement of the cytotoxic effect of free Cis-Pt and Dox in combination with D-g-PNIPAM copolymers was performed in cancer cells of the Lewis lung carcinoma line, which are both sensitive and resistant to Dox; in addition, the mechanism of their action in vitro was evaluated. [ABSTRACT FROM AUTHOR]

Abstract Background More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia. Methods Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 106 Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high‐resolution respirometry and transmission electron microscopy (TEM). Results Obese LLC mice experienced significant tumour‐free body weight loss similar to lean (−12.8% vs. −11.8%, P = 0.0001) but had reduced survival (33.3% vs. 6.67%, χ2 = 10.04, P = 0.0182). Obese LLC mice had reduced muscle weights (−24%, P

The responses of tumor stem cells and various populations of CD4 and CD8 T cells of young and aged C57BL/6 mice were studied in a lung cancer model. Using Lewis lung carcinoma cell line, an orthotopic model of lung cancer was modeled. Cancer stem cells, circulating tumor cells, and various populations of CD4 and CD8 T cells in the blood and lung tissue were studied by cytometry. We revealed age-related differences in the content of various populations of CD4 and CD8 T cells in the blood and lungs of intact young and aged mice. Age-related features of the reaction of various populations of cancer stem cells and CD4 and CD8 T cells in the blood and lungs of animals in the Lewis lung carcinoma were shown. [ABSTRACT FROM AUTHOR]

Background: Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease's evolution and the patient's quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a β2-adrenoceptor agonist, in managing muscle wasting caused by DOX. Methods and results: To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b. w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle. Conclusions: Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Cancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences. Results We found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another during the later stages of cachexia development. The early phase was associated with the upregulation of extracellular-matrix pathways, while the later phase was characterized by the downregulation of oxidative phosphorylation, electron transport chain, and TCA cycle. When DEGs were compared to a known list of mitochondrial genes (MitoCarta), ~ 47% of these genes were differently expressed in females exhibiting global cachexia, suggesting transcriptional changes to mitochondrial gene expression happens concomitantly to functional impairments previously published. In contrast, the JAK-STAT pathway was upregulated in both the early and late stages of CC. Additionally, we observed a consistent downregulation of Type-II Interferon signaling genes in females, which was associated with protection in skeletal muscle atrophy despite systemic cachexia. Upregulation of Interferon signaling was noted in the gastrocnemius muscle of cachectic and atrophic male mice. Comparison of female tumor-bearing mice with males revealed ~ 70% of DEGs were distinct between sexes in cachectic animals, demonstrating dimorphic mechanisms of CC. Conclusion Our findings suggest biphasic disruptions in the transcriptome of female LLC tumor-bearing mice: an early phase associated with ECM remodeling and a late phase, accompanied by the onset of systemic cachexia, affecting overall muscle energy metabolism. Notably, ~ 2/3 of DEGs in CC are biologically sex-specific, providing evidence of dimorphic mechanisms of cachexia between sexes. Downregulation of Type-II Interferon signaling genes appears specific to CC development in females, suggesting a new biological sex-specific marker of CC not reliant on the loss of muscle mass, that might represent a protective mechanism against muscle loss in CC in female mice.

BackgroundEven though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease’s evolution and the patient’s quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a β2-adrenoceptor agonist, in managing muscle wasting caused by DOX.Methods and resultsTo evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p

Extracts from the above-ground part of the elm-leaved meadowsweet Filipendula ulmaria (L.) Maxim. in 70% ethanol were prepared by extraction using heat (FUh) and countercurrent extraction (FU). Comparative analysis of the actions of these extracts in experiments on C57Bl/6 mice with Lewis lung carcinoma (LLC) indicated that FUh had greater efficacy when used in complex therapy with cyclophosphamide (CPX). FUh (25, 50 and 100 mg/kg) in combination with CPX increased the antitumor effect of CPX against primary tumors. No significant changes were found in the development of the metastatic process in mice given CPX and 50 and 100 mg/kg FUh; FUh at a lower dose (25 mg/kg) weakened the antimetastatic activity of CPX. FU at a dose of 25 mg/kg increased the efficacy of CPX against primary tumors, while use of FU at doses of 50 and 100 mg/kg did not influence the antitumor effect of CPX. In C57Bl/6 mice with lung cancer-67, all FUh doses studied (50, 100, and 200 mg/kg) increased the antimetastatic effect of CPX. [ABSTRACT FROM AUTHOR]

Background: Fibroblast activation protein‐α (FAP) and livin α are considered as cancer‐associated fibroblasts (CAFs) and tumor‐specific targets, respectively, for immunogenic tumor vaccines. This study is designed to decipher the antitumor effect of double‐gene modified dendritic cells (DCs) on Lewis lung carcinoma (LLC). Methods: By encoding mouse FAP cDNA and human livin α (i.e., hlivin α) cDNA into recombinant adenoviral vector (rAd), rAd‐FAP, rAd‐hlivin α, and rAd‐FAP/hlivin α were constructed, which were then transduced into mouse DCs. LLC‐bearinig mice were immunized with the infected DCs (5 × 105 cells/mouse), followed by calculation of tumor volume and survival rate. The identification of CAFs from mouse LLC as well as the determination on expressions of FAP and livin α, was accomplished by western blot. Cytotoxic T lymphocyte assay was harnessed to assess the effect of the infected DCs on inducing splenic lymphocytes to lyse CAFs. Results: DCs were successfully transduced with rAd‐FAP/hlivin α in vitro. FAP was highly expressed in CAFs. CAFs were positive for α‐SMA and negative for CD45 and CD31. Livin α level was upregulated in mouse LLC. Immunization with rAd‐FAP/hlivin α‐transduced DCs suppressed LLC volume and improved the survival of tumor‐bearing mice. Immunization with rAd‐FAP/hlivin α‐transduced DCs enhanced the cytotoxic effect of splenic lymphocytes on LLC tumor‐derived CAFs. Conclusion: Injection with rAd‐FAP/hlivin α‐transduced DCs promotes immune‐enhanced tumor microenvironment by decreasing CAFs and suppresses tumor growth in LLC mouse models. [ABSTRACT FROM AUTHOR]

Abstract Background Essential elements have functions in tumor progression by promoting protumoral cellular processes, such as proliferation, and migration, among others. Obtaining an understanding of how these elements relate to tumor progression processes is of great importance for research. Elemental profile studies in distant tissues, which can be modulated by tumor cells to promote metastasis, have not been sufficiently investigated. The main goal of this study is to evaluate multielemental distribution during tumor progression, focusing on tumor tissue and distant tissues that may be affected. Methods Tumor progression in vivo was simulated by inoculating C57BL/6 mice with Lewis Lung Carcinoma (LLC) cells. Samples of the primary tumor and distant tissues were collected during 5 weeks of tumor progression for the control and experimental (tumor-bearing) groups. The biological samples were analyzed using the synchrotron radiation X-Ray fluorescence technique. Data on the concentration of P, S, K, Ca, Mn, Fe, Cu, and Zn in the samples were obtained and statistically analyzed to evaluate the distribution of the elements during tumor progression in the primary tumor as well as distant tissues. Results It was possible to observe significant changes in the concentrations’ distribution of P, S, K, Ca, Mn, Fe, and Cu in distant tissues caused by the presence of tumor cells. It was also possible to detect a greater similarity between tumor tissue (which has the lung as tissue of origin) and a tissue of non-origin, such as the liver, which is an unprecedented result. Moreover, changes in the distributions of concentrations were detected and studied over time for the different tissues analyzed, such as primary tumor, liver and lung, in Control and Tumor groups. Conclusions Among other results, this paper could explore the modulation of distant tissues caused by the presence of a primary tumor. This could be achieved by the evaluation of several elements of known biological importance allowing the study of different biological processes involved in cancer. The role of essential elements as modulators of the tumor microenvironment is a relevant aspect of tumor progression and this work is a contribution to the field of tumoral metallomics.

Purpose of the study. The assessment of diabetes mellitus (DM) effect on levels of sex hormones in tumor and peritumoral tissues in BALB/c Nude mice with Lewis lung carcinoma (LLC).Materials and methods. The study included 42 male and female BALB/c Nude mice aged 8–9 weeks weighing 21–22 g. Alloxan-induced DM was reproduced in mice of the main group, and then LLC was transplanted. Levels of estrone (E1), estradiol (E2), testosterone (T), progesterone (P4) and prolactin (PRL), as well as steroid hormone receptors: estrogens (REα, REβ), androgens (RA), and progesterone (RP4) were measured by RIA and ELISA in samples of tumor and peritumoral tissues. Animals with LLC without DM were used as controls. The statistical analysis was performed using the Statistica 10 program; differences were considered significant at p < 0.05.Results. DM in males was reproduced only after a double injection of alloxan, and was characterized by lower blood glucose levels compared to females. The growth of LLC in animals with alloxan-induced DM was possible only in female BALB/c Nude mice; in BALB/c Nude males, the tumor could not be transplanted either independently or in combination with DM. Females in the main group showed greater average tumor volumes throughout the experiment and reduced survival, compared to the control group. Tumor samples from females with LLC+DM were more saturated with sex steroids, but depleted in steroid hormone receptors, which probably contributed to the ability to avoid the body's regulatory signals.Conclusion. The growth of LLC in presence of induced DM was sex-dependent, since the tumor could not be transplanted to male mice. DM affected the levels of sex steroids and their receptors tumor tissues in female BALB/c Nude mice.

PDT using PSs based on polycationic derivatives of synthetic bacteriochlorin against Lewis lung carcinoma provides effective inhibition of tumor growth with an increase in the lifespan and survival of mice in the group. PDT with polycationic photosensitizers destroys CSCs and tumor neovascularization, and activates the desmoplastic reaction. These results open up new opportunities for increasing the effectiveness of treatment and reducing the incidence of relapses and metastases after PDT.

The remarkable efficacy of cancer immunotherapy has been established in several tumor types. Of the various immunotherapies, PD-1/PD-L1 inhibitors are most extensively used in the treatment of many cancers in clinics. These inhibitors restore the suppressed antitumor immune response and inhibit tumor progression by blocking the PD-1/PD-L1 signaling. However, the low response rate is a major limitation in the clinical application of PD-1/PD-L1 inhibitors. Therefore, combination strategies that enhance the response rate are the need of the hour. In this investigation, PT-100 (also referred to as Talabostat, Val-boroPro, and BXCL701), an orally administered and nonselective dipeptidyl peptidase inhibitor, not only augmented the effectiveness of anti-PD-1 therapy but also significantly improved T immune cell infiltration and reversed the immunosuppressive tumor microenvironment. The combination of PT-100 and anti-PD-1 antibody increased the number of CD4+ and CD8+ T cells. Moreover, the mRNA expression of T cell-associated molecules was elevated in the tumor microenvironment. The results further suggested that PT-100 dramatically reduced the ratio of tumor-associated macrophages. These findings provide a promising combination strategy for immunotherapy in lung cancer.

The application of a biocompatible polymer nanocarrier can provide target delivery to tumor tissues, improved pharmacokinetics, controlled drug release, etc. Therefore, the proposed strategy was to use the water-soluble star-like copolymers with a Dextran core and Poly(N-isopropylacrylamide) grafts (D-g-PNIPAM) for conjugation with the widely used chemotherapy drugs in oncology–Cisplatin (Cis-Pt) and Doxorubicin (Dox). The molecular characteristics of the copolymer were received using size-exclusion chromatography. The physicochemical characterization of the D-g-PNIPAM-Cis-Pt (or Dox) nanosystem was conducted using dynamic light scattering and FTIR spectroscopy. Using traditional biochemical methods, a comparative analysis of the enhancement of the cytotoxic effect of free Cis-Pt and Dox in combination with D-g-PNIPAM copolymers was performed in cancer cells of the Lewis lung carcinoma line, which are both sensitive and resistant to Dox; in addition, the mechanism of their action in vitro was evaluated.

Abstract Background Fibroblast activation protein‐α (FAP) and livin α are considered as cancer‐associated fibroblasts (CAFs) and tumor‐specific targets, respectively, for immunogenic tumor vaccines. This study is designed to decipher the antitumor effect of double‐gene modified dendritic cells (DCs) on Lewis lung carcinoma (LLC). Methods By encoding mouse FAP cDNA and human livin α (i.e., hlivin α) cDNA into recombinant adenoviral vector (rAd), rAd‐FAP, rAd‐hlivin α, and rAd‐FAP/hlivin α were constructed, which were then transduced into mouse DCs. LLC‐bearinig mice were immunized with the infected DCs (5 × 105 cells/mouse), followed by calculation of tumor volume and survival rate. The identification of CAFs from mouse LLC as well as the determination on expressions of FAP and livin α, was accomplished by western blot. Cytotoxic T lymphocyte assay was harnessed to assess the effect of the infected DCs on inducing splenic lymphocytes to lyse CAFs. Results DCs were successfully transduced with rAd‐FAP/hlivin α in vitro. FAP was highly expressed in CAFs. CAFs were positive for α‐SMA and negative for CD45 and CD31. Livin α level was upregulated in mouse LLC. Immunization with rAd‐FAP/hlivin α‐transduced DCs suppressed LLC volume and improved the survival of tumor‐bearing mice. Immunization with rAd‐FAP/hlivin α‐transduced DCs enhanced the cytotoxic effect of splenic lymphocytes on LLC tumor‐derived CAFs. Conclusion Injection with rAd‐FAP/hlivin α‐transduced DCs promotes immune‐enhanced tumor microenvironment by decreasing CAFs and suppresses tumor growth in LLC mouse models.

The pathologies and lethality of lung cancers are associated with smoking, lifestyle, and genomic factors. Several experimental mouse models of lung cancer, including those induced via intrapulmonary injection and intratracheal injection, have been reported for evaluating the pharmacological effect of drugs. However, these models are not sufficient for evaluating the efficacy of drugs during screening, as these direct injection models ignore the native processes of cancer progression in vivo, resulting in the inadequate pathological formation of lung cancer. In the present study, we developed a novel intranasal injection model of lung cancer simulating the native lung cancer pathology for anticancer drug screening. A mouse lung cancer cell line (Lewis lung carcinoma; LCC) was intranasally injected into mouse lungs, and injected cell number‐dependent cancer proliferation was apparent in both the left and right lungs. Human non‐small‐cell lung cancer (NCI‐H460) cells were also intranasally injected into nude mice and similarly showed injected cell number‐dependent cancer growth. For the pharmacological evaluation of cisplatin, two different treatment frequencies were tested four times per month and twice a month. The intranasal injection model confirmed that cisplatin suppressed lung cancer progression to a greater extent under the more frequent treatment condition. In conclusion, these results indicated that our intranasal injection model is a powerful tool for investigating lung cancer pathology and may aid in the development of new anti‐lung cancer agents.

Purpose of the study. To study the levels of adrenal axis factors in the hypothalamus, adrenal glands, blood serum of mice and catecholamines in the adrenal glands during the independent growth of B16 melanoma and Lewis lung carcinoma (LLC) and their combined growth in female mice, and in males – with independent growth of B16 and combined growth of B16 and LLC.Materials and methods. Male and female BALB/c Nude mice were divided into groups, n = 7 each: group 1 involved intact animals, group 2 involved mice with B16/F10 melanoma, group 3 – mice with LLC, group 4 – synchronous growth of melanoma and LLC. Levels of corticotropin releasing, noradrenaline and dopamine were determined in homogenates of the hypothalamus and adrenal glands and in the blood serum of all animals by ELISA, and levels of 17‑hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S) and cortisol were determined by RIA. Statistical processing of results was performed using the Statistica 10.0 program.Results. All tumor-bearing females showed elevated corticotropin releasing in the hypothalamus together with an increase of all stress-characterizing parameters: cortisol, the cortisol/DHEA-S ratio, and noradrenaline. However, an increase in serum levels of cortisol was blocked by high levels of DHEA-S, and as a result, the cortisol/DHEA-S ratio was either within the normal range (B16 melanoma and B16+LLC combination) or reduced (LLC). Levels of corticotropin releasing in the hypothalamus of tumor-bearing males decreased, together with opposite changes in stress-characterizing parameters in the adrenal glands: cortisol increased, the cortisol/DHEA-S ratio did not differ significantly from the control values, and noradrenaline decreased. An increase in serum levels of cortisol was not blocked by high levels of DHEA-S, and as a result, the cortisol/DHEA-S ratio was sharply elevated in B16 melanoma and B16+LLC combination.Conclusion. At independent and primary multiple types of tumor growth, the sex-specific features of the functioning of the adrenal axis at the central and peripheral levels are observed, which determines a more pronounced stressful state of the body with B16+LLC combination growth, realized by various mechanisms.

Introduction. Thyroid dysfunction is known to be associated with higher risks of cancer development. The purpose of this study was to analyze levels of thyroid axis hormones in the hypothalamus, pituitary gland, thyroid, and blood serum of male and female Balb/c nude mice with B16/F10 melanoma and/or lewis lung carcinoma. Material and methods. Male and female Balb/c nude mice were divided into groups: 1 – intact mice (n=7), 2 – mice with b16/f10 melanoma (n=7), 3 – mice with lewis lung carcinoma (LLC) (n=7), 4 – mice with melanoma and LLC (n=7). Levels of thyroid-stimulating hormone (TSH), triiodothyronine (fT3), and thyroxine (fT4) were measured by ria in homogenates of the hypothalamus, pituitary gland, thyroid and blood serum of all animals, and TH-releasing was measured by ELISA. Statistical processing of results was performed using the Statistica 10.0 program. Results. TH-releasing was reduced in the hypothalamus of all tumor-bearing mice, compared to initial values. TSH levels in the pituitary gland and thyroid were changed only in males with the combination of tumors (increased by 2.8 and 1.5 times, respectively). Levels of free forms of hormones in the thyroid in animals of both genders sharply increased, together with the elevation of TSH in the blood serum and, as a result, the decrease of fТ3 and fТ4 levels. Conclusion. Female and male Balb/c nude mice of the studied groups demonstrated hypothalamic dysfunction manifested by the absence of regulation in the hypothalamus-pituitary-thyroid relationship, and by the hypothyroid status of animals.

Background: Essential elements have functions in tumor progression by promoting protumoral cellular processes, such as proliferation, and migration, among others. Obtaining an understanding of how these elements relate to tumor progression processes is of great importance for research. Elemental profile studies in distant tissues, which can be modulated by tumor cells to promote metastasis, have not been sufficiently investigated. The main goal of this study is to evaluate multielemental distribution during tumor progression, focusing on tumor tissue and distant tissues that may be affected. Methods: Tumor progression in vivo was simulated by inoculating C57BL/6 mice with Lewis Lung Carcinoma (LLC) cells. Samples of the primary tumor and distant tissues were collected during 5 weeks of tumor progression for the control and experimental (tumor-bearing) groups. The biological samples were analyzed using the synchrotron radiation X-Ray fluorescence technique. Data on the concentration of P, S, K, Ca, Mn, Fe, Cu, and Zn in the samples were obtained and statistically analyzed to evaluate the distribution of the elements during tumor progression in the primary tumor as well as distant tissues. Results: It was possible to observe significant changes in the concentrations’ distribution of P, S, K, Ca, Mn, Fe, and Cu in distant tissues caused by the presence of tumor cells. It was also possible to detect a greater similarity between tumor tissue (which has the lung as tissue of origin) and a tissue of non-origin, such as the liver, which is an unprecedented result. Moreover, changes in the distributions of concentrations were detected and studied over time for the different tissues analyzed, such as primary tumor, liver and lung, in Control and Tumor groups. Conclusions: Among other results, this paper could explore the modulation of distant tissues caused by the presence of a primary tumor. This could be achieved by the evaluation of several elements of known biological importance allowing the study of different biological processes involved in cancer. The role of essential elements as modulators of the tumor microenvironment is a relevant aspect of tumor progression and this work is a contribution to the field of tumoral metallomics. [ABSTRACT FROM AUTHOR]

The pathologies and lethality of lung cancers are associated with smoking, lifestyle, and genomic factors. Several experimental mouse models of lung cancer, including those induced via intrapulmonary injection and intratracheal injection, have been reported for evaluating the pharmacological effect of drugs. However, these models are not sufficient for evaluating the efficacy of drugs during screening, as these direct injection models ignore the native processes of cancer progression in vivo, resulting in the inadequate pathological formation of lung cancer. In the present study, we developed a novel intranasal injection model of lung cancer simulating the native lung cancer pathology for anticancer drug screening. A mouse lung cancer cell line (Lewis lung carcinoma; LCC) was intranasally injected into mouse lungs, and injected cell number‐dependent cancer proliferation was apparent in both the left and right lungs. Human non‐small‐cell lung cancer (NCI‐H460) cells were also intranasally injected into nude mice and similarly showed injected cell number‐dependent cancer growth. For the pharmacological evaluation of cisplatin, two different treatment frequencies were tested four times per month and twice a month. The intranasal injection model confirmed that cisplatin suppressed lung cancer progression to a greater extent under the more frequent treatment condition. In conclusion, these results indicated that our intranasal injection model is a powerful tool for investigating lung cancer pathology and may aid in the development of new anti‐lung cancer agents. [ABSTRACT FROM AUTHOR]

The effect of low-dose radiation was studied on the growth dynamics of transfused Lewis carcinoma cells in female C57Bl/6 mice. Fourfold total fractionated irradiation was conducted at a dose of 75 mGy (at a dose rate of 0.154 Gy/min and a voltage of 200 kV), starting from day 10 after the transplantation with a four-day interval. On days 14 and 22, a group of mice was euthanized to study the expression levels of genes and noncoding RNAs (microRNAs and long noncoding RNAs) in tumor cells, as well as in normal tissues (bone marrow, liver, spleen, thymus). The total RNA was obtained, and complementary DNA was synthesized according to the manufacturer's protocol. After that, a real-time PCR reaction was performed using the SYBR Green I dye (Thermo Scientific, United States) or a TaqMan probe and specific primers. Genes and noncoding RNAs were divided into groups of oncogenes and oncosuppressors according to scientific research. In the group of irradiated mice, a decrease in the tumor growth rate was observed, mainly from day 20, accompanied by a change in the activity of the studied genes. The ratio of the activity of oncosuppressors to oncogenes was calculated for the obtained tissues. These fractions were 0.5 for the tumor, 10.7 for the bone marrow, and 2.4 for the spleen and thymus. Thus, it can be stated that in the tumor there was a particularly pronounced activation of oncogenes compared to the activity of oncosuppressors, while the opposite effect was observed in normal tissues. [ABSTRACT FROM AUTHOR]

Using a model of Lewis lung carcinoma (LLC) in vitro and in vivo, we previously demonstrated increased antitumor activity in CD8+ T-cells reprogrammed with an MEK inhibitor and PD-1 blocker. In this follow-up study, we carried out the reprogramming of human CD8+ T-cells (hrT-cell) using the MEK inhibitor and PD-1 blocker and targeted LLC cells. The effects of hrT-cell therapy were studied in a mouse model of spontaneous metastasis of a solid LLC tumor. We found antimetastatic activity of hrT-cells, a decrease in the number of cancer cells and cancer stem cells in the lungs, and an increase in the number of T-cells in the blood (including effector T-cells). Thus, reprogramming of human CD8+ T-cells with an MEK inhibitor and PD-1 blocker with targeted training by tumor target cells is a potential platform for developing a new approach to targeted lung cancer therapy. [ABSTRACT FROM AUTHOR]

Selenium (Se) and fish oil (FO) exert anti-epidermal growth factor receptor (EGFR) action on tumors. This study aimed to compare the anti-cancer efficacy of EGFR inhibitors (gefitinib and erlotinib) alone and in combination with nutritional supplements of Se/FO in treating lung cancer. Lewis LLC1 tumor-bearing mice were treated with a vehicle or Se/FO, gefitinib or gefitinib plus Se/FO, and erlotinib or erlotinib plus Se/FO. The tumors were assessed for mRNA and protein expressions of relevant signaling molecules. Untreated tumor-bearing mice had the lowest body weight and highest tumor weight and volume of all the mice. Mice receiving the combination treatment with Se/FO and gefitinib or erlotinib had a lower tumor volume and weight and fewer metastases than did those treated with gefitinib or erlotinib alone. The combination treatment exhibited greater alterations in receptor signaling molecules (lower EGFR/TGF-β/TβR/AXL/Wnt3a/Wnt5a/FZD7/β-catenin; higher GSK-3β) and immune checkpoint molecules (lower PD-1/PD-L1/CD80/CTLA-4/IL-6; higher NKp46/CD16/CD28/IL-2). These mouse tumors also had lower angiogenesis, cancer stemness, epithelial to mesenchymal transitions, metastases, and proliferation of Ki-67, as well as higher cell cycle arrest and apoptosis. These preliminary results showed the Se/FO treatment enhanced the therapeutic efficacies of gefitinib and erlotinib via modulating multiple signaling pathways in an LLC1-bearing mouse model. [ABSTRACT FROM AUTHOR]

Purpose of the study. Evaluation of the effect of the benzimidazole derivative dihydrobromide‑2-(3,4‑dihydroxyphenyl)- 9‑diethylamino-ethylimidazo-[ 1,2‑a] benzimidazole (RU‑185) on the growth of Lewis lung epidermoid carcinoma and B16-F10 melanoma when administered intragastrically.Materials and methods. For the experiment, we used female C57Bl/6j mice, which were inoculated subcutaneously with syngeneic tumors: Lewis lung carcinoma (LLC) and B16-F10 melanoma. RU‑185 was administered intragastrically to animals in a volume of 0.3 ml for 10 days, 1 time per day. For both tumors, depending on single doses of the substance for administration, groups were divided: 1st and 4th – 50 mg/kg, 2nd and 5th – 220 and 3rd and 6th – 500 mg/kg. The control groups were injected intragastrically with physiological saline in the same volumes and according to the same scheme. The following parameters were assessed: tumor volume, increase in life expectancy (T/S, %) and tumor growth inhibition index (TGI, %).Results. For animals with LLC in the 2nd group there is an increase in the indicator of life expectancy (T/S 162.3 %), and in the 3rd group there is a tendency to an increase in the T/S indicator. On the 1st day after the end of treatment in the 2nd and 3rd groups TGI was 73.0 % and 30.1 %, respectively (р < 0.05). On the 7th and 14th days after the end of the use of RU‑185 in the 2nd and 3rd groups the volume of tumors is 3.5 and 1.4 times less (on the 7th day) and 2.3 and 1.3 times (on the 14th day), respectively than in the control group (р < 0.05). At a dose of 220 mg/kg, complete regression of LLC tumors was shown in 20 % of animals.With the growth of B16-F10, the life expectancy of all groups did not differ. Intergroup differences in the dynamics of tumor growth are provided. Highlighted changes were found in the 5th group (on the 14th day after the end of the administration of RU‑185, TGI was 48.7 %).Conclusion. The investigated chemical substance dihydrobromide‑2-(3,4‑dihydroxyphenyl)-9‑diethylamino-ethylimidazo- [1,2‑a] benzimidazole showed antitumor efficacy against syngeneic tumors: Lewis lung epidermoid carcinoma and B16-F10 melanoma when administered intragastrically which leads to further testing of RU‑185 as a potential drug for the treatment of malignant neoplasms.

Abstract Background Cancer cachexia, characterized by muscle and fat tissue wasting, is a major determinant of cancer‐related mortality without established treatment. Recent animal data revealed that cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 as surface proteins on extracellular vesicles (EVs). Here, we test a therapeutic strategy for ameliorating cancer cachexia by inhibiting the release of Hsp70 and Hsp90 using proton pump inhibitor omeprazole. Methods Omeprazole effect on Hsp70/90 release through EVs by Lewis lung carcinoma (LLC) cells in vitro, serum levels of Hsp70/90 and Hsp70/90‐carrying EVs in LLC tumour‐bearing mice, and LLC‐induced muscle protein degradation pathways in C2C12 myotubes and mice were determined. Omeprazole effect on endolysosomal pH and Rab27b expression in LLC cells were analysed. Results Omeprazole treatment of LLC cells inhibited Hsp70/90 and Hsp70/90‐carrying EV release in a dose‐dependent manner (1 to 10 μM) and attenuated the catabolic activity of LLC cell‐conditioned medium on C2C12 myotubes. Systemic omeprazole administration to LLC tumour‐bearing mice (5 mg/kg/day subcutaneously) for 2 weeks blocked elevation of serum Hsp70, Hsp90, and Hsp70/90‐carrying EVs, abrogated skeletal muscle catabolism, and prevented loss of muscle function as well as muscle and epididymal fat mass without altering tumour growth. Consequently, median survival increased by 23.3%. Mechanistically, omeprazole increased cancer cell endolysosomal pH level dose‐dependently (0.1 to 1 μM) by inhibiting vacuolar H+‐ATPase. Further, omeprazole suppressed the highly elevated expression of Rab27b, a key regulator of EV release, in LLC cells. Conclusions Omeprazole ameliorates cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90.

The tumor microenvironment, especially the vasculature, undergoes dynamic remodeling during tumor growth and progression. The aim of this study was to investigate changes in the structure and function of tumor microenvironment (TME), with a special focus on vasculature, during the growth of the Lewis Lung Carcinoma tumor (LLC). We have used several MRI techniques and ultrasound imaging of live animals to assess how heterogenous TME features change in time. Lewis lung carcinoma bearing C57BL/6 mice were examined for three weeks. During this time, assessment of tumor vasculature was performed with Time of Flight (TOF) angiography, Dynamic Contrast Enhanced (DCE) MRI and Power Doppler Ultrasound. Additionally, diffusion and perfusion were analyzed using Diffusion Weighted MRI (DWI). Consecutive measurements of the same animals revealed an approximately twofold decrease in the density of LLC vessels in time. Heterogeneity of vasculature was best uncovered by changes in histogram based DCE analysis and revealed deterioration of tumor vessels during its progression. The tumor vasculature became less dense and with slower blood flow, with larger and more permeable vessels. As a rule, tumor tissue perfusion and diffusion parameters decreased in time, but locally increase was observed. Time- and spatial heterogeneity of tumor microenvironment, including vasculature, was revealed by 3D imaging, demonstrating that local changes are often contradictory to parameters averaged over the whole tumor volume. [Display omitted] • Noninvasive imaging techniques can visualize temporal changes of tumor vasculature. • Tumor vasculature declined in time with vessels becoming more permeable and larger. • Spatial analysis enables deeper grasp of tumor microenvironment heterogeneity. • Differences between young and old preclinical tumors may impact therapy response. [ABSTRACT FROM AUTHOR]

Macrophages are the major tumor-infiltrating leukocytes, and tumor-associated macrophages (TAM) play a critical role in cancer-related inflammation since they show alternative polarization to M1 (tumor-inhibited macrophages) or M2 (tumor-promoted macrophages) phenotype. Brassica rapa L. (B. rapa) has been clinically proven to have anti-tumor and immunity-enhancing activity, and the polysaccharides of B. rapa (BRP) have been reported to have an immunoregulatory effect on macrophages. In this study, we focus on macrophage polarization to investigate the mechanism of anti-tumor response of BRP in vivo and in vitro. We found that BRP improved the expression of M1 markers, including iNOS, COX-2, HLA-DR, CD11b and M1-related cytokines. The expression of M2 markers Arg-1, CD206 and CD163 induced by IL-4 were inhibited by BRP treatment, resulting in the inhibition of tumor growth both in vivo and in co-culture experiments in vitro. The activation of STAT signaling pathway were significantly regulated by BRP, which are important signals in TAM polarization. Overall, the results indicated that BRP has anti-tumor effect through mediating macrophage polarization. [ABSTRACT FROM AUTHOR]

Both clinical and laboratory studies have shown that monocyte chemotactic protein-1 (MCP-1) is involved in cancer spread. To understand the role of MCP-1 in metabolism in the presence of metastasis, we conducted an untargeted metabolomic analysis of primary metabolism on plasma collected from a study showing that MCP-1 deficiency reduces spontaneous metastasis of Lewis lung carcinoma (LLC) to the lungs in mice fed a high-fat diet (HFD). In a 2 × 2 design, wild-type (WT) or Mcp-1 knockout (Mcp-1 -/-) mice maintained on the AIN93G standard diet or HFD were subcutaneously injected with LLC cells to induce lung metastasis. We identified 87 metabolites for metabolomic analysis from this study. Amino acid metabolism was altered considerably in the presence of LLC metastases with the aminoacyl-tRNA biosynthesis pathways as the leading pathway altered. The HFD modified lipid and energy metabolism, evidenced by lower contents of arachidonic acid, cholesterol, and long-chain saturated fatty acids and higher contents of glucose and pyruvic acid in mice fed the HFD. These findings were supported by network analysis showing alterations in fatty acid synthesis and glycolysis/gluconeogenesis pathways between the 2 diets. Furthermore, elevations of the citrate cycle intermediates (citric acid, fumaric acid, isocitric acid, and succinic acid) and glyceric acid in Mcp-1 -/- mice, regardless of diet, suggest the involvement of MCP-1 in mitochondrial energy metabolism during LLC metastasis. The present study demonstrates that MCP-1 deficiency and the HFD altered plasma metabolome in mice bearing LLC metastases. These findings can be useful in understanding the impact of obesity on prevention and treatment of cancer metastasis. [ABSTRACT FROM AUTHOR]

The results of studying the effect of the anthocyanin-containing complex from Sorbus aucuparia L. on the main indicators of erythropoiesis in the blood and bone marrow of mice with Lewis lung carcinoma against the background of doxorubicin administration were presented. It was shown that administration of the anthocyanin-containing complex from S. aucuparia L. to animals with the tumor prevented the development of anemic syndrome by promoting regeneration of the erythropoiesis after its depletion caused by single administration of a cytostatic agent. [ABSTRACT FROM AUTHOR]

CD8+ T-lymphocytes play a key role in antitumor immune response. Patients with lung cancer often suffer from T-lymphocyte dysfunction and low T-cell counts. The exhaustion of effector T-lymphocytes largely limits the effectiveness of therapy. In this study, reprogrammed T-lymphocytes used MEK inhibitors and PD-1 blockers to increase their antitumor activity. Antitumor effects of reprogrammed T-lymphocytes were shown in vitro and in vivo in the Lewis lung carcinoma model. The population of T- lymphocytes with persistent expression of CCR7 was formed as a result of reprogramming. Reprogrammed T-lymphocytes were resistant to apoptosis and characterized by high cytotoxicity against Lewis lung carcinoma (LLC) cells in vitro. Administration of reprogrammed T-lymphocytes to C57BL/6 mice with LLC reduced the number of lung metastases. The antitumor effect resulted from the elimination of tumor cells and cancer stem cells, and the effect of therapy on cytotoxic T-lymphocyte counts. Thus, reprogramming of T-lymphocytes using MEK inhibitors is a promising approach for targeted therapy of lung cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Berberine (Ber) is a herbal alkaloid with pharmacological activity in general and a high anticancer potency in particular. However, due to its low bioavailability, the difficulty in reaching a target and choosing the right dose, there is a need to improve approaches of Ber use in anticancer therapy. In this study, Ber, noncovalently bound to a carbon nanostructure C60 fullerene (C60) at various molar ratios of the components, was explored against Lewis lung carcinoma (LLC). Methods C60–Ber noncovalent nanocomplexes were synthesized in 1:2, 1:1 and 2:1 molar ratios. Ber release from the nanocomplexes was studied after prolonged incubation at different pH with the liquid chromatography–mass spectrometry analysis of free Ber content. Biological effects of the free and C60-complaxated Ber were studied in vitro towards LLC cells with phase-contrast and fluorescence microscopy, flow cytometry, MTT reduction, caspase activity and wound closure assays. The treatment with C60–Ber nanocomplex was evaluated in vivo with the LLC-tumored C57Bl mice. The mice body weight, tumor size, tumor weight and tumor weight index were assessed for four groups, treated with saline, 15 mg C60/kg, 7.5 mg Ber/kg or 2:1 C60-Ber nanocomplex (15 mg C60/kg, 7.5 mg Ber/kg). Results Ber release from C60–Ber nanocomplexes was promoted with medium acidification. LLC cells treatment with C60–Ber nanocomplexes was followed by enhanced Ber intracellular uptake as compared to free Ber. The cytotoxicity of the studied agents followed the order: free Ber

We have developed an approach to reprogramming immune cells by inhibiting the MAPK/ERK pathway through MEKi and the PD-1/PD-L1 immune checkpoint signaling pathway. We hypothesized that reprogramming of spleen CD8+ T-cells could also create a population of immune cells with high antitumor activity. We reprogrammed CD8+ T-cells derived from the spleen of C57BL/6 mice (rsCD8+T-cells). In the orthotopic LLC model, cell therapy with rsCD8+T-cells increased the amount of proliferating CD8+ and CD4+ T-cells in blood and lung tissue from mice. The amount of cancer stem cells (CSC) decreased in the blood and lung of mice treated with rsCD8+ T-cells. A morphological study revealed a decrease in the number of metastases in lung tissue. The antitumor effects of rsCD8+T-cells are based on the activation of the host immune response by increasing the populations of CD8+ and CD4+ T-cells and apoptosis of CSCs.

It is widely accepted that tumor metastasis is the dominant factor leading to cancer-related death. Tumor metastasis is mediated by cell invasion, blood circulation and lymphatic circulation. Paclitaxel, as a common anti-tumor drug and a mitotic inhibitor, promotes microtubule assembly and inhibits microtubule depolymerization. In addition, ticagrelor, an anti-platelet drug, is used to treat acute coronary syndrome. Increasing numbers of studies have reported that platelets can facilitate tumor metastasis. Therefore, inhibiting the effects of platelets can serve as a novel therapeutic strategy for cancer. To explore the effect of anti-tumor and anti-platelet drugs on tumor progression, we chose paclitaxel and ticagrelor. Interestingly, the results demonstrated that paclitaxel and ticagrelor could not only suppress the proliferation, migration and invasion of B16F10 and LLC cells, but they could also prevent tumor metastasis to the lungs. Furthermore, the inhibitory effect of paclitaxel and ticagrelor was more apparent when both drugs were used in combination. Collectively, the current study demonstrated that the combination of paclitaxel and ticagrelor could be considered as a potential anti-tumor therapy approach. [ABSTRACT FROM AUTHOR]

The effect of preliminary irradiation of an aqueous solution of sodium chloride (saline) with 1 MeV high-energy electron beams on optical and cytotoxic/cytostatic properties of the dissolved Doxorubicin cancer drug is studied. With the use of Lewis lung carcinoma cell culture, it has been shown that the said treatment results in an increased cytotoxic/cytostatic action of the Doxorubicin, being the most pronounced in the range of low concentrations of the drug. The delivered dose of ionizing radiation on the saline ranged from 4 to 80 kGy. The maximum changes in the IR absorption spectra of Doxorubicin have been observed for the solutions irradiated with 10 kGy. The possible causes of the observed effects are discussed. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer‐induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor‐bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2‐[3H]Deoxy‐Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor‐bearing mice, insulin‐stimulated glucose transport was abrogated concomitantly with abolished insulin‐induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor‐bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal‐S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle‐type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer. [ABSTRACT FROM AUTHOR]

The folate receptor alpha (FR), which is overexpressed in solid tumors including NSCLC, can be utilized for active tumor targeting to afford more effective cancer therapies. In this context, cytochrome c (Cyt c) has drawn attention to cancer research because it is non-toxic, yet, when delivered to the cytoplasm of cancer cells, can kill them by inducing apoptosis. Cyt c nanoparticles (NPs, 169 ± 9 nm) were obtained by solvent precipitation with acetonitrile, and stabilized by reversible homo-bifunctional crosslinking to accomplish a Cyt-c-based drug delivery system that combines stimulus-responsive release and active targeting. Cyt c was released under intracellular redox conditions, due to an S–S bond in the NPs linker, while NPs remained intact without any release under extracellular conditions. The NP surface was decorated with a hydrophilic folic acid–polyethylene glycol (FA–PEG) polymer for active targeting. The FA-decorated NPs specifically recognized and killed cancer cells (IC50 = 47.46 µg/mL) that overexpressed FR, but showed no toxicity against FR-negative cells. Confocal microscopy confirmed the preferential uptake and apoptosis induction of our NPs by FR-positive cancer cells. In vivo experiments using a Lewis lung carcinoma (LLC) mouse model showed visible NP accumulation within the tumor and inhibited the growth of LLC tumors. [ABSTRACT FROM AUTHOR]

Cancer cachexia (CC) is a devastating syndrome characterized by weight loss, reduced fat mass and muscle mass that affects approximately 80% of cancer patients and is responsible for 22%–30% of cancer-associated deaths. Understanding underlying mechanisms for the development of CC are crucial to advance therapies to treat CC and improve cancer outcomes. CC is a multi-organ syndrome that results in extensive skeletal muscle and adipose tissue wasting; however, CC can impair other organs such as the liver, heart, brain, and bone as well. A considerable amount of CC research focuses on changes that occur within the muscle, but cancer-related impairments in other organ systems are understudied. Furthermore, metabolic changes in organ systems other than muscle may contribute to CC. Therefore, the purpose of this review is to address degenerative mechanisms which occur during CC from a whole-body perspective. Outlining the information known about metabolic changes that occur in response to cancer is necessary to develop and enhance therapies to treat CC. As much of the current evidences in CC are from pre-clinical models we should note the majority of the data reviewed here are from pre-clinical models.

Background and Aims: A new technology based on the chronometric administration of cyclophosphamide and complex composite double-stranded DNA-based compound, which is scheduled in strict dependence on interstrand crosslinks repair timing, and named “Karanahan”, has been developed. Being applied, this technology results in the eradication of tumor-initiating stem cells and full-scale apoptosis of committed tumor cells. In the present study, the efficacy of this novel approach has been estimated in the model of Lewis carcinoma.Methods: To determine the basic indicative parameters for the approach, the duration of DNA repair in tumor cells, as well as their distribution along the cell cycle, have been assessed. Injections were done into one or both tumors in femoral region of the engrafted mice in accordance with the developed regimen. Four series of experiments were carried out at different periods of time. The content of poorly differentiated CD34+/TAMRA+ cells in the bone marrow and peripheral blood has been determined. Immunostaining followed by the flow cytometry was used to analyze the subpopulations of immune cells.Results: The high antitumor efficacy of the new technology against the developed experimental Lewis carcinoma was shown. It was found that the therapy efficacy depended on the number of tumor growth sites, seasonal and annual peculiarities. In some experiments, a long-term remission has been reached in 70% of animals with a single tumor and in 60% with two tumors. In mice with two developed grafts, mobilization capabilities of both poorly differentiated hematopoietic cells of the host and tumor stem-like cells decrease significantly. Being applied, this new technology was shown to activate a specific immune response. There is an increase in the number of NK cell populations in the blood, tumor, and spleen, killer T cells and T helper cells in the tumor and spleen, CD11b+Ly-6C+ and CD11b+Ly-6G+ cells in the tumor. A population of mature dendritic cells is found in the tumor.Conclusion: The performed experiments indicate the efficacy of the Karanahan approach against incurable Lewis carcinoma. Thus, the discussed therapy is a new approach for treating experimental neoplasms, which has a potential as a personalized anti-tumor therapeutic approach in humans.

Heparin is a centennial anticoagulant drug broadly employed for treatment and prophylaxis of thromboembolic conditions. Although unfractionated heparin (UFH) has already been shown to have remarkable pharmacological potential for treating a variety of diseases unrelated with thromboembolism, including cancer, atherosclerosis, inflammation, and virus infections, its high anticoagulant potency makes the doses necessary to exert non-hemostatic effects unsafe due to an elevated bleeding risk. Our group recently developed a new low-anticoagulant bovine heparin (LABH) bearing the same disaccharide building blocks of the UFH gold standard sourced from porcine mucosa (HPI) but with anticoagulant potency approximately 85% lower (approximately 25 and 180 Heparin International Units [IU]/mg). In the present work, we investigated the pharmacokinetics profile, bleeding potential, and anticancer properties of LABH administered subcutaneous into mice. LABH showed pharmacokinetics profile similar to HPI but different from the low-molecular weight heparin (LMWH) enoxaparin and diminished bleeding potential, even at high doses. Subcutaneous treatment with LABH delays the early progression of Lewis lung carcinoma, improves survival, and brings beneficial health outcomes to the mice, without the advent of adverse effects (hemorrhage/mortality) seen in the animals treated with HPI. These results demonstrate that LABH is a promising candidate for prospecting new therapeutic uses for UFH.