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Simple Summary: The body's defense system, which comprises immune cells, is an important factor contributing to tumor growth and treatment response. A "hot" tumor, infiltrated by various beneficial immune cells, usually corresponds with a better prognosis. A so-called "cold" tumor that lacks these beneficial immune cells or that contains harmful cells that block an immune response often results in a harder fight against cancer. Turning a "cold" tumor into a "hot" tumor may help cancer treatments, like immunotherapy, work better. In this study, we looked at the immune cell environment in lung, colorectal, and skin cancer. Tumors were grown in mice, and the different types of immune cells were studied using a fluorescent technique. We found differences in the immune cell infiltration of the diverse tumor types, with some tumors being more "hot" and others showing a tendency to be "cold". These findings can help us understand how various tumor types interact with the immune system. The tumor microenvironment (TME) is pivotal in cancer progression and the response to immunotherapy. A "hot" tumor typically contains immune cells that promote anti-tumor immunity, predicting positive prognosis. "Cold" tumors lack immune cells, suggesting a poor outlook across various cancers. Recent research has focused on converting "cold" tumors into "hot" tumors to enhance the success of immunotherapy. A prerequisite for the studies of the TME is an accurate knowledge of the cell populations of the TME. This study aimed to describe the immune TME of lung and colorectal cancer and melanoma, focusing on lymphoid and myeloid cell populations. We induced heterotopic immunocompetent tumors in C57BL/6 mice, using KP and LLC (Lewis lung carcinoma) cells for lung cancer, MC38 cells for colorectal cancer, and B16-F10 cells for melanoma. Immune cell infiltration was analyzed using multicolor flow cytometry in single-cell suspensions after tumor excision. KP cell tumors showed an abundance of neutrophils and eosinophils; however, they contained much less adaptive immune cells, while LLC cell tumors predominated in monocytes, neutrophils, and monocyte-derived dendritic cells. Monocytes and neutrophils, along with a significant T cell infiltration, were prevalent in MC38 tumors. Lastly, B16-F10 tumors were enriched in macrophages, while showing only moderate T cell presence. In conclusion, our data provide a detailed overview of the immune TME of various heterotopic tumors, highlighting the variabilities in the immune cell profiles of different tumor entities. Our data may be a helpful basis when investigating new immunotherapies, and thus, this report serves as a helpful tool for preclinical immunotherapy research design. [ABSTRACT FROM AUTHOR]

Drug Repurposing Patent Applications January-March 2023 Abbreviations Used Ace-2 angiotensin converting enzyme 2 LLC Lewis lung carcinoma nAChR nicotinic acetylcholine receptor NSCLC nonsmall cell lung cancer OHS obesity hypoventilation syndrome OSA obstructive sleep apnea PCD post-COVID syndrome Tmprss-2 transmembrane protease serine 2 REFERENCES 1 Chapman HD, Jeffers TK, Williams RB. Signal therapy of NF1-deficient tumor xenograft in mice by the anti-PAK1 drug FK228. In the present invention, the drug is not intended to treat the cancer as such but rather to reduce its invasiveness, and to prevent or treat development of venous thromboembolic events, a common problem in digestive tumors.[41] The basis of this is that in the course of a high-throughput I in silico i docking screen (using Autodock Vina 1.1.2), suramin has been identified as a potential inhibitor of hepsin, a transmembrane serine protease overexpressed in many cancers.[42] A subsequent fluorogenic assay with Boc-GIn-Arg-Arg-Amc substrate confirmed this (IC SB 50 sb = 0.66 M) with an irreversible mechanism. [Extracted from the article]

Cancer stem-like cells (CSCs) exist in tumor tissues composed of heterogeneous cell population and are characterized by their self-renewal capacity and tumorigenicity. Many studies demonstrate that eradication of CSCs prevents development and recurrences of tumor; yet, molecules critical for the maintenance of CSCs have not been completely understood. We previously reported that Semaphorin3A (Sema3a) knockdown suppressed the tumorigenicity and proliferative capacity of Lewis lung carcinoma (LLC) cells. Therefore, we identified Sema3a as an essential factor for the establishment or maintenance of CSCs derived from LLC (LLC-stem cell). shRNA against Sema3a was introduced into LLC cells to establish a LLC-stem cell line and its effects on tumorigenesis, sphere formation, and mTORC1 activity were tested. Sema3a knockdown completely abolished tumorigenicity and the sphere-formation and self-renewal ability of LLC-stem cells. The Sema3a knockdown was also associated with decreased expression of mRNA for stem cell markers. The self-renewal ability abolished by Sema3a knockdown could not be recovered by exogenous addition of recombinant SEMA3A. In addition, the activity of mammalian target of rapamycin complex 1 (mTORC1) and the expression of its substrate p70S6K1 were also decreased. These results demonstrate that Sema3a is a potential therapeutic target in eradication of CSCs. [ABSTRACT FROM AUTHOR]

Aberration of signaling pathways by genetic mutations or alterations in the surrounding tissue environments can result in tumor development or metastasis. However, signaling molecules responsible for these processes have not been completely elucidated. Here, we used mouse Lewis lung carcinoma cells (LLC) to explore the mechanism by which the oncogenic activity of Semaphorin3A (Sema3A) signaling is regulated. Sema3A knockdown by shRNA did not affect apoptosis, but decreased cell proliferation in LLCs; both the mammalian target of rapamycin complex 1 (mTORC1) level and glycolytic activity were also decreased. In addition, Sema3A knockdown sensitized cells to inhibition of oxidative phosphorylation by oligomycin, but conferred resistance to decreased cell viability induced by glucose starvation. Furthermore, recombinant SEMA3A rescued the attenuation of cell proliferation and glycolytic activity in LLCs after Sema3A knockdown, whereas mTORC1 inhibition by rapamycin completely counteracted this effect. These results demonstrate that Sema3A signaling exerts its oncogenic effect by promoting an mTORC1-mediated metabolic shift from oxidative phosphorylation to aerobic glycolysis. [ABSTRACT FROM AUTHOR]

The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex is a key early player in macroautophagy/autophagy. In this study, we assessed the contribution of PIK3C3 to T cell metabolism and function. We found that Pik3c3-deficient T cells exhibited impaired cellular metabolism, and Pik3c3-deficient CD4+ T cells failed to differentiate into T helper 1 cells. These alterations were associated with reduced levels of active mitochondria upon T cell activation. In addition, conditional Pik3c3-deficient animals failed to mount autoreactive T cell responses and were resistant to experimental autoimmune encephalomyelitis (EAE). Interestingly, the deletion of Pik3c3 had little effect on the capacity of animals to clear tumor metastases. Collectively, our studies have revealed a critical role of PIK3C3 in T cell metabolism and the pathogenicity of these cells during EAE. Our findings also have important implications for the development of immunotherapies to treat multiple sclerosis and other inflammatory diseases by targeting PIK3C3. Abbreviations: CNS: central nervous system; DC: dendritic cell; DEG: differentially expressed gene; EAE: experimental autoimmune encephalomyelitis; ECAR: extracellular acidification rate; iNKT: invariant natural killer T; LAP: LC3-associated phagocytosis; LLC: Lewis lung carcinoma; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MDSC: myeloid-derived suppressor cell; MOG: myelin oligodendrocyte glycoprotein; NK: natural killer; OCR: oxygen consumption rate; PI: propidium iodide; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; RNA-seq: RNA-sequencing; TCR: T cell receptor; TMRE: tetramethylrhodamine ethyl ester perchlorate [ABSTRACT FROM AUTHOR]

• Berberine is a natural compound known for its anti-tumor effects • Studies show Berberine inhibits lung cancer cell growth, invasion, and migration. • Berberine boosts cancer cell apoptosis and slows tumor growth in vivo. • Berberine affects DNA repair, modifies epigenetic factors, and interacts with non-coding RNAs. • Berberine enhances the efficacy of both chemotherapy and non-chemotherapy drugs. Lung cancer is a major cause of cancer-related deaths worldwide, and it poses a significant threat to global health due to its high incidence and mortality rates. There is an urgent need for better prevention, early detection, and effective treatments for this disease. The treatment options for lung cancer depend on various factors such as the stage of the disease, the type of cancer, and the patient's overall health. Currently, the primary treatment strategies include surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy, and combination therapies. Berberine, a natural alkaloid found in medicinal plants, has demonstrated potential as an effective anti-cancer agent against lung cancer. The present study aims to summarize the evidence supporting Berberine's ability to inhibit the growth of lung cancer cells, induce apoptosis, and slow down tumor growth in both laboratory and animal studies. The study also shed light on the complex molecular mechanisms involved in its anti-tumor effects, including its impact on signaling pathways, DNA repair systems, and interaction with non-coding RNAs, all of which contribute to tumor suppression. Additionally, the synergistic effects of Berberine with other natural compounds and chemotherapy drugs are discussed. Overall, its multifaceted approach and proven effectiveness justify further research to develop Berberine into a viable treatment option for lung cancer patients. Abbreviations: BBR, Berberine; EMT, epithelial-mesenchymal transition; NSCLC, non-small cell lung cancer; ROS, reactive oxygen species; ASK1, Apoptosis Signal-regulating Kinase 1; JNK, c-Jun N-terminal kinase; BHC, Berberine Hydrochloride; DSB, double-strand breaks; CSN, COP9 signalosome; NIR, near-infrared; LLC, Lewis lung carcinoma; RTK, receptor tyrosine kinase; B-Phyt-LCNs, Berberine-Phytantriol liquid crystalline nanoparticles; ER, endoplasmic reticulum; Ber-LCNs, Berberine-loaded liquid crystalline nanoparticles; BNS, Berberine nanostructure; BER-CS-NPs, Berberine-loaded chitosan nanoparticles; B-Phyt-LCNs, Berberine-Phytantriol liquid crystalline nanoparticles; B-Phyt-LCNs, Berberine-loaded liquid crystalline nanoparticles; Ber-LCNs, Berberine-loaded liquid crystalline nanoparticles; B-ZnO NPs, Berberine-loaded zinc oxide nanoparticles; B-C60, Berberine-C60 complex; LTP, Low-Temperature Plasma. [ABSTRACT FROM AUTHOR]

Oncolytic vaccinia viruses (VVs) are potent stimulators of the immune system and induce immune-mediated tumor clearance and long-term surveillance against tumor recurrence. As such they are ideal treatment modalities for solid tumors including lung cancer. Here, we investigated the use of VVL-m12, a next-generation, genetically modified, interleukin-12 (IL-12)-armed VV, as a new therapeutic strategy to treat murine models of lung cancer and as a mechanism of increasing lung cancer sensitivity to antibody against programmed cell death protein 1 (α-PD1) therapy. The cytotoxicity and replication of VVL-m12, VVL-h12 and control VVs were assessed in lung cancer cell lines. Subcutaneous lung cancer mouse models were established to investigate the anti-tumor activity of the viruses after intratumoral delivery in an immunocompetent disease model. Synergy with α-PD1 or a VV armed with soluble PD-1 (VV-sPD1) was investigated and functional mechanisms behind efficacy probed. Tumor-targeted VVL-m12 replicated to high levels, was cytotoxic in lung cancer cell lines. VVL-m12 demonstrated superior antitumor efficacy in subcutaneous lung cancer models compared with other VVs examined. Importantly, rational combination of VVL-m12 and PD-1 blockade worked synergistically to significantly enhance survival of animals and safely cured lung cancer with no evidence of recurrence. VVL-m12 therapy induced increased intratumoral infiltration of CD4+ and CD8+ T cells and was able to clear tumor at early time points via increased induction and infiltration of effector T cells and central memory T cells (TCM). In addition, VVL-m12 increased dendritic cell activation, induced polarization of M2 macrophages towards an M1 phenotype, and inhibited tumor angiogenesis in vivo. These results demonstrate that VVL-12 has strong potential as a safe and effective antitumor therapeutic for lung cancer. Importantly, VVL-12 can sensitize lung cancers to α-PD1 antibody therapy, and the combined regime creates a highly effective treatment option for patients. [ABSTRACT FROM AUTHOR]

Although immune checkpoint blockade (ICB) therapy has attained unprecedented clinical success, the tolerance and immune suppression mechanisms evolved by tumor cells and their tumor microenvironment (TME) hinder its maximum anti-cancer potential. Ferroptosis therapy can partially improve the efficacy of ICB, but it is still subject to immune suppression by myeloid-derived suppressor cells (MDSCs) in the TME. Recent research suggests that an MDSC blockade can unleash the full therapeutic potential of the combined therapy of ferroptosis and ICB in liver cancer treatment. However, whether blocking the intrinsic ferroptosis pathways of MDSCs can relieve imidazole ketone erastin (IKE)-initiated ferroptosis-induced immune suppression and ultimately trigger the optimal therapeutic effect of the combined ferroptosis and ICB therapy is still unknown. Here, we report that TIPE2, a phospholipid transfer protein, regulated the ferroptosis susceptibility in MDSCs through reprogramming lipid peroxidation-related phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species composition. TIPE2-deficient MDSCs resisted IKE-induced ferroptosis by up-regulating SLC7A11 and GPX4, and dissolved ferroptosis-induced immunosuppressive function by down-regulating lipid ROS whilst encouraging T cell proliferation and infiltration into tumor tissues to improve ferroptosis therapy. More importantly, TIPE2-deficient MDSCs achieved the full anti-tumor therapeutic potential of IKE-induced ferroptosis therapy and a PD-L1 blockade. These findings indicate that TIPE2 confers the ferroptosis sensitivity of MDSCs, and combining the targeting of the TIPE2 of MDSCs, ferroptosis therapy, and ICB is a novel therapeutic option for cancer treatment. [ABSTRACT FROM AUTHOR]

Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis. In this context, mitochondria, which are primarily used to maintain energy homeostasis and support balanced biosynthesis in normal cells, become central organelles for fulfilling the heightened biosynthetic and energetic demands of proliferating cancer cells. Mitochondrial coordination and metabolite exchange with other cellular compartments are crucial. The human SLC25 mitochondrial carrier family, comprising 53 members, plays a pivotal role in transporting TCA intermediates, amino acids, vitamins, nucleotides, and cofactors across the inner mitochondrial membrane, thereby facilitating this cross-talk. Numerous studies have demonstrated that mitochondrial carriers are altered in cancer cells, actively contributing to tumorigenesis. This review comprehensively discusses the role of SLC25 carriers in cancer pathogenesis and metabolic reprogramming based on current experimental evidence. It also highlights the research gaps that need to be addressed in future studies. Understanding the involvement of these carriers in tumorigenesis may provide valuable novel targets for drug development. [ABSTRACT FROM AUTHOR]

Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA. Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival. Furthermore, MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth, and elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients. Together, these findings reveal a role for MT-CO2 in adapting to metabolic stress and highlight MT-CO2 as a putative therapeutic target for Ras-driven cancers. Metabolic rewiring supports cancer progression and therapy resistance. Here, the authors show that upregulation of the mitochondrial genome-encoded complex IV protein MT-CO2 is induced upon glucose deprivation to promote glutaminolysis through epigeneticmediated mechanisms. [ABSTRACT FROM AUTHOR]

Bone cancer pain (BCP) is a common clinical problem in cancer patients. The plasticity of excitatory neurons within the spinal dorsal horn plays a significant role in the development of BCP. This study explored the roles of absent in melanoma 2 (AIM2) and stimulator of interferon gene (STING) in BCP using male C57BL/6J mice. Cancers cells were cultured and implanted into the tibia to induce pain-like behavior. AIM2-RNAi lentivirus was injected into spinal dorsal horn or STING agonist was injected intraperitoneally. The protein expressions and localization were evaluated by qRT-PCR and WB or IF, respectively. The mechanical pain threshold was measured using the von Frey test. Immunofluorescence showed that AIM2 and STING were co-localized in spinal cord neurons, and AIM2 was expressed in the presynaptic membrane. qRT-PCR and western blotting showed that AIM2 expression was increased, and STING expression was decreased in cancer implanted mice. Inhibition of AIM2 enhanced the expression of STING and reduced the expression of GluN1, and attenuated mechanical allodynia. After injecting of STING agonist, the mechanical pain threshold was increased and the expression of GluN1 was decreased. These results emphasizes the involvement of AIM2 in BCP development by downregulating STING expression and increasing GluN1 expression. [ABSTRACT FROM AUTHOR]

Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body's immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influencing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed. [ABSTRACT FROM AUTHOR]

Ferroptosis is a nonapoptotic form of cell death characterized by iron‐dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis‐targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6‐methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis‐targeted therapies in the context of human health and disease. [ABSTRACT FROM AUTHOR]

The use of industrial drugs to treat inflammatory diseases, cancer, and diabetes has become controversial because compared with natural products, these drugs have been found to cause adverse side effects. However, an alternative to synthetic medications has been uncovered from natural sources such as kelp, a term used for large brown seaweed, which is a class of seaweed. Although brown algae are one of the most common and largest subgroups used for food, they have been reported to have increased health benefits owing to the high biological activities of the compounds that are extracted from these brown seaweeds. Fucoidan, a major component obtained from various species of brown algae, is a rather varied group of sulfated polysaccharides (SPs) with complex and heterogeneous structures that lack uniformity and have high nutritional value, and health benefits when consumed. This review discusses some of the key areas in which Fucoidan plays a crucial role in promoting human health and its practical applications. As a result, the analytical literature pertaining to the bioactive characteristics of SPs isolated from the Fucaceae, Laminariaceae, Sargassum, and other groups is emphasized, along with information about their prospective biomedical applications as valuable natural resources in the near future for use in human health. Stability studies, Fucoidan structure, Fucoidan and nanoparticles, the biological activity of Fucoidan, the safety of Fucoidan in humans and animals, Fucoidan patents and commercial applications, and the nutraceutical benefits of Fucoidan extract were performed. [ABSTRACT FROM AUTHOR]

Background: Platinum compounds are commonly used for lung cancer treatment. However, the severe side effects and relatively poor prognosis limit their therapeutic effect. Therefore, developing novel platinum derivative and treatment strategy are critical for current lung cancer therapy. Methods: Flow cytometry, HMGB1 and ATP release, and immunoblotting were performed to evaluate the Oxaliplatin-induced immunogenic cell death (ICD) in two lung carcinoma cells. Vaccination approach and subcutaneous tumor models were created to analyze the tumor regression effect of Oxaliplatin. PD-L1 mRNA and protein levels were detected in LLC (Lewis lung carcinoma). Enhanced therapeutic efficacy of LLC was assessed by co-administration Oxaliplatin and aPD-L1 in murine lung tumor model. Results: Oxaliplatin induced robust ICD in LLC cells, activated dendritic cells (DCs, CD80+CD86+) and enhanced cytotoxic T cells (CD8+) in LLC tumor tissues, which resulted in tumor regression. Co-administration of Oxaliplatin and checkpoint inhibitor, aPD-L1, could enhance the therapeutic efficacy of LLC in murine lung carcinoma. Conclusion: This study reveals Oxaliplatin can induce robust ICD in tumor tissues and suppress tumor growth by activating DCs and enhancing T-cell infiltration. Notably, the Oxaliplatin-induced ICD provides an immunogenic microenvironment, which enhances the checkpoint inhibitor therapeutic efficacy of LLC. [ABSTRACT FROM AUTHOR]

Recently, the growth in the consumption of functional foods with potential nutritional and health benefits revealed rapid progress in phytochemical analysis to assure quality and profile the chemical composition. Bee propolis, a gummy exudate produced in beehives after harvesting from different plant species and showed to contain bioactive secondary metabolites with biological importance. The main goal of the current study is to profile the chemical composition of red propolis samples from the Brazilian stingless bee Tetragonula biroi for the first time using HPLC-UV-ELSD and NMR analysis for assignment of the abundant metabolites' classes as well as extraction and isolation of the major compounds. Column chromatography and size exclusion chromatography were applied for the purification of the major compounds in red Brazilian propolis. Further, testing the antitrypanosomal and cytotoxic activities against Trypanosoma brucei and human leukemia cell lines (U937) was performed. A total of 29 secondary metabolites were identified as two anthocyanins, 6 flavonoids, 8 isoflavonoids, 10 phenolics, two phenolic acids, and one triterpenoid. Two phenolic compounds were purified and identified using 1D and 2D NMR analysis along with MS analysis as liquiritigenin and calycosin. Red Brazilian propolis FB-3 fraction showed the highest inhibitory activity against T. brucei at 1.6 μg/ml, compared to 12.4 μg/ml of the crude extract. The isolated compounds showed moderate activity with an MIC of 8.5 μg/ml for liquiritigenin and 8.7 μg/ml for calycosin. Moreover, FB-3 fraction and calycosin were showed the potent cytotoxic effect with IC50 = 45.1 and 35.8μg/ml, respectively compared to IC50 = 29.5 μg/ml of the standard diminazen. Hence, red Brazilian propolis is rich source of polyphenols with myriad biological importance. Propolis fractions and purified compounds showed moderate antiprotozoal activity and potent cytotoxic activity against human leukemia cell lines. [ABSTRACT FROM AUTHOR]

Melanoma, recognized as the most aggressive type of skin cancer, has experienced a notable increase in cases, especially within populations with fair skin. This highly aggressive cancer is largely driven by UV radiation exposure, resulting in the uncontrolled growth and malignant transformation of melanocytes. The cGAS-STING pathway, an immune signaling mechanism responsible for detecting double-stranded DNA in the cytoplasm, is essential for mediating the immune response against melanoma. This pathway serves a dual purpose: it enhances antitumor immunity by activating immune cells, but it can also promote tumor growth when chronically activated by creating an immunosuppressive environment. This review comprehensively examines the multifaceted implication of the cGAS-STING pathway in melanoma pathogenesis and treatment. We explore its molecular mechanisms, including epigenetic regulation, interaction with signaling pathways such as AR signaling, and modulation by various cellular effectors like TG2 and activin-A. The therapeutic potential of modulating the cGAS-STING pathway is highlighted, with promising results from STING agonists, combination therapies with immune checkpoint inhibitors, and novel drug delivery systems, including nanoparticles and synthetic drugs. Our findings underscore the importance of the cGAS-STING pathway in melanoma, presenting it as a critical target for enhancing anti-tumor immunity. By leveraging this pathway, future therapeutic strategies can potentially convert 'cold' tumors into 'hot' tumors, making them more susceptible to immune responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeting ferroptosis provides new therapeutic opportunities to treat refractory cancers, but myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) hinder the curative effect of ferroptosis-induced cancer therapy. This study demonstrated that blocking CPT1A by etomoxir sodium salt (Eto) augments imidazole ketone erastin (IKE)-induced MDSC actual ferroptotic death and blocks MDSC immunosuppressive function and accumulation by breaking the SLC7A11 and GPX4 ferroptosis defense systems and downregulating the expression of ARG1, which impair tumor growth via promoting T-cell proliferation and infiltration into tumor tissues. Although ferroptosis inducers trigger ferroptotic tumor cells and immune cells in the tumor microenvironment (TME), imidazole ketone erastin (IKE)'s induction of ferroptosis shows no effect on tumor growth in immunocompetent tumor-bearing mice due to the presence of myeloid-derived suppressor cells (MDSCs). Treatment of the carnitine palmitoyltransferase 1a (CPT1A)-specific inhibitor decreases the immunosuppressive function of MDSCs and enhances ferroptotic inducer-initiated tumor cell ferroptosis. However, whether blocking CPT1A could enhance IKE-induced MDSC ferroptosis and thereby inhibit tumor growth is still unclear. Here, we report that a CPT1A-specific inhibitor, etomoxir sodium salt (Eto), and IKE combined treatment increased MDSC ferroptosis. Interestingly, the combination treatment of Eto and IKE blocked MDSCs' immunosuppressive function and accumulation by downregulating the expression of SLC7A11, GPX4, and ARG1 while promoting T-cell proliferation and infiltration into tumor tissues to enhance cancer therapy. These data provide a rationale for the combination therapy of a specific CPT1A inhibitor, Eto, with IKE in clinical settings. [ABSTRACT FROM AUTHOR]

The interplay between cancer and the immune system has captivated researchers for a long time. Recent developments in cancer immunotherapy have substantiated this interest with a significant benefit to cancer patients. Tumor and immune cells are regulated via a wide range of molecular mechanisms involving intricate transcriptional and epigenetic networks. Epigenetic processes influence chromatin structure and accessibility, thus governing gene expression, replication, and DNA damage repair. However, aberrations within epigenetic signatures are frequently observed in cancer. One of the key epigenetic marks is the trimethylation of histone 3 at lysine 9 (H3K9me3), confined mainly within constitutive heterochromatin to suppress DNA accessibility. It is deposited at repetitive elements, centromeric and telomeric loci, as well as at the promoters of various genes. Dysregulated H3K9me3 deposition disrupts multiple pathways, including immune signaling. Consequently, altered H3K9me3 dynamics may modify the efficacy of immunotherapy. Indeed, growing evidence highlights the pivotal roles of various proteins mediating H3K9me3 deposition (SETDB1/2, SUV39H1/2), erasure (KDM3, KDM4 families, KDM7B, LSD1) and interpretation (HP1 proteins, KAP1, CHD4, CDYL, UHRF1) in modulating immunotherapy effectiveness. Here, we review the existing literature to synthesize the available information on the influence of these H3K9me3 writers, erasers, and readers on the response to immunotherapy. [ABSTRACT FROM AUTHOR]

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal's body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action's molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect. [ABSTRACT FROM AUTHOR]

Background: Awareness of age‐related features of carcinogenesis and the importance of cellular immunity is crucial for developing effective antitumor therapies for specific patient groups. Methods: In this study, we examined different populations of cancer stem cells (CSCs) and circulating tumor cells (CTCs) in "young" (8‐10 weeks) and "aged" (80‐82 weeks) C57BL/6 male mice. We used an orthotopic model of Lewis lung carcinoma (LLC) to evaluate the effectiveness of cell therapy targeting lung cancer through reprogrammed CD8‐positive T cells (rCD8+ T cells) in mice from two different ages. Results: The findings revealed that tumor progression with age is primarily caused by impaired recruitment of T cells to the lungs. Additionally, a lower number of CTCs and CSCs were observed in younger mice compared to the older mice. The antitumor effect of rCD8+ T cells in aged mice was found to be inferior to that in young mice, which can be attributed to the reduced impact of therapy on specific CSCs populations. Conclusions: These results offer new insights into the treatment of lung cancer using rCD8+ T cells. Considering the age‐related characteristics influencing disease progression, this therapy has the potential to significantly enhance the effectiveness of treatment methods. [ABSTRACT FROM AUTHOR]

This research aims to investigate the impact of Didang decoction (DD) on the formation of neutrophil extracellular traps (NETs) and cancer‐associated thrombosis in lung cancer. BALB/c nude mice were used to establish xenograft models for inducing deep vein thrombosis. Tumor growth and thrombus length were assessed. The impact of DD on NET generation was analyzed using enzyme‐linked immunosorbent assay, immunofluorescence staining, quantitative real‐time PCR, and western blot analysis, both in vivo and in vitro. CI‐amidine, a PAD4 inhibitor, was employed to evaluate the role of PAD4 in the generation of NETs. In vivo studies demonstrated that treatment with DD reduced tumor growth, inhibited thrombus formation, and decreased the levels of NET markers in the serum, tumor tissues, neutrophils, and thrombus tissues of mice. Additional data indicated that DD could suppress neutrophil counts, the release of tissue factor (TF), and the activation of thrombin‐activated platelets, all of which contributed to increased formation of NETs in mouse models. In vitro, following incubation with conditioned medium (CM) derived from Lewis lung carcinoma cells, the expression of NET markers in neutrophils was significantly elevated, and an extracellular fibrous network structure was observed. Nevertheless, these NET‐associated changes were partially counteracted by DD. Additionally, CI‐amidine reduced the expression of NET markers in CM‐treated neutrophils, consistent with the effects of DD. Collectively, DD inhibits cancer‐associated thrombosis in lung cancer by decreasing PAD4‐dependent NET formation through the regulation of TF‐mediated thrombin‐platelet activation. This presents a promising therapeutic strategy for preventing and treating venous thromboembolism in lung cancer. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-β-adrenergic receptor (βAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice. Methods: Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a βAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1β. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH. Results: CIH led to an increase in catecholamine. Catecholamine-βAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1β, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited. Conclusions: Our study underscores the significant contribution of β-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer. [ABSTRACT FROM AUTHOR]

Modest response rates to immunotherapy observed in advanced lung cancer patients underscore the need to identify reliable biomarkers and targets, enhancing both treatment decision-making and efficacy. Factors such as PD-L1 expression, tumor mutation burden, and a 'hot' tumor microenvironment with heightened effector T cell infiltration have consistently been associated with positive responses. In contrast, the predictive role of the abundantly present tumor-infiltrating myeloid cell (TIMs) fraction remains somewhat uncertain, partly explained by their towering variety in terms of ontogeny, phenotype, location, and function. Nevertheless, numerous preclinical and clinical studies established a clear link between lung cancer progression and alterations in intra- and extramedullary hematopoiesis, leading to emergency myelopoiesis at the expense of megakaryocyte/erythroid and lymphoid differentiation. These observations affirm that a continuous crosstalk between solid cancers such as lung cancer and the bone marrow niche (BMN) must take place. However, the BMN, encompassing hematopoietic stem and progenitor cells, differentiated immune and stromal cells, remains inadequately explored in solid cancer patients. Subsequently, no clear consensus has been reached on the exact breadth of tumor installed hematopoiesis perturbing cues nor their predictive power for immunotherapy. As the current era of single-cell omics is reshaping our understanding of the hematopoietic process and the subcluster landscape of lung TIMs, we aim to present an updated overview of the hierarchical differentiation process of TIMs within the BMN of solid cancer bearing subjects. Our comprehensive overview underscores that lung cancer should be regarded as a systemic disease in which the cues governing the lung tumor-BMN crosstalk might bolster the definition of new biomarkers and druggable targets, potentially mitigating the high attrition rate of leading immunotherapies for NSCLC. [ABSTRACT FROM AUTHOR]

Aberrant activation of the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8+ T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8+ T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8+ T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology. Editor's summary: Overactivation of the innate immune sensing cGAS-STING pathway can lead to inflammation and autoimmunity. To investigate how cGAS hyperactivation drives lung inflammation, Zhao et al. generated a cGAS conditional knockin mouse model. Hyperactivation of cGAS resulted in the formation of tertiary lymphoid structures (TLSs) in the lung, which enhanced antibody responses and antitumor immunity. CCL5-producing endothelial cells in the lung promoted CD8+ T cell recruitment to TLSs via CCR5 signaling, which was induced by T cell–intrinsic cGAS expression. Blocking CCR5/CCL5 impaired TLS formation, suggesting that CCR5/CCL5 could be targeted therapeutically to treat autoimmunity or to enhance antitumor immunity. —Hannah Isles [ABSTRACT FROM AUTHOR]

Background: Immunosurveillance is pivotal in the effectiveness of anticancer therapies and tumor control. The ineffectiveness of cisplatin in activating the immunosurveillance is attributed to its lack of adjuvanticity resulting from its inability to stimulate endoplasmic reticulum stress. Dihydroartemisinin demonstrates the anti-tumor effects through various mechanisms, including the activation of the endoplasmic reticulum stress. This study aimed to develop a novel strategy to enhance the immunogenicity of dying tumor cells by combining cisplatin with dihydroartemisinin, thereby triggering effective anti-tumor immunosurveillance and improving the efficacy of cisplatin in clinical practice. Methods: Lewis lung carcinoma (LLC) and CT26 colon cancer cell lines and subcutaneous tumor models were used in this study. The importance of immunosurveillance was validated in both immunocompetent and immunodeficient mouse models. The ability of dihydroartemisinin and cisplatin therapy to induce immunogenic cell death and tumor growth control in vivo was validated by prophylactic tumor vaccination and therapeutic tumor models. The underlying mechanism was elucidated through the pharmaceutical or genetic intervention of the PERK/eIF2α pathway in vitro and in vivo. Results: Dihydroartemisinin enhanced the generation of reactive oxygen species in cisplatin-treated LLC and CT26 cancer cells. The combination treatment of dihydroartemisinin with cisplatin promoted cell death and ensured an optimal release of damage-associated molecular patterns from dying cancer cells, promoting the phagocytosis of dendritic cells. In the tumor vaccination model, we confirmed that dihydroartemisinin plus cisplatin treatment induced immunogenic cell death. Utilizing immunocompetent and immunodeficient mouse models, we further demonstrated that the combination treatment suppressed the tumor growth of CT26 colon cancer and LLC lung cancer, leading to an improved prognosis through the restoration of cytotoxic T lymphocyte responses and reinstatement of anti-cancer immunosurveillance in vivo. Mechanistically, dihydroartemisinin restored the immunogenicity of cisplatin by activating the adjuvanticity of damage-associated molecular patterns, such as calreticulin exposure, through the PERK/eIF2α pathway. Additionally, the inhibition of eIF2α phosphorylation attenuated the anti-tumor efficiency of C + D in vivo. Conclusions: We highlighted that dihydroartemisinin acts as an immunogenic cell death rescuer for cisplatin, activating anticancer immunosurveillance in a PERK/eIF2α-dependent manner and offering a strategy to enhance the anti-tumor efficacy of cisplatin in clinical practice. [ABSTRACT FROM AUTHOR]

Pericytes, recognized as mural cells, have long been described as components involved in blood vessel formation, playing a mere supporting role for endothelial cells (ECs). Emerging evidence strongly suggests their multifaceted roles in tissues and organs. Indeed, pericytes exhibit a remarkable ability to anticipate endothelial cell behavior and adapt their functions based on the specific cells they interact with. Pericytes can be activated by pro-inflammatory stimuli and crosstalk with immune cells, actively participating in their transmigration into blood vessels. Moreover, they can influence the immune response, often sustaining an immunosuppressive phenotype in most of the cancer types studied. In this review, we concentrate on the intricate crosstalk between pericytes and immune cells in cancer, highlighting the primary evidence regarding pericyte involvement in primary tumor mass dynamics, their contributions to tumor reprogramming for invasion and migration of malignant cells, and their role in the formation of pre-metastatic niches. Finally, we explored recent and emerging pharmacological approaches aimed at vascular normalization, including novel strategies to enhance the efficacy of immunotherapy through combined use with anti-angiogenic drugs. [ABSTRACT FROM AUTHOR]

Background: Cancer is characterized by dysregulated cellular metabolism. Thus, understanding the mechanisms underlying these metabolic alterations is important for developing targeted therapies. In this study, we investigated the pro-tumoral effect of PDZ and LIM domain 2 (PDLIM2) downregulation in lung cancer growth and its association with the accumulation of mitochondrial ROS, oncometabolites and the activation of hypoxia-inducible factor-1 (HIF-1) α in the process. Methods: Databases and human cancer tissue samples were analyzed to investigate the roles of PDLIM2 and HIF-1α in cancer growth. DNA microarray and gene ontology enrichment analyses were performed to determine the cellular functions of PDLIM2. Seahorse assay, flow cytometric analysis, and confocal microscopic analysis were employed to study mitochondrial functions. Oncometabolites were analyzed using liquid chromatography–mass spectrometry (LC–MS). A Lewis lung carcinoma (LLC) mouse model was established to assess the in vivo function of PDLIM2 and HIF-1α. Results: The expression of PDLIM2 was downregulated in lung cancer, and this downregulation correlated with poor prognosis in patients. PDLIM2 highly regulated genes associated with mitochondrial functions. Mechanistically, PDLIM2 downregulation resulted in NF-κB activation, impaired expression of tricarboxylic acid (TCA) cycle genes particularly the succinate dehydrogenase (SDH) genes, and mitochondrial dysfunction. This disturbance contributed to the accumulation of succinate and other oncometabolites, as well as the buildup of mitochondrial reactive oxygen species (mtROS), leading to the activation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, the expression of HIF-1α was increased in all stages of lung cancer. The expression of PDLIM2 and HIF-1α was reversely correlated in lung cancer patients. In the animal study, the orally administered HIF-1α inhibitor, PX-478, significantly reduces PDLIM2 knockdown-promoted tumor growth. Conclusion: These findings shed light on the complex action of PDLIM2 on mitochondria and HIF-1α activities in lung cancer, emphasizing the role of HIF-1α in the tumor-promoting effect of PDLIM2 downregulation. Additionally, they provide new insights into a strategy for precise targeted treatment by suggesting that HIF-1α inhibitors may serve as therapy for lung cancer patients with PDLIM2 downregulation. [ABSTRACT FROM AUTHOR]

Biological nanoparticles, or bionanoparticles, are small molecules manufactured in living systems with complex production and assembly machinery. The products of the assembly systems can be further engineered to generate functionalities for specific purposes. These bionanoparticles have demonstrated advantages such as immune system evasion, minimal toxicity, biocompatibility, and biological clearance. Hence, bionanoparticles are considered the new paradigm in nanoscience research for fabricating safe and effective nanoformulations for therapeutic purposes. Harnessing the power of the immune system to recognize and eradicate malignancies is a viable strategy to achieve better therapeutic outcomes with long-term protection from disease recurrence. However, cancerous tissues have evolved to become invisible to immune recognition and to transform the tumor microenvironment into an immunosuppressive dwelling, thwarting the immune defense systems and creating a hospitable atmosphere for cancer growth and progression. Thus, it is pertinent that efforts in fabricating nanoformulations for immunomodulation are mindful of the tumor-induced immune aberrations that could render cancer nanotherapy inoperable. This review systematically categorizes the immunosuppression mechanisms, the regulatory immunosuppressive cellular players, and critical suppressive molecules currently targeted as breakthrough therapies in the clinic. Finally, this review will summarize the engineering strategies for affording immune moderating functions to bionanoparticles that tip the tumor microenvironment (TME) balance toward cancer elimination, a field still in the nascent stage. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis plays an important role in the occurrence and development of non‐small cell lung cancer (NSCLC). The atypical mitogen‐activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear. Methods: Adult male C57BL/6 wild‐type mice were randomly divided into the control group and p‐siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on. Results: We found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c‐Jun n‐terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo. Conclusion: Our results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC. [ABSTRACT FROM AUTHOR]

Functional foods enriched with plant polyphenol anthocyanins attract particular attention due to their health-promoting properties, including antitumor activity. We evaluated the effects of a grain diet rich in anthocyanins in a mouse model of Lewis lung carcinoma. Mice of the C57BL/6 strain were fed with wheat of near-isogenic lines differing in the anthocyanin content for four months prior to tumor transplantation. Although a significant decrease in the size of the tumor and the number of metastases in the lungs was revealed in the groups with both types of grain diet, the highest percentage of animals without metastases and with attenuated cell proliferation in the primary tumor were observed in the mice with the anthocyanin-rich diet. Both grain diets reduced the body weight gain and spleen weight index. The antitumor effects of the grain diets were associated with the activation of different mechanisms: immune response of the allergic type with augmented interleukin(IL)-9 and eotaxin serum levels in mice fed with control grain vs. inhibition of the IL-6/LIF system accompanied by a decrease in the tumor-associated M2 macrophage marker arginase 1 gene mRNA levels and enhanced autophagy in the tumor evaluated by the mRNA levels of Beclin 1 gene. Thus, anthocyanin-rich wheat is suggested as a promising source of functional nutrition with confirmed in vivo antitumor activity. [ABSTRACT FROM AUTHOR]

Morphological features of angiogenesis processes in Lewis lung carcinoma (LLC) regrowth tumors were investigated and analyzed during their independent development and under the influence of cryopreserved mesenchymal stem cells of the human placenta (hP-MSC) under different administration conditions. In LLC tumors, an earlier (day 1) onset of angiogenesis was revealed, with pronounced extramedullary hematopoiesis and the formation of unstructured provascular structures. It was shown that, in general, hP-MSC provides a more structurally perfect angiogenesis in the tumor, with the formation on the 15th day of vascular formations surrounded by a cell wall formed from the cells of the tumor itself. Different morphological forms of neoangiogenesis were detected both in LLC tumors that develop independently, and with different methods of hP-MSC administration—with simultaneous inoculation with tumor cells and with systemic (intravenous) administration. However, more active neoangiogenesis in LLC tumors was noted with systemic intravenous administration of hP-MSC. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate pharmacokinetic profile, biodistribution and therapeutic effect of cationic thermosensitive liposomes (CTSL) encapsulating doxorubicin (Dox) upon mild hyperthermia (HT). Methods: Non-targeted thermosensitive liposomes (TSL) and CTSL were developed, loaded with Dox and characterized. Blood kinetics and biodistribution of Dox-TSL and Dox-CTSL were followed in B16BL6 tumor bearing mice upon normothermia (NT) or initial hyperthermia conditions. Efficacy study in B16BL6 tumor bearing mice was followed with Dox-TSL or Dox-CTSL upon NT or HT. Efficacy study in LLC tumor bearing mice was performed upon two HT conditions. Intravital microscopy was performed on B16BL6 tumors implanted in dorsal-skin fold window-bearing mice. Results: Targeting did not cause faster blood clearance of CTSL compared to TSL. Highest uptake of liposomes was observed in spleen, kidneys and liver. Applying HT prior to CTSL administration increased drug delivery to the tumor and CTSL delivered ~1.7 fold higher Dox concentration compared to TSL. Efficacy in B16BL6 murine melanoma showed that HT had a significant effect on CTSL in tumor suppression and prolonged survival. Efficacy in LLC Lewis lung carcinoma tumor model demonstrates that two HT treatments hold promises for a successful treatment option. Conclusion: CTSL have potency to increase drug efficacy in tumors due to their targeted and drug release functions. [ABSTRACT FROM AUTHOR]

The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors. [ABSTRACT FROM AUTHOR]

Cancer cachexia (CC) is a debilitating syndrome that affects 50–80% of cancer patients, varying in incidence by cancer type and significantly diminishing their quality of life. This multifactorial syndrome is characterized by muscle and fat loss, systemic inflammation, and metabolic imbalance. Extracellular vesicles (EVs), including exosomes and microvesicles, play a crucial role in the progression of CC. These vesicles, produced by cancer cells and others within the tumor environment, facilitate intercellular communication by transferring proteins, lipids, and nucleic acids. A comprehensive review of the literature from databases such as PubMed, Scopus, and Web of Science reveals insights into the formation, release, and uptake of EVs in CC, underscoring their potential as diagnostic and prognostic biomarkers. The review also explores therapeutic strategies targeting EVs, which include modifying their release and content, utilizing them for drug delivery, genetically altering their contents, and inhibiting key cachexia pathways. Understanding the role of EVs in CC opens new avenues for diagnostic and therapeutic approaches, potentially mitigating the syndrome's impact on patient survival and quality of life. [ABSTRACT FROM AUTHOR]