Cell Lung Carcinoma Research Articles

Real time monitoring of heavy metal adulteration in biodiesel using Arduino UNO platform@A promising multi-purpose stimuli-responsive azomethine based chemoreceptor for hierarchical tri-ionic sensing

The presence of metallic adulteration even in very trace level may lead to deleterious impact on the biodiesel quality and ultimately may be responsible for the dropping down of system efficiency, which necessitates the trace level recognition of heavy metal adulteration from biodiesel. In this context, herein using an azomethine functionalized chromogenic chemoreceptor, 1-((E)-(4-hydroxyphenylimino) methyl) napthalen-2-ol (HMN) has been reported for the selective chemodosimetric recognition of Cu2+ with a lower detection threshold of 7.8 ppb via distinct chromogenic variation of HMN. In addition to this, it has also exhibited selective and reversible naked eye chromogenic sensing behaviour towards F− (LOD=160 ppb) and Al3+ (LOD=48 ppb) at very trace level, which is quite lower than the WHO permissible limit. Distinct chromogenic recognition of F− by HMN proceeds via strong intermolecular hydrogen bonding mediated improved intramolecular charge transfer. The spectroscopic response of HMN in alternate presence and absence of the targeted analytes made it suitable to formulate AND-NOT-XNOR-NAND-OR gate based ‘Castle-like’ complicated logic circuitry. In-vitro cell imaging study using A549, human lung carcinoma cell line attests intracellular recognition capability of HMN, demonstrating its effectual bio-medicinal applications. Interestingly, inspired by the capability of HMN towards recognition of copper from biodiesel specimen, an RGB-assisted device comprised of TCS color sensor and an Arduino UNO 8-bit microcontroller has been developed for real-time quantitative analysis of the biodiesel adulteration. Going one step further, utilization of lab-on-a-box based prototype to monitor the concentration-dependent chromogenic fluctuation via RGB analysis is undoubtedly beneficial for the determination of copper adulteration in biodiesel sample. The presently developed chemoreceptor can thus be regarded as a valuable addition in the field of supramolecular chemistry as well as a significant initiative towards regular monitoring of the biodiesel quality control parameters as a part of sustainable environment.

From 2D to 3D In Vitro World: Sonodynamically-Induced Prooxidant Proapoptotic Effects of C60-Berberine Nanocomplex on Cancer Cells.

The primary objective of this research targeted the biochemical effects of SDT on human cervix carcinoma (HeLa) and mouse Lewis lung carcinoma (LLC) cells grown in 2D monolayer and 3D spheroid cell culture. HeLa and LLC monolayers and spheroids were treated with a 20 µM C60-Ber for 24 h, followed by irradiation with 1 MHz, 1 W/cm2 US. To evaluate the efficacy of the proposed treatment on cancer cells, assessments of cell viability, caspase 3/7 activity, ATP levels, and ROS levels were conducted. Our results revealed that US irradiation alone had negligible effects on LLC and HeLa cancer cells. However, both monolayers and spheroids irradiated with US in the presence of the C60-Ber exhibited a significant decrease in viability (32% and 37%) and ATP levels (42% and 64%), along with a notable increase in ROS levels (398% and 396%) and caspase 3/7 activity (437% and 246%), for HeLa monolayers and spheroids, respectively. Similar tendencies were observed with LLC cells. In addition, the anticancer effects of C60-Ber surpassed those of C60, Ber, or their mixture (C60 + Ber) in both cell lines. The detected intensified ROS generation and ATP level drop point to mitochondria dysfunction, while increased caspase 3/7 activity points on the apoptotic pathway induction. The combination of 1 W/cm2 US with C60-Ber showcased a promising platform for synergistic sonodynamic chemotherapy for cancer treatment.

Targeting the p90RSK/MDM2/p53 Pathway Is Effective in Blocking Tumors with Oncogenic Up-Regulation of the MAPK Pathway Such as Melanoma and Lung Cancer

In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. Thus, the inhibition of p90RSK restores p53 expression, which in turn inhibits cell proliferation and promotes apoptosis. In the present study, we demonstrated that the p90RSK/MDM2/p53 pathway proved to be an excellent target in the therapy of tumors with MAPK hyperactivation. For this purpose, we selected p53wt melanoma, lung and medullary thyroid carcinoma cell lines with high activation of p90RSK. In these cell lines, we demonstrated that the p90RSK/MDM2/p53 pathway is implicated in the regulation of the cell cycle and apoptosis through p53-dependent transcriptional control of p21 and Bcl-2. Furthermore, with an immunohistochemical evaluation of primary melanomas and lung tumors, which exhibit highly activated p90RSK compared to corresponding normal tissue, we demonstrated that MDM2 stabilization was associated with p90RSK phosphorylation. The results indicate that p90RSK is able to control the proliferative rate and induction of apoptosis through the regulation of p53wt levels by stabilizing MDM2 in selected tumors with constitutively activated MAPKs, making p90RSK a new attractive target for anticancer therapy.

Gossypol Inhibits Metastasis of Lung Cell Carcinoma by Reversing Epithelial to Mesenchymal Transition and Suppressing Proteases Activity.

Gossypol, a natural polyphenolic compound, possesses antivirus activity and induces cell death of different types of tumors. However, the efficacy of gossypol on lung carcinoma metastases and epithelial to mesenchymal transition remains unknown. The aim of the present work was to determine the cellular and molecular mechanism of the anti-cancer and anti-metastatic efficacies of gossypol on human lung carcinoma cells. Gossypol showed a marked suppression of the viability, motility, and invasion in H1299 and A549 cells. Zymography assay showed that gossypol was sufficient to suppress the activities of urokinase-type plasminogen activator and matrix metalloproteinase-2. Gossypol reversed TGF-β-induced epithelial to mesenchymal transition. Gossypol reduced vimentin, p-FAK, p-Src and p-paxillin. In vivo studies of gossypol were performed using subcutaneous inoculation and tail vein injection of A549 into immunodeficient BALB/c nude mice and severe combined immunodeficient mice.

A monoclonal antibody recognizing CD98 on human embryonic stem cells shows anti-tumor activity in hepatocellular carcinoma xenografts

CD98, also known as SLC3A2, is a multifunctional cell surface molecule consisting of amino acid transporters. CD98 is ubiquitously expressed in many types of tissues, but expressed at higher levels in cancerous tissues than in normal tissues. CD98 is also upregulated in most hepatocellular carcinoma (HCC) patients; however, the function of CD98 in HCC cells has been little studied. In this study, we generated a panel of monoclonal antibodies (MAbs) against surface proteins on human embryonic stem cells (hESCs). NPB15, one of the MAbs, bound to hESCs and various cancer cells, including HCC cells and non-small cell lung carcinoma (NSCLC) cells, but not to peripheral blood mononuclear cells (PBMCs) and primary hepatocytes. Immunoprecipitation and mass spectrometry identified the target antigen of NPB15 as CD98. CD98 depletion decreased cell proliferation, clonogenic survival, and migration and induced apoptosis in HCC cells. In addition, CD98 depletion decreased the expression of cancer stem cell (CSC) markers in HCC cells. In tumorsphere cultures, the expression of CD98 interacting with NPB15 was significantly increased, as were known CSC markers. After cell sorting by NPB15, cells with high expression of CD98 (CD98-high) showed higher clonogenic survival than cells with low expression of CD98 (CD98-low) in HCC cells, suggesting CD98 as a potential CSC marker on HCC cells. The chimeric version of NPB15 was able to induce antibody-dependent cellular cytotoxicity (ADCC) against HCC cells in vitro. NPB15 injection showed antitumor activity in an HCC xenograft mouse model. The results suggest that NPB15 may be developed as a therapeutic antibody for HCC patients.

ASMase is Essential for the Immune Response to Partial-Tumor Radiation Exposure.

Tumor response to radiation is thought to depend on the direct killing of tumor cells. Our laboratory has called this into question. Firstly, we showed that the biology of the host, specifically the endothelial expression of acid sphingomyelinase (ASMase), was critical in determining tumor radiocurability. Secondly, we have shown that the immune system can enhance radiation response by allowing a complete tumor control in hemi-irradiated tumors. In this paper, we focus on the integration of these two findings. We used Lewis Lung Carcinoma (LLC) cells, injected in the flank of either: (i) ASMase knockout or (ii) WT of matched background (sv129xBl/6) or (iii) C57Bl/6 mice. Radiation therapy (RT) was delivered to 50% or 100% of the LLC tumor volume. Tumor response, immune infiltration (CD8+ T cells), ICAM-1, and STING activation were measured. Radiotherapy was also combined with methyl-cyclodextrin, to inhibit the ASMase-mediated formation of ceramide-enriched lipid rafts. We recapitulated our previous finding, namely that tumor hemi-irradiation was sufficient for tumor control in the LLC/C57Bl/6 model. However, in ASMase KO mice hemi-irradiation was ineffective. Likewise, pharmacological inhibition of ASMase significantly reduced the tumor response to hemi-irradiation. Further, we demonstrated elevated ICAM-1 expression, increased levels of CD8+ T cells, ICAM-1, and STING activation in tumors growing in C57Bl/6 mice, as well as the ASMase WT strain. However, no such changes were seen in tumors growing in ASMase KO mice. ASMase and ceramide generation are necessary to mediate a radiation-induced anti-tumor immune response via STING activation.

Stable Cyclometallated Palladium Complexes of Arylamides: Synthesis, Redox and Anticancer Activities

AbstractAir‐stable cyclometalated palladium(II) complexes with benzamide ligands were synthesized in high yields and characterized by X‐ray diffraction analysis, CVA, 1H NMR, 13C NMR spectroscopy, MALDI‐MS, and ESI‐MS. The electrochemical oxidation of the complexes is reversible in the presence of a quinoline substituent in the ligand and gives Pd (III) species that do not undergo reductive elimination and are detectable by ESR spectroscopy. The complexes showed high cytotoxicity against cervical cancer (M‐HeLa) and duodenal adenocarcinoma (HuTu 80), a human mammary ductal adenocarcinoma line (MCF‐7) and a human lung carcinoma cell line (A549). The possibility of generating reactive oxygen species in solution (such as OH−radicals), which can be responsible for the antitumor activity of the studied complexes, using the ESR method was shown.

Novel biocompatible pH-fluorescence responsive MOF nanocarriers for lung cancer treatment

In this study, we synthesized two novel metal–organic frameworks [Cd(C4H4N2)(C12H19P3O9)]n (1) and {Ca[Cd(H2O)3]2(C24H15N6O6)2}n (2) distinguished by exceptional fluorescence properties. Focusing on 1, we innovatively combined it with hydroxypropyl cellulose (HPC) to create a pH-responsive, fluorescence-guided nanocarrier system (HPC-1@DOX) for targeted delivery of doxorubicin (DOX) in cancer treatment. We thoroughly evaluated the loading and release efficiency of DOX under varied pH conditions, demonstrating sustained and controlled drug release characteristics in vitro, along with substantial drug-loading capacity. Notably, HPC-1@DOX exhibited pH-responsive behavior, releasing DOX preferentially at pH 6.8, indicative of targeted delivery to tumor and inflammatory sites while minimizing release at higher pH values. Moreover, we explored its biological impact, confirming HPC-1@DOX’s ability to up-regulate miR-493-3p expression in lung carcinoma cells, thereby inhibiting proliferation, reducing invasiveness, and inducing apoptosis. This multifunctional nanocarrier system represents a significant advancement towards targeted and effective cancer therapy.

Inducing Immunogenic Cancer Cell Death through Oxygen‐Economized Photodynamic Therapy with Nitric Oxide‐Releasing Photosensitizers

AbstractPhotodynamic therapy (PDT) utilizes reactive oxygen species (ROS) for eradication of cancer cells. Its effectiveness is governed by the oxygen content, which is scarce in the hypoxic tumor microenvironment. We report herein two zinc(II) phthalocyanines substituted with two or four nitric oxide (NO)‐releasing moieties, namely ZnPc‐2NO and ZnPc‐4NO, which can suppress the mitochondrial respiration, thereby sparing more intracellular oxygen for PDT. Using HT29 human colorectal adenocarcinoma cells and A549 human lung carcinoma cells, we have demonstrated that both conjugates release NO upon interaction with the intracellular glutathione, which can reduce the cellular oxygen consumption rate and adenosine triphosphate generation and alter the mitochondrial membrane potential. They can also relieve the hypoxic status of cancer cells and decrease the expression of hypoxia‐inducible factor protein HIF‐1α. Upon light irradiation, both conjugates can generate ROS and induce cytotoxicity even under a hypoxic condition, overcoming the oxygen‐dependent nature of PDT. Interestingly, the photodynamic action of ZnPc‐2NO elicits the release of damage‐associated molecular patterns, inducing the maturation of dendritic cells and triggering an antitumor immune response. The immunogenic cell death caused by this oxygen‐economized PDT has been demonstrated through a series of in vitro and in vivo experiments.

Inducing Immunogenic Cancer Cell Death through Oxygen-Economized Photodynamic Therapy with Nitric Oxide-Releasing Photosensitizers.

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) for eradication of cancer cells. Its effectiveness is governed by the oxygen content, which is scarce in the hypoxic tumor microenvironment. We report herein two zinc(II) phthalocyanines substituted with two or four nitric oxide (NO)-releasing moieties, namely ZnPc-2NO and ZnPc-4NO, which can suppress the mitochondrial respiration, thereby sparing more intracellular oxygen for PDT. Using HT29 human colorectal adenocarcinoma cells and A549 human lung carcinoma cells, we have demonstrated that both conjugates release NO upon interaction with the intracellular glutathione, which can reduce the cellular oxygen consumption rate and adenosine triphosphate generation and alter the mitochondrial membrane potential. They can also relieve the hypoxic status of cancer cells and decrease the expression of hypoxia-inducible factor protein HIF-1α. Upon light irradiation, both conjugates can generate ROS and induce cytotoxicity even under a hypoxic condition, overcoming the oxygen-dependent nature of PDT. Interestingly, the photodynamic action of ZnPc-2NO elicits the release of damage-associated molecular patterns, inducing the maturation of dendritic cells and triggering an antitumor immune response. The immunogenic cell death caused by this oxygen-economized PDT has been demonstrated through a series of in vitro and in vivo experiments.

A Newly Developed Anti-L1CAM Monoclonal Antibody Targets Small Cell Lung Carcinoma Cells.

Few effective treatments are available for small cell lung cancer (SCLC), indicating the need to explore new therapeutic options. Here, we focus on an antibody-drug conjugate (ADC) targeting the L1 cell adhesion molecule (L1CAM). Several publicly available databases reveal that (1) L1CAM is expressed at higher levels in SCLC cell lines and tissues than in those of lung adenocarcinoma and (2) the expression levels of L1CAM are slightly higher in SCLC tissues than in adjacent normal tissues. We conducted a series of in vitro experiments using an anti-L1CAM monoclonal antibody (termed HSL175, developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. Our HSL175-DT3C conjugates theoretically kill cells only when the conjugates are internalized by the target (L1CAM-positive) cells through antigen-antibody interaction. The conjugates (an ADC analog) were effective against two SCLC-N (NEUROD1 dominant) cell lines, Lu-135 and STC-1, resulting in decreased viability. In addition, L1CAM silencing rendered the two cell lines resistant to HSL175-DT3C conjugates. These findings suggest that an ADC consisting of a humanized monoclonal antibody based on HSL175 and a potent anticancer drug would be effective against SCLC-N cells.

Novel circular RNA hsa_circ_0036683 suppresses proliferation and migration by mediating the miR-4664-3p/CDK2AP2 axis in non-small cell lung cancer.

The aim of the present study was to investigate the function of novel circular RNA hsa_circ_0036683 (circ-36683) in non-small cell lung cancer (NSCLC). RNA sequencing was used to screen out differentially expressed miRNAs. Expression levels of miR-4664-3p and circ-36683 were evaluated in lung carcinoma cells and tissues by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The effects of miR-4664-3p and circ-36683 on proliferation and migration were assessed using cell counting kit-8 (CCK-8), wound healing and transwell migration assays and xenograft experiments. The targeting relationship of circ-36683/miR-4664-3p/CDK2AP2 was assessed by luciferase reporter assays, western blot, qRT-PCR and argonaute2-RNA immunoprecipitation (AGO2 RIP). Co-immunoprecipitation (Co-IP), 5-ethynyl-2'-deoxyuridine (EdU) staining and CCK-8 were used to validate the indispensable role of CDK2AP2 in suppressing cell proliferation as a result of CDK2AP1 overexpression. By RNA sequencing, miR-4664-3p was screened out as an abnormally elevated miRNA in NSCLC tissues. Transfection of miR-4664-3p could promote cell proliferation, migration and xenograft tumor growth. As a target of miR-4664-3p, CDK2AP2 expression was downregulated by miR-4664-3p transfection and CDK2AP2 overexpression could abolish the proliferation promotion resulting from miR-4664-3p elevation. Circ-36683, derived from back splicing of ABHD2 pre-mRNA, was attenuated in NSCLC tissue and identified as a sponge of miR-4664-3p. The functional study revealed that circ-36683 overexpression suppressed cell proliferation, migration and resulted in G0/G1 phase arrest. More importantly, the antioncogenic function of circ-36683 was largely dependent on the miR-4664-3p/CDK2AP2 axis, through which circ-36683 could upregulate the expression of p53/p21/p27 and downregulate the expression of CDK2/cyclin E1. The present study revealed the antioncogenic role of circ-36683 in suppressing cell proliferation and migration and highlighted that targeting the circ-36683/miR-4664-3p/CDK2AP2 axis is a promising strategy for the intervention of NSCLC.

3-Aminobenzamide-linked multifunctional nanoparticles enhances anticancer activity of low-dose cisplatin chemotherapy in lung adenocarcinoma

Chemotherapy is one of the main treatment methods for cancer patients, but its effectiveness is limited by drug resistance. Combining a chemotherapeutic agent with targeted molecular therapy may improve the curative effect of the chemotherapeutic agent. In this study, we investigate the efficacy of combining a 3-Aminobenzamide (3AB)-linked multifunctional platform with low-dose cisplatin chemotherapy aiming to modulate poly [ADP-ribose] polymerase 1 (PARP1) function in DNA repair to increase cytotoxic activity of the platinum-based cisplatin. The structure of the synthesized nanoplatforms was characterized by several physicochemical techniques, including dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and an in vitro pH-dependent release study. Cellular uptake experiments demonstrated preferentially targeted delivery of nanoparticles in lung carcinoma A549 cells, whereas the cellular uptake capacity was minimal in normal lung BEAS-2B cells. On the other hand, cytotoxicity experiments showed a reduction of cancer cell viability compared to free formulations. Furthermore, the combination treatment was examined by detecting the loss of mitochondrial membrane potential and the apoptotic cell population, confirming the treatment's functional involvement in apoptosis. Soft agar colony formation and cell invasion tests were also performed to detect the cancer cell's tumorigenic potential, confirming the synergistic effect of this combination in the reduction of tumorigenicity. Moreover, we analyzed the expression profiles of three candidate genes, which play important roles in cancer initiation, promotion and progression. Cell biology experiments indicated that this novel combination treatment possesses significant synergy between 3AB and low-dose cisplatin and is promising for development as an antitumor treatment for lung cancer.

Polyallylamine antiviral activity against influenza and acute respiratory viral infection in various cell cultures

Acute respiratory viral infections, including influenza, comprise the most common group of seasonal viral infections. Influenza is the most common and dangerous viral infection. The only way to control it is influenza vaccination. Regarding infections caused by parainfluenza and respiratory syncytial virus, only symptomatic treatment is available. Influenza virus quickly bypasses post-vaccination immunity due to its ability to antigenic drift and genetic reassortment. Available antiviral drugs quickly lose effectiveness, especially in relation to highly contagious influenza virus strains. The aim of the study was to create chemotherapeutic agent with a multi-layered effect on all viral structures: surface proteins, lipid membrane and ribonucleoprotein. Such drugs include polyelectrolytes (PE), particularly, polyallylamine (PAA), which showed strong virus-inhibiting effect in combination with low cytotoxicity against several influenza strains in MDCK cell culture and as well as measles virus in Vero cell culture. Materials and methods. In this work, an extended study on PAA antiviral activity and cytotoxicity was carried out using three influenza virus strains in A549 cell line, parainfluenza virus type 3 (HPIV-3) and respiratory syncytial virus (RSV) in A549, HEp-2, Vero, L-41, MA-104 cell lines. Results. It was shown that influenza and RSV were the most sensitive to PAA,so that virus activity decreased by 3 orders of magnitude in human lung carcinoma cells A549. The lowest antiviral activity was registered in Vero cells, which may be because it lacks interferon production system. Based on the results of in vitro experiments, PAA can be considered as a broad-spectrum antiviral drug not only against influenza, but also other human respiratory viruses.

Abstract Mo019: Angiotensin II Links Cardiovascular Disease With Enhanced Cancer Growth

Introduction: It has been demonstrated that CVD promote tumor growth in mouse models of breast, lung, and colon cancer, suggesting a causal relationship between both diseases. Cancer and CVD share several risk factors and pathophysiological mechanisms, e.g. inflammation and oxidative stress, that could explain why patients with CVD are prone to develop cancer. Recent reports also suggest a link between hypertension, hypertrophy and lung cancer. Angiotensin II (ANGII) is a hormone involved in blood pressure regulation, vascular hemostasis and hypertrophy development. Moreover, ANGII is cancerogenic by increasing proliferation of several cancer cell types. Hence, ANGII could be a link in CVD-induced enhancement of cancer growth. Hypothesis: We hypothesized that ANGII treatment, and subsequent hypertension and cardiac hypertrophy, could promote cancer growth. Methods: ANGII (2000 ng.kg -1 .min -1 ; 4w) was administered to 10w old C57B6/J mice using osmotic minipumps. After 4w, pumps were removed and 5*10 5 Lewis lung carcinoma (LLC) cells injected onto the right flank. To study the direct impact of the ANGII peptide on the cancer growth mice were treated with ANGII as mentioned above and LLC cells were injected after 3w to allow concomitant ANGII treatment and cancer growth. A similar experiment was performed by injecting 2*10 5 MC38 colon cancer cells. Tumor growth was monitored for 21d after which the mice were sacrificed. Results are expressed as mean ± SEM. Results: ANGII treatment concomitantly with cancer growth resulted in significantly larger tumors as shown by post-mortem tumor volume (881 ± 111 control vs. 1467 ± 154 mm^3 ANGII, P=0.013). In contrast, no increased tumor growth was observed when ANGII was administered non-concomitant with cancer growth. Interestingly, MC38 tumor growth significantly decreased in the ANGII treated group as portrayed by tumor volume (462 ± 65 control vs. 227 ± 81 mm^3 ANGII). Conclusion: Our data suggest a role for ANGII in CVD-enhanced cancer growth, but also that this effect is not universal, illustrated by a differential effect of ANGII on distinct cancer types. Although further investigation is required to unravel the role of ANGII, screening cancer patients with CVD comorbidities for ANGII involvement might be warranted.

Aloe and coconut extracts mediated CuInS2 nanoparticles induce apoptosis in non-small lung cancer cells (A549)

The most prevalent type of cancer found in the world is lung cancer. Furthermore, chemotherapeutic intervention for lung carcinomas is frequently associated with severe off-target effects. As a result, there is a worldwide push to investigate alternative medicines with superior tolerance profiles, such as natural compounds, to substitute routinely used chemotherapeutics. The purpose of this study is to examine the anticancer potential of aloe (S1) and coconut (S2) extract-mediated CuInS2 (CIS) nanoparticles against non-small cell lung carcinoma (A549) cells. S1 and S2 both efficiently showed a dose-proportionate cytotoxic effect on A549 cells, while causing negligible toxic effects on normal healthy lung cells (WI-38), indicating their safety against healthy cells. Reduced cell viability was validated by acridine orange and ethidium bromide double staining, demonstrating that apoptosis was induced in A549 cells treated with both nanoparticles. In addition, the mitochondrial membrane potential was reduced by both nanoparticles, leading to an increase in ROS generation. Both nanoparticles increased caspase-3, caspase-9, and caspase-8 levels in A549 cells. To summarize, both nanoparticles induced apoptotic cell damage in A549 cells by targeting mitochondria, causing increased ROS production, activating the caspase cascade, and inducing apoptosis. Aloe (S1) and coconut (S2) extract-mediated CIS nanoparticles may represent viable therapeutic options for lung cancer management.

Dihydroartemisinin restores the immunogenicity and enhances the anticancer immunosurveillance of cisplatin by activating the PERK/eIF2α pathway

BackgroundImmunosurveillance 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.MethodsLewis 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.ResultsDihydroartemisinin 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.ConclusionsWe 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.

Selenium nanoparticles enhance the anti-tumor immune responses of anti-4-1BB antibody and alleviate the adverse effects on mice

4-1BB agonists for cancer immunotherapy have shown good preliminary efficacy in clinical trials, but several of the first-generation 4-1BB agonistic antibodies entering the clinic have failed due to safety issues. Selenium nanoparticles (SeNPs) exhibit anti-inflammatory, anti-tumor, antioxidant, and immune-modulating properties. In addition, they have been shown to have detoxifying effects and prevent oxidative liver damage. In this study, we used an anti-4-1BB antibody in combination with SeNPs to evaluate the anti-lung cancer effects in in vitro and in vivo experiments and explore the underlying mechanisms by pathological analyses, quantitative PCR, and enzyme-linked immunoassay. We found that 5 μmol·L–1 anti-4-1BB antibody combined with 1 μmol·L–1 SeNPs increased the expression of IFN-γ and promoted the killing effects of peripheral blood mononuclear cells on Lewis lung carcinoma cells, with a lethality rate up to 56.88 %. Experiments in tumor-bearing mice showed that the tumor inhibition rate was 58.61 % after treatment with 3.5 mg/kg anti-4-1BB antibody combined with 0.25 mg/kg SeNPs, and the liver function index returned to normal. When the combined treatment was compared with the antibody treatment alone, detection of immune relevant factors demonstrated that the expression of FOXP3, IL-2, IL-12, and TNF-α in the spleen was downregulated, whereas the expression of IFN-γ in the spleen, serum, and tumor was upregulated, accompanied by increased Fas ligand expression in the tumor tissues. Based on these findings, we get the conclusion that anti-4-1BB antibody combined with SeNPs may alleviate the immunosuppression of regulatory T cells, promote the immune cell proliferation and metastasis to synergistically kill tumor cells. This combination also reduces the inflammatory damage to normal tissues and slows overstimulation of the splenic immune response.

Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor.

Antagonism of the human adenosine A3 receptor (hA3R) has potential therapeutic application. Alchemical relative binding free energy calculations of K18 and K32 suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA3R affinity. Of the 25 new analogues synthesized, 37 and 74 showed improved hA3R affinity compared to K18 (and K32). This was further improved through the addition of a bromine group to the 2-pyridinyl at the 5-position, generating compound 39. Alchemical relative binding free energy calculations, mutagenesis studies and MD simulations supported the compounds' binding pattern while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, so highlighting the importance of rigidification of the carbonyloxycarboximidamide moiety. MD simulations highlighted the importance of rigidification of the carbonyloxycarboximidamide, while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, which was supported through mutagenesis studies 39 also selectively antagonized endogenously expressed hA3R in nonsmall cell lung carcinoma cells, while pharmacokinetic studies indicated low toxicity enabling in vivo evaluation. We therefore suggest that 39 has potential for further development as a high-affinity hA3R antagonist.

Co-delivery of Bcl-2 siRNA and doxorubicin using liposome-incorporated poly(ε-caprolactone) /chitosan nanofibers for the treatment of lung cancer

The small interfering RNA (siRNA) and chemotherapeutic drugs-incorporated liposome-nanofiber hybrid delivery system could inhibit tumor growth and decrease the adverse side effects. In the present study, doxorubicin (DOX) anticancer drug and Bcl-2 siRNA have been incorporated into the liposome-embedded chitosan-poly (ethylene oxide)/poly (ε-caprolactone) (CS/PEO/PCL) pH-sensitive nanofibrous hybrid formulation for treating lung cancer. The mean particle size & zeta potential of liposome, DOX-liposome, and DOX-Bcl-2-liposome were 130 ± 10 nm & 27.85 ± 1.65 mV, 155 ± 15 nm & 26.30 ± 1.3 mV, and 195 ± 30 nm &11.31 ± 0.65 mV, respectively. The average diameter of electrospun CS/PEO/PCL/DOX-siRNA-liposome simple and CS/PEO/PCL/DOX-siRNA-liposome core-shell nanofibers was 385 ± 80, and 485 ± 100 nm, respectively. The extended release of DOX and si-RNA (30 days) were achieved from DOX-Bcl-2-liposome-incorporated CS/PEO/PCL core-shell nanofibers. The maximum down-regulation of Bcl-2 siRNA, apoptosis of cancer cells, and reduction in the cell viability of A549 lung carcinoma cells were achieved using DOX-Bcl-2 liposome-incorporated CS/PEO/PCL core-shell nanofibers. The in vivo results indicated the maximum suppress of tumor growth without change in the body weight for the mice treated with DOX-Bcl-2 liposome-incorporated CS/PEO/PCL nanofibers. The obtained results demonstrated that the prepared hybrid delivery system presented a novel effective formulation for treating lung cancer.