Antitumor Properties Research Articles

Lobetyolin protects mice against LPS-induced sepsis by downregulating the production of inflammatory cytokines in macrophage

Introduction: Sepsis is a clinical syndrome characterized by dysregulation of the host immune response due to infection, resulting in life-threatening organ damage. Despite active promotion and implementation of early preventative measures and bundle treatments, sepsis continues to exhibit high morbidity and mortality rates with no optimal pharmacological intervention available. Lobetyolin (LBT), the crucial component of polyacetylenes found in Codonopsis pilosula, has been scientifically proven to possess potent antioxidant and antitumor properties. However, its therapeutic potential for sepsis remains unknown.Methods: The mice received pretreatment with intraperitoneal injections of LBT, followed by injection with lipopolysaccharide (LPS) to induce sepsis. Peripheral blood samples were collected to detect TNF-α, IL-1β, and IL-6 levels. The survival status of different groups was recorded at various time intervals. RNA-Seq was utilized for the analysis of gene expression in peritoneal macrophages treated with LBT or LPS.Results: In this study, we observed a significant increase in the survival rate of mice pretreated with LBT in LPS induced sepsis mouse model. LBT demonstrated a remarkable reduction in the production of IL-6, TNF-α, and IL-1β in the serum, along with mitigated lung and liver tissue damage characterized by reduced inflammatory cell infiltration. Additionally, through RNA-seq analysis coupled with GO and KEGG analysis, it was revealed that LBT effectively suppressed genes associated with bacterium presence, cellular response to lipopolysaccharide stimulation, as well as cytokine-cytokine receptor interaction involving Cxcl10, Tgtp1, Gbp5, Tnf, Il1b and IRF7 specifically within macrophages. We also confirmed that LBT significantly downregulates the expression of IL-6, TNF-α, and IL-1β in macrophage activation induced by LPS.Discussion: Therefore, our findings demonstrated that LBT effectively inhibits the production of inflammatory cytokines (IL-6, TNF-α, and IL-1β) and mitigates sepsis induced by LPS through modulating macrophages' ability to generate these cytokines. These results suggest that LBT holds promise as a potential therapeutic agent for sepsis treatment.

The Evolution of Nadofaragene Firadenovec: A Review and the Path Forward

BACKGROUND: The intravesical gene therapy nadofaragene firadenovec (rAd-IFNα/Syn3) was FDA approved in 2022 for non-muscle invasive bladder cancer (NMIBC) unresponsive to frontline treatment with BCG, and the first gene therapy developed for bladder cancer. This non-replicating recombinant adenovirus vector delivers a copy of the human interferon alpha-2b gene into urothelial and tumor cells, causing them to express this pleotropic cytokine with potent antitumor effects. OBJECTIVE: To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC. METHODS: We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC. RESULTS: The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon’s direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene. CONCLUSIONS: Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.

3-Hydroxytanshinone Inhibits the Activity of Hypoxia-Inducible Factor 1-α by Interfering with the Function of α-Enolase in the Glycolytic Pathway

Tumor cells in hypoxic conditions control cancer metabolism and angiogenesis by expressing HIF-1α. Tanshinone is a traditional Chinese medicine that has been shown to possess antitumor properties and exerts a therapeutic impact on angiogenesis. However, the precise molecular mechanism responsible for the antitumor activity of 3-Hydroxytanshinone (3-HT), a type of tanshinone, has not been fully understood. Therefore, our study aimed to investigate the mechanism by which 3-HT regulates the expression of HIF-1α. Our findings demonstrate that 3-HT inhibits HIF-1α activity and expression under hypoxic conditions. Additionally, 3-HT inhibits hypoxia-induced angiogenesis by suppressing the expression of VEGF. Moreover, 3-HT was found to directly bind to α-enolase, an enzyme associated with glycolysis, resulting in the suppression of its activity. This inhibition of α-enolase activity by 3-HT leads to the blockade of the glycolytic pathway and a decrease in glycolysis products, ultimately altering HIF1-α expression. Furthermore, 3-HT negatively regulates the expression of HIF-1α by altering the phosphorylation of AMP-activated protein kinase (AMPK). Our study’s findings elucidate the mechanism by which 3-HT regulates HIF-1α through the inhibition of the glycolytic enzyme α-enolase and the phosphorylation of AMPK. These results suggest that 3-HT holds promise as a potential therapeutic agent for hypoxia-related angiogenesis and tumorigenesis.

In vitro assessment of the effect of magnetic fields on efficacy of biosynthesized selenium nanoparticles by Alborzia kermanshahica

Cyanobacteria represent a rich resource of a wide array of unique bioactive compounds that are proving to be potent sources of anticancer drugs. Selenium nanoparticles (SeNPs) have shown an increasing potential as major therapeutic platforms and led to the production of higher levels of ROS that can present desirable anticancer properties. Chitosan–SeNPs have also presented antitumor properties against hepatic cancer cell lines, especially the Cht-NP (Chitosan–NPs), promoting ROS generation and mitochondria dysfunction. It is proposed that magnetic fields can add new dimensions to nanoparticle applications. Hence, in this study, the biosynthesis of SeNPs using Alborzia kermanshahica and chitosan (CS) as stabilizers has been developed. The SeNPs synthesis was performed at different cyanobacterial cultivation conditions, including control (without magnetic field) and magnetic fields of 30 mT and 60 mT. The SeNPs were characterized by uv-visible spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), Dynamic light scattering (DLS), zeta potential, and TEM. In addition, the antibacterial activity, inhibition of bacterial growth, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC), as well as the antifungal activity and cytotoxicity of SeNPs, were performed. The results of uv-visible spectrometry, DLS, and zeta potential showed that 60 mT had the highest value regarding the adsorption, size, and stabilization in compared to the control. FTIR spectroscopy results showed consistent spectra, but the increased intensity of peaks indicates an increase in bond number after exposure to 30 mT and 60 mT. The results of the antibacterial activity and the inhibition zone diameter of synthesized nanoparticles showed that Staphylococcus aureus was more sensitive to nanoparticles produced under 60 mT. Se-NPs produced by Alborzia kermanshahica cultured under a 60 mT magnetic field exhibit potent antimicrobial and anticancer properties, making them a promising natural agent for use in the pharmaceutical and biomedical industries.

Arbuscular Mycorrhizal Fungi Diversity in Sophora japonica Rhizosphere at Different Altitudes and Lithologies

Arbuscular mycorrhizal fungi play a key role in mediating soil–plant relationships within karst ecosystems. Sophora japonica, a medicinal plant with anti-inflammatory and antitumor properties, is widely cultivated in karst areas of Guangxi, China. We considered limestone, dolomite, and sandstone at altitudes ranging from 100 to 800 m and employed Illumina sequencing to evaluate AMF diversity and identify the factors driving S. japonica rhizosphere AMF community changes. We showed that the increase in altitude increased S. japonica AMF colonization and the Shannon index. The colonization of limestone plots was higher than that of other lithology. In total, 3,096,236 sequences and 5767 OTUs were identified in S. japonica rhizosphere soil. Among these, 270 OTUs were defined at the genus level and divided into 7 genera and 35 species. Moreover, available nitrogen, soil organic matter, and available calcium content had a coupling effect and positive influence on AMF colonization and Shannon and Chao1 indices. Conversely, available phosphorus, available potassium, and available magnesium negatively affected AMF Shannon and Chao1 indices. Lithology, altitude, pH, and available phosphorus are important factors that affect the dynamics of AMF in the S. japonica rhizosphere.

Biological impact and therapeutic potential of a novel camptothecin derivative (FLQY2) in pancreatic cancer through inactivation of the PDK1/AKT/mTOR pathway

BackgroundCamptothecin (CPT), a pentacyclic alkaloid with antitumor properties, is derived from the Camptotheca acuminata. Topotecan and irinotecan (CPT derivatives) were first approved by the Food and Drug Administration for cancer treatment over 25 years ago and remain key anticancer drugs today. However, their use is often limited by clinical toxicity. Despite extensive development efforts, many of these derivatives have not succeeded clinically, particularly in their effectiveness against pancreatic cancer which remains modest. Aim of the studyThis study aimed to evaluate the therapeutic activity of FLQY2, a CPT derivative synthesized in our laboratory, against pancreatic cancer, comparing its efficacy and mechanism of action with those of established clinical drugs. MethodsThe cytotoxic effects of FLQY2 on cancer cells were assessed using an MTT assay. Patient-derived organoid (PDO) models were employed to compare the sensitivity of FLQY2 to existing clinical drugs across various cancers. The impact of FLQY2 on apoptosis and cell cycle arrest in Mia Paca-2 pancreatic cancer cells was examined through flow cytometry. Transcriptomic and proteomic analyses were conducted to explore the underlying mechanisms of FLQY2′s antitumor activity. Western blotting was used to determine the levels of proteins regulated by FLQY2. Additionally, the antitumor efficacy of FLQY2 in vivo was evaluated in a pancreatic cancer xenograft model. ResultsFLQY2 demonstrated (1) potent cytotoxicity; (2) superior tumor-suppressive activity in PDO models compared to current clinical drugs such as gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infinitinib, and lenvatinib; (3) significantly greater tumor inhibition than paclitaxel liposomes in a pancreatic cancer xenograft model; (4) robust antitumor effects, closely associated with the inhibition of the TOP I and PDK1/AKT/mTOR signaling pathways. In vitro studies revealed that FLQY2 inhibited cell proliferation, colony formation, induced apoptosis, and caused cell cycle arrest at nanomolar concentrations. Furthermore, the combination of FLQY2 and gemcitabine exhibited significant inhibitory and synergistic effects. ConclusionThe study confirmed the involvement of topoisomerase I and the PDK1/AKT/mTOR pathways in mediating the antitumor activity of FLQY2 in treating Mia Paca-2 pancreatic cancer. Therefore, FLQY2 has potential as a novel therapeutic option for patients with pancreatic cancer.

Schisandrol A, the Major Active Constitute in Schisandra chinensis: A Review of Its Preparation, Biological Activities, and Pharmacokinetics Analysis.

Schisandra chinensis (S. chinensis) has a long history as a traditional Chinese medicine that is astringent, beneficial to vital energy, tonifies the kidney, tranquilizes the heart, etc. Significantly, Schisandrol A (SA) is extracted from S. chinensis and shows surprising and satisfactory biological activity, including anti-inflammatory, hepatoprotective, cardiovascular protection, and antitumor properties, among others. SA has a more pronounced protective effect on central damaged nerves among its numerous pharmacological effects, improving neurodegenerative diseases such as Alzheimer's and Parkinson's through the protection of damaged nerve cells and the enhancement of anti-oxidant capacity. Pharmacokinetic studies have shown that SA has a pharmacokinetic profile with a rapid absorption, wide distribution, maximal concentration in the liver, and primarily renal excretion. However, hepatic and intestinal first-pass metabolism can affect SA's bioavailability. In addition, the content of SA, as an index component of S. chinensis Pharmacopoeia, should not be less than 0.40%, and the content of SA in S. chinensis compound formula was determined with the help of high-performance liquid chromatography (HPLC), which is a stable and reliable method, and it can lay a foundation for the subsequent quality control. Therefore, this paper systematically reviews the preparation, pharmacological effects, pharmacokinetic properties, and content determination of SA with the goal of updating and deepening the understanding of SA, as well as providing a theoretical basis for the study of SA at a later stage.

"Exploring the Biochemical and Nutra-pharmaceutical Prospects of Some Thymus Species- A Review.

The Thymus genus includes various medicinal and aromatic species, cultivated worldwide for their unique medicinal and economic value. Besides, their conventional use as a culinary flavoring agent, Thymus species are well-known for their diverse biological effects, such as antioxidant, anti-fungal, anti-bacterial, anti-viral, anti-tumor, anti-inflammatory, anti-cancer, and anti-hypertensive properties. Hence, they are used in the treatment of fever, colds, and digestive and cardiovascular diseases. The pharmaceutical significance of Thymus plants is due to their high levels of bioactive components such as natural terpenoid phenol derivatives (p-cymene,carvacrol, thymol, geraniol), flavonoids, alkaloids, and phenolic acids. This review examines the phytochemicals, biological properties, functional food and nutraceutical attributes of some important Thymus species, with a specific focus on their potential uses in the nutra-pharmaceutical industries. Furthermore, the review provides an insight into the mechanisms of biological activities of key phytochemicals of Thymus species exploring their potential for the development of novel natural drugs.

Antioxidant, anticancer and antimicrobial activity of secondary metabolites from Fusarium species

To evaluate the biological activities of secondary metabolites obtained from Fusarium species. The secondary metabolites of Fusarium oxysporum showed a proliferative effect on MCF-7 cells. The secondary metabolites of Fusarium solani reduced the viability of the MCF-7 cell in 48 hours. The metabolites of both fungi showed significant antibacterial activity (p<0.0010) in E. coli strains at all concentrations. F.oxysporum and solani significantly inhibited S. aureus at all concentrations within 24h. F. oxysporum metabolites significantly reduced C. albicans at all concentrations within 24h. The secondary metabolites of Fusarium solani significantly (p<0.0001) reduced the viability of C. albicans at all concentrations. There are compounds in Fusarium solani with antitumor and antimicrobial properties.

Preparation of Single-Helical Curdlan Hydrogel and Its Activation with Coagulation Factor G

β-1,3-glucans are a kind of natural polysaccharide with immunomodulatory, antitumor, and anti-inflammatory properties. Curdlan, as the simplest linear β-1,3-glucan, possesses a variety of biological activities and thermogelation properties. However, due to the complexity and variability of the conformations of curdlan, the exact structure–activity relationship remains unclear. We prepare a chemically crosslinked curdlan hydrogel with the unique single-helical skeleton (named S gel) in 0.4 wt% NaOH at 40 °C, confirmed by diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). X-ray diffractometry (XRD) data show that S gel maintains the single-helical crystal structure, and the degree of crystallinity of the S gel is ~24%, which is slightly lower than that of the raw powder (~31%). Scanning electron microscopy (SEM) reveals that S gel has a continuous network structure, with large pores measuring 50–200 μm, which is consistent with its high swelling property. Using the 13C high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) method, we determine that most of the single-helical skeleton carbon signals in the swollen S gel are visible, suggesting that the single-helical skeleton of S gel exhibits fascinating mobility at room temperature. Finally, we reveal that the binding of S gel to coagulation Factor G from tachypleus amebocyte lysate increases and saturates at 20 μL tachypleus amebocyte lysate per mg of S gel. Our prepared S gel can avoid the transformation of curdlan conformations and retain the bioactivity of binding to coagulation Factor G, making it a valuable material for use in the food industry and the pharmaceutical field. This work deepens the understanding of the relationship between the single-helical structure and the activity of curdlan, promoting the development and application of β-1,3-glucans.

Novel Combretastatin A-4 Analogs—Design, Synthesis, and Antiproliferative and Anti-Tubulin Activity

Combretastatins isolated from the Combretum caffrum tree belong to a group of closely related stilbenes. They are colchicine binding site inhibitors which disrupt the polymerization process of microtubules in tubulins, causing mitotic arrest. In vitro and in vivo studies have proven that some combretastatins exhibit antitumor properties, and among them, combretastatin A-4 is the most active mitotic inhibitor. In this study, a series of novel combretastatin A-4 analogs containing carboxylic acid, ester, and amide moieties were synthesized and their cytotoxic activity against six tumor cell lines was determined using sulforhodamine B assay. For the most cytotoxic compounds (8 and 20), further studies were performed. These compounds were shown to induce G0/G1 cell cycle arrest in MDA and A549 cells, in a concentration-dependent manner. Moreover, in vitro tubulin polymerization assays showed that both compounds are tubulin polymerization enhancers. Additionally, computational analysis of the binding modes and binding energies of the compounds with respect to the key human tubulin isotypes was performed. We have obtained a satisfactory correlation of the binding energies with the IC50 values when weighted averages of the binding energies accounting for the abundance of tubulin isotypes in specific cancer cell lines were computed.

Uptake and Biotransformation of Guvermectin in Three Crops after In Vivo and In Vitro Exposure.

Guvermectin, as a novel nucleoside-like biopesticide, could increase the rice yield excellently, but the potential environmental behaviors remain unclear, which pose potential health risks. Therefore, the uptake and biotransformation of guvermectin in three types of crops (rice, lettuce, and carrot) were first evaluated with a hydroponic system. Guvermectin could be rapidly absorbed and reached equilibrium in roots (12-36 h) and shoots (24-60 h) in three plants, and guvermectin was also vulnerable to dissipation in roots (t1/2 1.02-3.65 h) and shoots (t1/2 9.30-17.91 h). In addition, 8 phase I and 2 phase II metabolites, transformed from guvermectin degradation in vivo and in vitro exposure, were identified, and one was confirmed as psicofuranine, which had antibacterial and antitumor properties; other metabolites were nucleoside-like chemicals. Molecular simulation and quantitative polymerase chain reaction further demonstrated that guvermectin was metabolized by the catabolism pathway of an endogenous nucleotide. Guvermectin had similar metabolites in three plants, but the biotransformation ability had a strong species dependence. In addition, all the metabolites exhibit neglectable toxicities (bioconcentration factor <2000 L/kg b.w., LC50,rat > 5000 mg/kg b.w.) by prediction. The study provided valuable evidence for the application of guvermectin and a better understanding of the biological behavior of nucleoside-like pesticides.

Synthesis and Antitumor Activities of Novel 5-amino-3-(halophenyl)- 1- phenyl-1H-pyrazole-4-carbonitriles.

This study aimed to synthesize a series of new 3-(halophenyl)-1-phenyl-1Hpyrazole moieties and survey the antitumor properties of these compounds. 3-(halophenyl)-1-phenyl-1H-pyrazoles (4a-j) were prepared by reaction of phenyl hydrazine (3) with different halogen aromatic aldehydes (1a-j) and malononitrile (2) in C2H5OH and piperidine. The reaction took place under microwave irradiation settings for two minutes at140°C. Three human cancer cell lines were used as in vitro test subjects for compounds 4a - j. Three cell lines from mammals HeLa (a cell line for human cervical cancer), MCF-7 (a cell line for human breast cancer), and PC-3 (a cell line for human prostate cancer), all with 5- fluorouracil as the standard reference drug were used. A series of novel 3-(halophenyl)-1-phenyl-1H-pyrazoles were synthesized in this work. All substances had their anticancer properties assessed.

Aspartate β-Hydroxylase Is Upregulated in Head and Neck Squamous Cell Carcinoma and Regulates Invasiveness in Cancer Cell Models.

Aspartate β-hydroxylase (ASPH) is a protein associated with malignancy in a wide range of tumors. We hypothesize that inhibition of ASPH activity could have anti-tumor properties in patients with head and neck cancer. In this study, we screened tumor tissues of 155 head and neck squamous cell carcinoma (HNSCC) patients for the expression of ASPH using immunohistochemistry. We used an ASPH inhibitor, MO-I-1151, known to inhibit the catalytic activity of ASPH in the endoplasmic reticulum, to show its inhibitory effect on the migration of SCC35 head and neck cancer cells in cell monolayers and in matrix-embedded spheroid co-cultures with primary cancer-associated fibroblast (CAF) CAF 61137 of head and neck origin. We also studied a combined effect of MO-I-1151 and HfFucCS, an inhibitor of invasion-blocking heparan 6-O-endosulfatase activity. We found ASPH was upregulated in HNSCC tumors compared to the adjacent normal tissues. ASPH was uniformly high in expression, irrespective of tumor stage. High expression of ASPH in tumors led us to consider it as a therapeutic target in cell line models. ASPH inhibitor MO-I-1151 had significant effects on reducing migration and invasion of head and neck cancer cells, both in monolayers and matrix-embedded spheroids. The combination of the two enzyme inhibitors showed an additive effect on restricting invasion in the HNSCC cell monolayers and in the CAF-containing co-culture spheroids. We identify ASPH as an abundant protein in HNSCC tumors. Targeting ASPH with inhibitor MO-I-1151 effectively reduces CAF-mediated cellular invasion in cancer cell models. We propose that the additive effect of MO-I-1151 with HfFucCS, an inhibitor of heparan 6-O-endosulfatases, on HNSCC cells could improve interventions and needs to be further explored.

Influence of TLR4 signaling on Cannabidiol’s antitumor effectiveness in lung adenocarcinoma cells

Abstract Objectives Lung cancer remains a predominant cancer type with high incidence and low survival rates. Key challenges in its treatment include impaired cellular mechanisms, notably resistance to apoptosis and altered immune responses. A critical aspect in this context is the heightened TLR4-mediated signaling, known to promote cell survival, metastasis, and resistance to cell death, particularly impacting immune microenvironment regulation. This study focuses on evaluating the impact of TLR4 signaling activation on potential therapeutic strategies. Methods Our research utilizes Cannabidiol (CBD), a compound already employed in mitigating chemotherapy side effects in lung adenocarcinoma, recognized for its antitumor properties including antiproliferative, antimetastatic, and apoptosis-inducing effects. However, the effectiveness of CBD in lung cancer cells with elevated TLR4 signaling remains uncertain. Results Our findings reveal that the combination of CBD and TLR4 agonist affects cell viability, proliferation, cell cycle progression, apoptosis, and gene expression related to immune response and extracellular matrix regulation. In lung adenocarcinoma cells with activated TLR4, CBD shows an increased IC50 value, reflecting reduced antiproliferative capacity. Furthermore, its efficacy in arresting the cell cycle and inducing apoptosis is also compromised. The influence on immune response and extracellular matrix regulation is also altered in TLR4-activated cells. Conclusions These results indicate that TLR4 activation significantly diminishes the antitumor efficacy of CBD. This highlights the importance of considering TLR4 signaling activation in future research on therapeutic agents like CBD for cancer treatment.

Abstract PO4-28-04: Curcumin inhibits breast cancer cell proliferation by regulating ciRS-7/miR-7-5p/CKS2 axis

Abstract Background Breast cancer (BC) is the most common cancer in women worldwide. Curcumin is a polyphenolic turmeric-derived compound that has anti-proliferative and anti-tumor properties in different cancer types by acting on multiple molecules. Circular RNAs (circRNAs) are non-coding, single-stranded, covalently closed RNA molecules that act as regulators of the microRNA (miRNA) activity. Recent studies show that circRNAs are potential contributors to the onset and progression of many cancer types. CircRNA ciRS-7 acts as an oncogene and accelerates tumor progression by competitively suppressing miR-7-5p in BC. However, whether curcumin can regulate ciRS-7 to inhibit BC progression is still unclear. Method Breast Cancer cell lines (MCF-7 and T47D) and normal epithelial cell line (MCF-10A) were cultivated and treated with Curcumin (5μM, 10 μM, 20 μM) or DMSO as a control. Also, the cell lines were transfected with ciRS-7 siRNA, miR-7-5p mimic, and their non-targeted controls. The cell viability was detected by Cell Viability Detection Kit-8 (CVDK-8) using an ELISA plate reader. To detect cell migration, scratch assay was performed after 24hs of transfection and a phase contrast microscope was used to acquire images. The effect on apoptosis was detected by Annexin V-FITC Apoptosis Detection Kit using flow cytometry. Potential target genes of miR-7-5p were identified by searching for the overlapping genes in miRNet and miRTarBase v8 with the overexpressed genes in BC patient tissue samples in the TCGA database. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of ciRS-7, miR-7-5p, and the selected genes. qRT-PCR experiments were performed in duplicate and the 2−ΔΔCt method was used for relative quantitation analysis. Results Curcumin treatment, depending on the increased doses, decreased cell proliferation through inducing apoptosis in MCF-7 and T47D cancer cells. Curcumin's anti-proliferative effect was shown to be quite restricted on normal MCF-10A cells, as compared to MCF-7 and T47D cancer cells. In MCF-7 and T47D cells treated with curcumin, cell migration was dramatically inhibited. Curcumin has very little influence on the migration of MCF-10A cells. In both cancer cell group that was transfected with ciRS-7 siRNA and miR-7-5p mimic, it was observed that apoptosis was increased, proliferation was suppressed, and migration was decreased compared to its control groups. Moreover, the expression of ciRS-7 was found to be significantly decreased in the curcumin-treated group, while miR-7-5p was shown to be significantly higher. CKS2 gene one of the possible target genes of miR-7-5p that was identified by using in silico approaches, was also downregulated in curcumin-treated BC cell lines compared to its control group. ciRS-7 and CKS2 expression levels were found to be downregulated, whereas miR-7-5p expression level was found to be elevated in MCF-7 and T47D cells that were transfected with ciRS-7 siRNA. Additionally, CKS2 gene expression was found to be downregulated in miR-7-5p mimic transfected cells. Conclusion Curcumin is derived from the turmeric plant (Curcuma longa) and has been used since 3000 B.C. as a food additive. Nowadays, curcumin is one of the most essential anti-cancer substances that was examined. However, investigations on the influence of curcumin on the circRNA-miRNA-mRNA axis are scarce. Curcumin has been demonstrated to inhibit proliferation and induce apoptosis of BC cells via the ciRS-7/miR-7-5p/CKS2 axis in the present study. Keywords Breast Cancer, Curcumin, ciRS-7, miR-7-5p, CKS2 Citation Format: Asmaa Abuaisha, Murat Kaya, Ilknur Suer, Selman Emiroglu, Fahrunnisa Abanoz, Mustafa Tukenmez, Neslihan Cabıoğlu, Mahmut Muslumanoglu, Kivanc Cefle, Sukru Palanduz, Sukru Ozturk. Curcumin inhibits breast cancer cell proliferation by regulating ciRS-7/miR-7-5p/CKS2 axis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-28-04.

A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity

Cancer cells are highly dependent on bioenergetic processes to support their growth and survival. Disruption of metabolic pathways, particularly by targeting the mitochondrial electron transport chain complexes (ETC-I to V) has become an attractive therapeutic strategy. As a result, the search for clinically effective new respiratory chain inhibitors with minimized adverse effects is a major goal. Here, we characterize a new OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and uncoupling effect. MS-L6 is effective on both intact and sub-mitochondrial particles, indicating that its efficacy does not depend on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines. MS-L6 either dose-dependently inhibits cell proliferation or induces cell death in a variety of cancer cell lines, including B-cell and T-cell lymphomas as well as pediatric sarcoma. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI-1) partially restores the viability of B-lymphoma cells treated with MS-L6, demonstrating that the inhibition of NADH oxidation is functionally linked to its cytotoxic effect. Furthermore, MS-L6 administration induces robust inhibition of lymphoma tumor growth in two murine xenograft models without toxicity. Thus, our data present MS-L6 as an inhibitor of OXPHOS, with a dual mechanism of action on the respiratory chain and with potent antitumor properties in preclinical models, positioning it as the pioneering member of a promising drug class to be evaluated for cancer therapy.MS-L6 exerts dual mitochondrial effects: ETC-I inhibition and uncoupling of OXPHOS. In cancer cells, MS-L6 inhibited ETC-I at least 5 times more than in isolated rat hepatocytes. These mitochondrial effects lead to energy collapse in cancer cells, resulting in proliferation arrest and cell death. In contrast, hepatocytes which completely and rapidly inactivated this molecule, restored their energy status and survived exposure to MS-L6 without apparent toxicity.

Honokiol suppress the PD-L1 expression to improve anti-tumor immunity in lung cancer

Lung cancer is a serious health issue globally, and current treatments have proven to be inadequate. Therefore, immune checkpoint inhibitors (ICIs) that target the PD-1/PD-L1 pathway have become a viable treatment option in lun cancer. Honokiol, a lignan derived from Magnolia officinalis, has been found to possess anti-inflammatory, antioxidant, and antitumor properties. Our research found that honokiol can effectively regulate PD-L1 through network pharmacology and transcriptome analysis. Cell experiments showed that honokiol can significantly reduce PD-L1 expression in cells with high PD-L1 expression. Molecular docking, cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI)indicated that Honokiol can bind to PD-L1. Co-culture experiments on lung cancer cells and T cells demonstrated that honokiol mediates PD-L1 degradation, stimulates T cell activation, and facilitates T cell killing of tumor cells. Moreover, honokiol activates CD4 + and CD8 + T cell infiltration in vivo, thus suppressing tumor growth in C57BL/6 mice. In conclusion, this study has demonstrated that honokiol can inhibit the growth of lung cancer by targeting tumor cell PD-L1, suppressing PD-L1 expression, blocking the PD-1/PD-L1 pathway, and enhancing anti-tumor immunity.

PLA2-MjTX-II from Bothrops moojeni snake venom exhibits antimetastatic and antiangiogenic effects on human lung cancer cells

Phospholipases A2 (PLA2s) from snake venom possess antitumor and antiangiogenic properties. In this study, we evaluated the antimetastatic and antiangiogenic effects of MjTX-II, a Lys49 PLA2 isolated from Bothrops moojeni venom, on lung cancer and endothelial cells. Using in vitro and ex vivo approaches, we demonstrated that MjTX-II reduced cell proliferation and inhibited fundamental processes for lung cancer cells (A549) growth and metastasis, such as adhesion, migration, invasion, and actin cytoskeleton decrease, without significantly interfering with non-tumorigenic lung cells (BEAS-2B). Furthermore, MjTX-II caused cell cycle alterations, increased reactive oxygen species production, modulated the expression of pro- and antiangiogenic genes, and decreased vascular endothelial growth factor (VEGF) expression in HUVECs. Finally, MjTX-II inhibited ex vivo angiogenesis processes in an aortic ring model. Therefore, we conclude that MjTX-II exhibits antimetastatic and antiangiogenic effects in vitro and ex vivo and represents a molecule that hold promise as a pharmacological model for antitumor therapy.

Genome-wide analysis of bZIP transcription factors and their expression patterns in response to methyl jasmonate and low-temperature stresses in Platycodon grandiflorus.

Platycodon grandiflorus belongs to the genus Platycodon and has many pharmacological effects, such as expectorant, antitussive, and anti-tumor properties. Among transcription factor families peculiar to eukaryotes, the basic leucine zipper (bZIP) family is one of the most important, which exists widely in plants and participates in many biological processes, such as plant growth, development, and stress responses. However, genomic analysis of the bZIP gene family and related stress response genes has not yet been reported in P. grandiflorus. P. grandiflorus bZIP (PgbZIP) genes were first identified here, and the phylogenetic relationships and conserved motifs in the PgbZIPs were also performed. Meanwhile, gene structures, conserved domains, and the possible protein subcellular localizations of these PgbZIPs were characterized. Most importantly, the cis-regulatory elements and expression patterns of selected genes exposed to two different stresses were analyzed to provide further information on PgbZIPs potential biological roles in P. grandiflorus upon exposure to environmental stresses. Forty-six PgbZIPs were identified in P. grandiflorus and divided into nine groups, as displayed in the phylogenetic tree. The results of the chromosomal location and the collinearity analysis showed that forty-six PgbZIP genes were distributed on eight chromosomes, with one tandem duplication event and eleven segmental duplication events identified. Most PgbZIPs in the same phylogenetic group have similar conserved motifs, domains, and gene structures. There are cis-regulatory elements related to the methyl jasmonate (MeJA) response, low-temperature response, abscisic acid response, auxin response, and gibberellin response. Ten PgbZIP genes were selected to study their expression patterns upon exposure to low-temperature and MeJA treatments, and all ten genes responded to these stresses. The real-time quantitative polymerase chain reaction (RT-qPCR) results suggest that the expression levels of most PgbZIPs decreased significantly within 6 h and then gradually increased to normal or above normal levels over the 90 h following MeJA treatment. The expression levels of all PgbZIPs were significantly reduced after 3 h of the low-temperature treatment. These results reveal the characteristics of the PgbZIP family genes and provide valuable information for improving P. grandiflorus's ability to cope with environmental stresses during growth and development.