Tumor Weight Research Articles

OGFr overexpression exerts anti-hepatocellular carcinoma effects by activating P16 and P21 to inhibit proliferation and migration of HepG2 cells.

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the second leading cause of cancer death worldwide [19]. Opioid growth factor (OGF) has been shown to exhibit antitumour potential, binding to OGF receptor (OGFr). Naltrexone (NTX), an OGFr antagonist, is considered as a potential anti-cancer agent. However, the specific mechanism of how OGFr acts on HCC cells is yet to be elucidated. HepG2 cells were inoculated into subcutaneous areas of nude mice's back (200 μL, 2.5×10⁷/mL) to establish HCC in vivo models. HepG2 cells were transfected with lentiviral plasmids containing short hairpin RNA (shRNA) targeting OGFr (sh-OGFr) or negative control shRNA (sh-NC), and OGFr over-expression (OE-OGFr) or over-expression negative control (OE-NC) plasmids. Subsequently, male BALB/c nude mice were randomized into Control, sh-NC, sh-OGFr, OE-NC, and OE-OGFr groups (n = 6). Measurement of tumour size weekly for four weeks, TUNEL staining for apoptosis, and immunohistochemistry were performed. In vitro, HepG2 cells were randomized into OE-NC, OE-OGFr, and OE-OGFr+NTX (100 μmol/L) groups, and sh-NC, sh-OGFr, sh-OGFr+sh-P21, and sh-OGFr+sh-P16 groups. Cell viability by CCK8 assay, cell proliferation by EDU staining, cell migration by cell scratch, and Western blot were performed. In vivo, sh-OGFr-transfected HepG2 cells increased tumour weight, volume, and Ki67 expression, decreased P21 and P16 expression, and did not affect apoptosis rate. But the effect of OE-OGFr in HepG2 cells was completely the opposite. In vitro, OE-OGFr inhibited HepG2 cells' viability, proliferation, and migration, and further NTX intervention reversed its inhibitory effects. The transfection of HepG2 cells with sh-OGFr+sh-P21 and sh-OGFr+sh-P16 further enhanced the cell proliferation and migration abilities compared to the sh-OGFr group. OGFr overexpression may inhibit HCC progression by activating P16 and P21 expression to inhibit cell proliferation and migration, thereby providing new potential targets for HCC treatment.

Defining “Giant” Mediastinal Tumors: Proposal of a New Clinical–Radiological Classification and Case Report

Background/Objectives: Mediastinal tumors, regardless of their location, can grow to significant sizes, causing compression-related symptoms. The term “giant” mediastinal tumor is inconsistently defined in the literature. This study presents a new clinical–radiological classification (CRC) for mediastinal tumors and evaluates its applicability through a systematic review and a detailed case analysis of a giant thymolipoma. Methods: A systematic review of the literature from the past decade was conducted using PubMed to identify relevant studies on “giant” mediastinal tumors. The inclusion criteria focused on studies involving adult patients with documented tumor size and symptomatology. The review identified 22 studies, with most anterior mediastinal tumors classified as CRC 3 (81%), indicating “giant” tumors. Thymolipomas accounted for 58% of these cases. Tumor volume and weight correlated with symptom severity, guiding surgical approaches. The proposed CRC effectively standardized the definition of “giant” tumors. The case analysis of a 6.84 kg thymolipoma highlighted the challenges of surgical resection, confirming the importance of tailored surgical strategies for large tumors. Conclusions: The novelty of the study lies mainly in the new clinical–radiological classification (CRC) of mediastinal tumors. This classification integrates clinical presentation and cross-sectional imaging findings, offering a standardized framework for tumor reporting. In addition, it provides a precise definition of “giant” mediastinal tumors. The findings emphasize the need for early surgical intervention to prevent severe symptoms and complications. This study also showcases the largest enbloc-resected thymolipoma reported in the recent literature, supporting the utility of the proposed classification in clinical practice.

Discovery of highly active kynureninases for cancer immunotherapy through protein language model.

Tailor-made enzymes empower a wide range of versatile applications, although searching for the desirable enzymes often requires high throughput screening and thus poses significant challenges. In this study, we employed homology searches and protein language models to discover and prioritize enzymes by their kinetic parameters. We aimed to discover kynureninases as a potentially versatile therapeutic enzyme, which hydrolyses L-kynurenine, a potent immunosuppressive metabolite, to overcome the immunosuppressive tumor microenvironment in anticancer therapy. Subsequently, we experimentally validated the efficacy of four top-ranked kynureninases under in vitro and in vivo conditions. Our findings revealed a catalytically most active one with a nearly twofold increase in turnover number over the prior best and a 3.4-fold reduction in tumor weight in mouse model comparisons. Consequently, our approach holds promise for the targeted quantitative enzyme discovery and selection suitable for specific applications with higher accuracy, significantly broadening the scope of enzyme utilization. A web-executable version of our workflow is available at seekrank.steineggerlab.com and our code is available as free open-source software at github.com/steineggerlab/SeekRank.

Doxycycline Restores Gemcitabine Sensitivity in Preclinical Models of Multidrug-Resistant Intrahepatic Cholangiocarcinoma

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA. Methods: We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models. Results: Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC50 ~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine. Conclusions: These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease.

Strengthening Effect of Thalidomide Combined with an Anti-PD1 Antibody on Enhancing Immunity for Lung Cancer Therapy.

Combining immune checkpoint inhibitors and antiangiogenic agents offers a promising strategy to counteract the cooperative promotion of solid tumor growth by immune checkpoints and intratumoral angiogenesis. We investigated the potential of thalidomide (THD) and anti-PD-1 antibody (PD-1 mAb) in suppressing tumor growth, enhancing immunity, and inhibiting angiogenesis. THD exhibited regulatory effects on PD-1 in CD4+ T cells and PD-L1 in cancer cells, along with tumor growth inhibition in A549 and Lewis lung carcinoma (LLC) cell lines. Combined with PD-1 mAb, THD increased intracellular IL-2 and IFN-γ expression in CD4+ T cells, enhanced granzyme (Gzm-B) expression in peripheral blood mononuclear cells (PBMCs), and reduced TNF-α expression in CD4+ T cells. In C57BL/6 mice, THD plus PD-1 mAb decreased LLC-derived lung tumor weight and volume, boosted CD8+ T cell infiltration in tumors, and reduced CD34+ intratumoral microvessel density. This study highlights THD's role in modifying the tumor microenvironment to enhance PD-1 mAb efficacy, proposing a clinically feasible approach for improving PD-1 mAb treatment outcomes.

Enhanced antitumor immunity in breast cancer: Synergistic effects of ADAM10/ADAM17 inhibition, metabolic modulation, and camptothecin-loaded selenium nanoparticles.

In this study, we investigate the impact of a multi-targeted therapeutic approach that includes camptothecin (CPT), a potent chemotherapeutic topoisomerase inhibitor; metformin (Met), a metabolic modulator with emerging anti-tumor effects; and GW280264X, an inhibitor of ADAM 10/ADAM 17 enzymes, which are associated with tumor invasion and immune response. The study aims to assess the combined effects of these agents in enhancing CD8+ T cell-mediated anti-tumor immunity and suppressing cancer cell growth in triple-negative breast cancer (TNBC) models, both in vitro and in vivo. Cell viability was performed on the 4T1 human TNBC cell line. Furthermore, we examined c-MYC protein expression by western blot, TOX and NR4A expression by Real-time PCR, and the number of CD8+ CD28+ T cells by immunofluorescence assay to demonstrate the anticancer effects of combined of CPT, Met and GW280264X in BC growth, exhaustion and senescence of T cells. Regarding cell viability, HA-Se@CPT+Met and HA-Se@CPT+Met+GW280264X treatments decreased 4T1 cell growth (p<0.001). Combination therapy of Met, HA-Se@CPT, and GW280264X significantly reduced tumor volume and weight in vivo. This treatment also increased the number of CD8+ CD28+ T cells in the tumor microenvironment (TME) of BC (p<0.0001) and decreased the expression of TOX and NR4A (p<0.0001, p<0.01). Furthermore, decreased expression of c-MYC as an oncogene protein was seen in the single and combined treatment by HA-Se@CPT and GW280264X (p<0.05). These findings suggest that of HA-Se@CPT, Met, and GW280264X may inhibit tumor progression in BC by improving the function and infiltration of CD8+ T cells. Their effect is more pronounced when used in combination.

An antigen/chemotherapy co-loaded DNA nanocube inserts into tumor cell plasma membrane and enhances chemo- and immunotherapy.

Breast cancer is the most frequently diagnosed female cancer. Combined chemo- and immunotherapies have been extensively explored to treat breast cancer. To improve the efficacy of the combined therapies, this study designed a hollow DNA nanocube with four cholesterol anchors (C2.2) that could be inserted into breast cancer cell plasma membrane. A model antigen-ovalbumin (OVA257-264) was further conjugated to C2.2 to construct C2.2-OVA and a model chemotherapy-Doxorubicin (DOX) was also loaded to C2.2-OVA to prepare DOX@C2.2-OVA for the combined chemo- and immunotherapy to treat breast cancer. C2.2, C2.2-OVA, and DOX@C2.2-OVA were successfully prepared and possessed square-like shape and small size. C2.2 and C2.2-OVA could be anchored in breast cancer cell plasma membrane for at least 10h. C2.2-OVA demonstrated the significantly higher activation rates of DC cells than free OVA. Although C2.2 showed no cytotoxicity, C2.2 increased the potency of 5-FU and carboplatin to MCF-7 and 4T1 breast cancer cells. DOX@C2.2-OVA treatment to 4T1 tumor in vivo showed the significant reduction of tumor size and weight, and resulted in more DCs and CD8+ T cells in 4T1 tumor. In summary, DOX@C2.2-OVA that could be inserted into tumor cell plasma membrane enhanced the combined chemo- and immunotherapy for the breast cancer treatment.

Longikaurin A, a natural ent-kaurane, suppresses proliferation, invasion and tumorigenicity in oral squamous cell carcinoma cell by via inhibiting PI3K/Akt pathway in vitro and in vivo.

Background: Longikaurin A (LK-A), a naturally occurring ent-kaurane diterpenoid, has been identified as a promising anti-cancer agent. This study aims to elucidate the anti-tumorigenic effects of LK-A on oral squamous cell carcinoma (OSCC) cells and to unravel its underlying mechanisms. Methods: In vitro assays, including CCK-8 and EdU, were performed to assess cell viability and proliferation. Transwell migration and invasion assays evaluated cell mobility and invasive potential. Apoptotic effects were analyzed using Annexin V-FITC/PI staining and TUNEL assays. Western blot analysis was conducted to examine protein expression related to cell cycle, apoptosis, and the PI3K/Akt signaling pathway. In vivo experiments involved treating mouse xenograft models with LK-A and evaluating tumor growth and signaling pathway inhibition through immunohistochemistry and Western blot assays. Results: LK-A significantly suppressed cell viability and proliferation in a dose-dependent manner, with IC50 values of 4.36 μM and 4.93 μM at 24 h, and 1.98 μM and 2.89 μM at 48 h for CAL27 and TCA-8113 cells, respectively. EdU assays revealed a reduction in the EdU positive rate, and cell cycle analysis showed G2/M phase arrest. Western blot analysis confirmed decreased expression of CyclinB1 and Cdc2. LK-A significantly inhibited OSCC cell mobility and invasive potential, with downregulation of MMP-2 and MMP-9 expression. Apoptotic effects were confirmed by increased apoptosis, upregulation of Bax and cleaved caspase-3, and downregulation of Bcl-2. LK-A suppressed the PI3K/AKT signaling pathway, as evidenced by reduced phosphorylation of PI3K, AKT, and mTOR. The AKT activator SC79 reversed the antiproliferative and pro-apoptotic effects of LK-A. In vivo, LK-A significantly inhibited tumor growth in mouse xenograft models, with reduced tumor weights and volumes, and no significant loss in body weight. Immunohistochemistry and Western blot assays confirmed the inhibition of p-Akt and Ki-67 expression. Conclusion: These findings suggest that LK-A exerts potent antiproliferative, anti-migratory, and pro-apoptotic effects on OSCC cells through the suppression of the PI3K/AKT signaling pathway, demonstrating its potential as a therapeutic agent for OSCC.

Anticancer effect of the antipsychotic agent penfluridol on epithelial ovarian cancer.

Chemoresistant-epithelial ovarian cancer (EOC) has a poor prognosis, prompting the search for new therapeutic drugs. The diphenylbutylpiperidine (DPBP) class of antipsychotic drugs used in schizophrenia has shown anticancer effects. This study aimed to investigate the preclinical efficacy of penfluridol, fluspirilene, and pimozide (DPBP) using in vitro and in vivo models of EOC. Human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with penfluridol, fluspirilene, and pimozide, and cell proliferation, apoptosis, and migration were assessed. The preclinical efficacy of DPBP was also investigated using in vivo mouse models, including cell lines and patient-derived xenografts (PDX) of EOC. DPBP drugs significantly decreased cell proliferation in chemosensitive (A2780, HeyA8, and SKOV3ip1) and chemoresistant (A2780-CP20, HeyA8-MDR, and SKOV3-TR) cell lines. Among these drugs, penfluridol exerted a relatively stronger cytotoxic effect on all cell lines. Penfluridol significantly increased apoptosis and inhibited migration of EOC cells. In the cell line xenograft mouse model with HeyA8, the penfluridol group showed significantly decreased tumor weight compared with the control group. In the paclitaxel-resistant model with HeyA8-MDR, the penfluridol group had significantly decreased tumor weight compared with the paclitaxel or control groups. Penfluridol exerted anticancer effects on the PDX model. Penfluridol exerted significant anticancer effects on EOC cells and xenograft models, including PDX. Thus, penfluridol therapy, as a drug repurposing strategy, might be a potential therapeutic for EOCs.

Circ_RPPH1 facilitates progression of breast cancer via miR-1296-5p/TRIM14 axis

ABSTRACT Circular RNA Ribonuclease P RNA Component H1 (circ_RPPH1) and microRNA (miRNA) miR-1296-5p play a crucial role in breast cancer (BC), but the molecular mechanism is vague. Evidence showed that miR-1296-5p can activate tripartite motif-containing 14 (TRIM14). Clinical indications of eighty BC patients were collected and the circ_RPPH1 expression was detected using real-time quantitative PCR. MCF-7 and MDA-MB-231 cells were transfected with overexpression or knockdown of circ_RPPH1, miR-1296-5p, or TRIM14. Cell counting kit-8, cell cloning formation, wound healing, Transwell, and flow cytometry assays were performed to investigate the malignant phenotype of BC. The dual-luciferase reporter gene analyses were applied to reveal the interaction between these target genes. Subcutaneous tumorigenic model mice were established with circ_RPPH1 overexpression MDA-MB-231 cells in vivo; the tumor weight and volume, levels of miR-1296-5 and TRIM14 mRNA were measured. Western blot and immunohistochemistry were used to detect TRIM14 in cells and mice. Circ_RPPH1 levels were notably higher in BC patients and have been found to promote cell proliferation, invasion, and migration of BC cells. Circ_RPPH1 altered cell cycle and hindered apoptosis. Circ_RPPH1 knockdown or miR-1296-5p overexpression inhibited the malignant phenotype of BC. Furthermore, miR-1296-5p knockdown reversed circ_RPPH1’s promotion effects on BC. Interestingly, TRIM14 overexpression counteracts the inhibitory effects of miR-1296-5p overexpression and circ_RPPH1 silencing on BC. Moreover, in BC tumor-bearing mice, circ_RPPH1 overexpression led to increased TRIM14 expression and facilitated tumor growth. Circ_RPPH1 enhanced BC progression through miR-1296-5p/TRIM14 axis, indicating its potential as a biomarker and therapeutic target in BC.

Effects of Antioxidant Amino Acids on Cancer Sarcopenia.

Cancer sarcopenia is highly prevalent in patients with advanced cancer, which is closely related to the disease prognosis. Overcoming cancer sarcopenia is important for cancer treatment. Cystine and theanine (CT), antioxidant amino acids, have been applied to the nutritional intervention of various diseases but their effects remain unclear on cancer sarcopenia. We attempt to examine the effect of CT on cancer sarcopenia. Both mouse and in vitro cachexia models showed that CT reduced oxidative stress, inhibited autophagy and apoptosis, improved oxidative phosphorylation and the suppression of high mobility group box-1 production, and improved sarcopenia and muscle maturity. When treated with 5-fluorouracil in a mouse cachexia model, tumor weight decreased but oxidative stress increased and muscle weight and muscle maturity were suppressed regardless of diet. However, in the CT group, oxidative stress was reduced and the exacerbation of sarcopenia by 5-fluorouracil was suppressed. Thus, in cancer cachexia, oxidative stress plays a major role in skeletal muscle damage, and CT, which has an anti-oxidative stress effect, has a strong protective effect on skeletal muscle. In the future, it will be important to conduct clinical studies on nutritional intervention for cancer sarcopenia using CT.

Knockdown of IGF2BP2 overcomes cisplatin-resistance in lung cancer through downregulating Spon2 gene

BackgroundCisplatin (DDP) resistance has long posed a challenge in the clinical treatment of lung cancer (LC). Insulin-like growth factor 2 binding protein 2 (IGF2BP2) has been identified as an oncogenic factor in LC, whereas its specific role in DDP resistance in LC remains unclear.ResultsIn this study, we investigated the role of IGF2BP2 on DDP resistance in DDP-resistant A549 cells (A549/DDP) in vitro and in a DDP-resistant lung tumor-bearing mouse model in vivo. Additionally, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted to identify the potential mRNAs regulated by IGF2BP2, an N6-methyladenosine (m6A) regulator, in the tumor tissues of mice. Compared to normal tissues, IGF2BP2 levels were increased in LC tissues and in relapsed/resistant LC tissues. Most importantly, IGF2BP2 levels were significantly higher in relapsed/resistant LC tissues than in LC tissues. Significantly, knockdown of IGF2BP2 or DDP treatment inhibited A549 cell viability, migration, and cell cycle progression. Consistently, DDP treatment suppressed the viability and migration and triggered cell cycle arrest in A549/DDP cells in vitro, as well as reduced tumor volume and weight of A549/DDP tumor-bearing mice; meanwhile, the combination of DDP and IGF2BP2 siRNA further significantly inhibited A549/DDP cell growth in vitro and in vivo compared to DDP treatment alone. Furthermore, MeRIP-seq data showed that IGF2BP2 downregulation remarkably elevated m6A levels of spondin 2 (Spon2) and reduced mRNA levels of Spon2 in tumor tissues from A549 tumor-bearing mice. Meanwhile, the combination of DDP and IGF2BP2 siRNA notably reduced Spon2 levels, as well as inhibited the viability and induced apoptosis in A549/DDP cells; however, these effects were reversed by Spon2 overexpression.ConclusionCollectively, downregulation of IGF2BP2 could overcome DDP resistance in LC through declining the Spon2 gene expression in an m6A-dependent manner. These results may provide a new strategy for overcoming DDP resistance in LC.

Drug-carrying properties and targeted delivery of biomimetic nanoparticles delivering wild baicalin and Adriamycin

The extensive application of biomaterials and nanotechnology in biomedical technology can enhance the drug-carrying performance and targeted therapeutic ability of drug nanoparticles. In the article, biomimetic nanoparticles of wild baicalin and adriamycin were prepared based on conventional means, and the drug release performance of SCU/DOX was analysed using drug release kinetics and the inhibitory effect of SCU/DOX nanoparticles on tumour cells. The nanoparticles were produced through nanotechnology after the main experimental scheme was prepared for the preparation of the basic medicine. At the same time, the study combines the biological electrical signal to obtain the value of the relevant measurement index. When the SCU/DOX nanodrug concentration was elevated from 10 μM to 16010 μM, the viability of mouse tumour cells was reduced from 82.54% to about 47.69%. This shows that nanoparticles can effectively deliver drugs. After the use of SCU drug alone and SCU/DOX nanoparticles, the IC50 values of both were 59.42 μM and 8.75 μM, respectively, with a reversal of resistance multiplier of 6.79-fold. Tumour cell treatment with SCU/DOX nanoparticles reduced the tumour volume from 15.1*102mm3 to 6.05*102mm3 and tumour weight by 64.14% in mice. The cumulative drug release from SCU/DOX nanoparticles was 11.18% at 2h, and higher than that of the esterase-free condition after 20h (17.61%). The data of the cumulative release of the drug show that the release of biomimetic nanoparticles can actually target the target. The unique quality of nanomaterials can allow drugs to release drugs in the set target environment. On the basis of this study, if clinical trials can also achieve good results, they are expected to be applied in practice. The preparation of baicalin and adriamycin mimetic nanoparticles based on the drug delivery system can enhance the drug-carrying property and target delivery effect of the drug, which can provide a reliable technical support to enhance the therapeutic effect of the disease.

The Discovery of a Novel AXL/Triple Angiokinase Inhibitor Based on 6-Chloro-Substituted Indolinone and Side Chain Methyl Substitution Inhibiting Pancreatic Cancer Growth and Metastasis.

In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor 11b by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that 11b potently inhibited AXL expression with the IC50 value of 3.75 nM and possessed similar inhibitory activity on KDR as Nintedanib. In the assay of antiproliferative activity on NIH/3T3, HUVEC, Bxpc-3, and MDA-MB-231, 11b showed better inhibitory ability than Nintedanib. In pancreatic cancer xenograft mouse models from Bxpc-3 cells, even when the dosage was halved, 11b exhibited better or comparable effects to Nintedanib (tumor growth inhibition (TGI) based on tumor volume change during the trial or tumor weight). Notably, we also found that 11b prohibited Bxpc-3 resulted lung metastasis by inhibiting its epithelial-mesenchymal transition (EMT) process. Another mechanism assay also proved that 11b inhibited the function of blood vessels and fibroblasts, promoted apoptosis of cancer and fibroblast cells, and exhibited low toxicity and good metabolic stability.

Rhodium complex [RhLI2]I: a novel anticancer agent inducing tumor inhibition and apoptosis

Numerous chemotherapeutic agents are currently employed in cancer treatment, but many are associated with significant side effects. This study aims to identify a novel anticancer drug that minimizes or eliminates these adverse effects. The anticancer activity of the Rhodium (III) complex cis-[RhLI2]I was evaluated through both in vivo and in vitro functional assays. Apoptosis in cancer cells post-treatment was assessed using microscopy and gene expression analysis. In cytotoxicity screening via the brine shrimp lethality bioassay, the compound exhibited an LC50 value of 25.90 µg/mL (P < 0.001). It also achieved an 88.96% inhibition of cell growth (P < 0.001), an 82.39% increase in lifespan (P < 0.001), and a significant reduction in tumor weight at a dosage of 200 µg/kg in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. Restoration of hematological parameters, such as RBC, WBC, and hemoglobin levels, was observed in treated tumor-bearing mice compared to untreated EAC-bearing mice. The compound inhibited the growth and proliferation of breast cancer (MCF7) cells in a dose-dependent manner, achieving a maximum inhibition of 88.9% at 200 µg/mL. Apoptotic induction in MCF7 cells occurred through the upregulation of p53, Bax, caspase-3, -8, and -9, alongside the downregulation of the anti-apoptotic protein Bcl-2. No long-term adverse effects on hematological or biochemical parameters or tissue levels were observed in the mice. Given these findings, this compound demonstrates significant cytotoxic effects and has the potential to serve as a promising chemotherapeutic agent, warranting further investigation at more advanced stages.

Indoleamine 2, 3-dioxygenase Regulates the Differentiation of T Lymphocytes to Promote the Growth of Gastric Cancer Cells through the PI3K/Akt/mTOR Pathway.

To investigate the regulatory mechanism of indoleamine 2, 3-dioxygenase (IDO) in T lymphocyte differentiation and its role in promoting the growth of gastric cancer (GC) cells through the PI3K/Akt/mTOR pathway. GC cell lines (MFC and NCI-N87) and PBMC cells were co-cultured and IDO inhibitor 1-methyl-tryptophan (1-MT) was added. The proliferation was detected by CCK-8, the apoptosis was detected by flow cytometry, and the contents of TNF-α, IL-1β, IL-6, IL-8, and INF-γ were detected by ELISA. The expression levels of PI3K, p-PI3K, Akt, p-Akt, mTOR, and p-mTOR were tested using Western blot, and the proportion of CD4+/CD8+, CD4+CD25+Foxp3+Treg cells was detected by flow cytometry. C57BL/6 mice were used to establish the MFC GC mouse model and treated with 1-MT. The changes in body weight and tumor diameter were measured. Ki-67, CD4+, CD8+, and CD25+ expressions were detected by immunohistochemistry. IDO promoted the proliferation of MFC and NCI-N87 cells, inhibited apoptosis, and decreased the levels of TNF-α, IL-1β, IL-6, IL-8, and INF-γ in the supernatant after co-culture with BPMC. The expressions of p-AKT, p-mTOR, and p-PI3K increased after 1-MT treatment. The proportion of CD4+/CD8+ cells was increased and the proportion of Treg cells was decreased in PBMC cells after the addition of 1-MT. Overexpression of IDO suppressed T cells differentiation by inhibiting the PI3K/Akt/mTOR pathway. In vivo, 1-MT treatment reduced the tumor size and weight, increased CD4+ and CD8+ positive area proportion, and decreased Ki-67 and CD25+ positive area proportion. Co-culture of GC cells and immune cells promotes the proliferation of GC cells and inhibits apoptosis, which can be reversed by 1-MT. IDO may suppress the proliferation of T lymphocyte through inhibiting the PI3K/Akt/mTOR signaling pathway. This provides new evidence for the potential of exploiting IDO inhibitors for GC treatment.

Investigation of the synergic effect of mocetinostat and capecitabine in a triple-negative breast neoplasms mouse model.

Combined administration of two or more drugs is emerging as a new strategy in triple-negative breast neoplasms. This is the first study to investigate the combination of the histone deacetylase inhibitor mocetinostat and the antimetabolite drug capecitabine in triple-negative mammary neoplasms in a preclinical mouse model. Thirty-five female mice were grouped into the control group, capecitabine group, mocetinostat group, and combined drugs group. At the end of the experimental period, body weight, and tumor weight were measured and tumor tissue and lung tissue were histologically examined. The results showed that the body weight of mice in the drug-treated groups was reduced by about 18%. Tumor weights were also reduced by 21% in the mocetinostat group, 27.5% in the capecitabine group, and 45% in the combined group. The combination of mocetinostat and capecitabine decreased the formation of tumors and metastases in lung tissue. In summary, the combination of mocetinostat and capecitabine was more effective than either drug alone in reducing the size of triple-negative breast neoplasms in a mouse model.

IGF2BP2 promotes lung adenocarcinoma progression by regulating LOX1 and tumor-associated neutrophils.

Lung adenocarcinoma (LUAD) is the common form of lung cancer and is prone to distant metastasis. IGF2BP2, an m6A modification regulator, is upregulated in lung cancer tissue, but its specific role within the LUAD tumor microenvironment (TME) is unknown. We explored the role of IGF2BP2 in the progression of LUAD. IGF2BP2 expression in LUAD patient specimens and controls was evaluated through bioinformatics, Western blot, and immunohistochemistry. LUAD subcutaneous and orthotopic xenograft tumor models were established, alongside a co-culture system of tumor-associated neutrophils (TANs) and A549 cells. Functional assays assessed IGF2BP2's role under treatment with JX5, an IGF2BP2 inhibitor. Mechanistic assays explored the interaction between IGF2BP2 and LOX1 in 293T cells. IGF2BP2 was significantly upregulated in LUAD tissues, with higher expression levels predicting worse prognosis for patients (p < 0.001). In subcutaneous and orthotopic xenograft models, treatment with JX5, an IGF2BP2 inhibitor, reduced tumor size, volume, and weight (p < 0.001). JX5 also significantly reduced the concentrations of pro-inflammatory cytokines in peripheral blood (p < 0.01 and p < 0.001). Flow cytometry analysis indicated JX5 reduced CD11b+Ly6G+/CD45+ cells (TANs) in the TME (p < 0.001). Mechanistically, JX5 downregulated LOX1 expression in vivo, and co-culture experiments further demonstrated that IGF2BP2 promotes LUAD progression through LOX1-mediated regulation of TAN activity (p < 0.01 and p < 0.001). Overexpression of LOX1 reversed the inhibitory effects of JX5 on TAN infiltration, tumor cell viability, and apoptosis (p < 0.01 and p < 0.001). Additionally, RNA immunoprecipitation revealed that IGF2BP2 binds to LOX1 mRNA at its m6A modification site, stabilizing LOX1 and enhancing its function in the TME. Knockdown of IGF2BP2 accelerated LOX1 mRNA degradation, confirming its role in maintaining LOX1 stability (p < 0.01 and p < 0.001). IGF2BP2 recognizes and stabilizes LOX1 through m6A modification, contributing to TAN-mediated LUAD progression. Overall, these findings offer new insights into LUAD progression and demonstrate that IGF2BP2 is a key regulator that promotes tumor advancement, highlighting the IGF2BP2-LOX1 axis as a potential therapeutic target for LUAD.

Interleukin-22 promotes endometrial carcinoma cell proliferation and cycle progression via ERK1/2 and p38 activation.

Endometrial carcinoma (EC) is one of the most common gynecological malignant tumors, but its underlying pathogenic mechanisms are largely obscure. Interleukin-22 (IL-22), one cytokine in the tumor immune microenvironment, was reported to be associated with carcinoma progression. Here, we aimed to investigate the regulation of IL-22 in endometrial carcinoma. Enzyme-linked immunosorbent assay (ELISA) analysis of IL-22 was done in 27 controls and 51 patients with EC. We examined the proliferative potential, cycle progression, and signaling pathways modulated by IL-22 in EC cells. Western blot analysis was performed to investigate the expression of proliferative and cycle-related proteins in EC cells. The effect of IL-22 mediated by interleukin-22 receptor alpha 1 (IL-22RA1) was examined using cell transfection with small interfering RNA (siRNA). In addition, a xenograft tumor model was performed to assess the effect of IL-22 in vivo. We demonstrated significant up-regulation of serum IL-22 concentrations in EC patients (42.59 ± 23.72pg/mL) compared to the control group (27.47 ± 8.29pg/mL). High levels of IL-22 concentrations appear to correlate with malignant clinicopathological features of EC. Treatment with IL-22 promoted cell proliferation and G1/S phase progression in Ishikawa and HEC-1B cells. Western blot analysis revealed that c-Myc, cyclin E1, cyclin-dependent kinase (CDK)2, cyclin D1, CDK4, CDK6, p-extracellular signal-regulated kinase1/2 (p-ERK1/2), and p-p38 were highly expressed in EC cells exposed to IL-22. Moreover, in the EC mice model, we found that giving exogenous IL-22 increased tumor volume and weight. Immunohistochemistry showed that intra-tumor Ki-67 expression was up-regulated upon IL-22 treatment. The IL-22-mediated changes in cell proliferation, cycle progression, and protein expression can be effectively inhibited by the ERK1/2 inhibitor U0126 and the p38 inhibitor SB202190. In addition, the role of IL-22 in EC is receptor-dependent. Our findings suggest that IL-22 promotes endometrial carcinoma cell proliferation and G1/S phase progression by activating ERK1/2 and p38 signaling. Therefore, IL-22 may represent a potential therapeutic target for the treatment of endometrial carcinoma.

Discrimination of T-stage using tumor weight and size - a potential approach to guide perioperative decision making in patients with bladder cancer.

To examine the value of tumor size, weight, and density in predicting pathological tumor stage in patients with suspected bladder cancer (BCa), minimize interobserver variability of estimated tumor size, and thus provide a more objective instrument to describe the extent of local tumor growth. An institutional dataset of 588 consecutive patients undergoing TUR-BT for suspected BCa from 05/2016 - 09/2018 was used. Separate Mann-Whitney-U tests examined differences in each unit between non-muscle-invasive (NMIBC) and muscle-invasive BCa (MIBC) and between Ta/CIS and T1 NMIBC. Intraoperative tumor size, weight, and respective density were calculated. We then calculated multivariable logistic regression models to examine each unit's predictive value and distinguish between endpoints. Overall, 367 patients undergoing TUR-BT were diagnosed with BCa. In patients with MIBC (n=73), the median size (p<0.001) and weight (p<0.001) were higher compared to NMIBC. In contrast, tumor density (p<0.001) was lower. On multivariable analysis, increasing size and weight were associated with higher odds of T1 (size: OR 2.50, 95%CI 1.87-3.35; weight: OR 1.65, 95%CI 1.26-2.15) and muscle-invasive disease (size: OR 1.51, 95%CI 1.29-1.78; weight: OR 1.09, 95%CI 1.03-1.15). Meanwhile, an increasing density was associated with lower odds of both outcomes (T1:OR 0.96, 95%CI 0.89-1.02; MIBC: OR 0.81, 95%CI 0.69-0.96). In patients diagnosed with BCa, tumor size, and weight showed similar predictive power concerning T1 NMIBC and MIBC. Tumor density failed to predict the local tumor stage sufficiently. These results may lay the foundation for improving objective measurement of the local tumor burden in patients with BCa and may help guide further immediate treatment decisions.