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Glioblastomas are the most aggressive type of brain tumour, with poor prognosis even after standard treatment such as surgical resection, temozolomide and radiation therapy. The overexpression of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) in glioblastomas is recognized as an important treatment target. Thus, an urgent need regarding glioblastomas is the development of a new, suitable agent that may show potential for the inhibition of extracellular signal‐regulated kinase (ERK)/NF‐κB–mediated glioblastoma progression. Imipramine, a tricyclic antidepressant, has anti‐inflammatory actions against inflamed glial cells; additionally, imipramine can induce glioblastoma toxicity via the activation of autophagy. However, whether imipramine can suppress glioblastoma progression via the induction of apoptosis and blockage of ERK/NF‐κB signalling remains unclear. The main purpose of this study was to investigate the effects of imipramine on apoptotic signalling and ERK/NF‐κB–mediated glioblastoma progression by using cell proliferation (3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide [MTT] assay), flow cytometry, Western blotting, and cell invasion/migration assay analysis in vitro. The ERK and NF‐κB inhibitory capacity of imipramine is detected by NF‐κB reporter gene assay and Western blotting. Additionally, a glioblastoma‐bearing animal model was used to validate the therapeutic efficacy and general toxicity of imipramine. Our results demonstrated that imipramine successfully triggered apoptosis through extrinsic/intrinsic pathways and suppressed the invasion/migration ability of glioblastoma cells. Furthermore, imipramine effectively suppressed glioblastoma progression in vivo via the inhibition of the ERK/NF‐κB pathway. In summary, imipramine is a potential anti‐glioblastoma drug which induces apoptosis and has the capacity to inhibit ERK/NF‐κB signalling.

Addressing the challenges of identifying suitable targets and effective delivery strategies is critical in pursuing therapeutic solutions for glioblastoma (GBM). This study focuses on the therapeutic potential of microRNA-124 (miR-124), known for its tumor-suppressing properties, by investigating its ability to target key oncogenic pathways in GBM. The results reveal that CDK4 and CDK6—cyclin-dependent kinases that promote cell cycle progression—are significantly overexpressed in GBM brain samples, underscoring their role in tumor proliferation and identifying them as critical targets for miR-124 intervention. However, delivering miRNA-based therapies remains a major obstacle due to the instability of RNA molecules and the difficulty in achieving targeted, efficient delivery. To address these issues, this research introduces an innovative, non-viral dual-gene delivery platform that utilizes umbilical cord mesenchymal stem cells (UMSCs) and their exosomes to transport miR-124 and programmed cell death protein-1 (PD-1). The efficacy of this dual-gene delivery system was validated using an orthotopic GBM model, which closely mimics the tumor microenvironment seen in patients. Experimental results demonstrate that the UMSC/ miR-124-PD-1 complex and its exosomes successfully induce apoptosis in GBM cells, significantly inhibiting tumor growth. Notably, these treatments show minimal cytotoxic effects on normal glial cells, highlighting their safety and selectivity. Moreover, the study highlights the immunomodulatory properties of UMSC/ miR-124-PD-1 and its exosomes, enhancing the activation of immune cells such as T cells and dendritic cells, while reducing immunosuppressive cells populations like regulatory T cells and myeloid-derived suppressor cells. The orchestrated dual-gene delivery system by UMSCs and exosomes showcased targeted tumor inhibition and positive immune modulation, emphasizing its potential as a promising therapeutic approach for GBM.

Background The persistent activation of the epidermal growth factor receptor (EGFR) leads to the activation of downstream oncogenic kinases and transcription factors, resulting in tumor progression and an increased resistance to cisplatin in bladder cancer (BC) cells. Lenvatinib, an oral multikinase inhibitor, has the potential to offer therapeutic benefits as an adjuvant treatment for BC patients. The investigation into its application in bladder cancer treatment is a valuable endeavor. The primary goal of this study is to confirm the effectiveness and mechanism of lenvatinib in inhibiting the progression of BC and enhancing the anticancer efficacy of cisplatin. Materials Three BC cell lines, namely, TSGH-8301, T24, and MB49, along with an MB49-bearing animal model, were utilized in this study. Results In vitro experiments utilizing MTT assays demonstrated that lenvatinib sensitized BC cells to cisplatin, exhibiting a synergistic effect. Flow cytometry indicated apoptotic events and signaling, presenting that lenvatinib effectively induced apoptosis and triggered extrinsic/intrinsic apoptotic pathways. In vivo studies using a mouse model of BC confirmed the antitumor efficacy of lenvatinib, demonstrating significant tumor growth suppression without inducing toxicity in normal tissues. Western blotting analysis and immunohistochemistry stain revealed EGF-phosphorylated EGFR and EGFR-mediated ERK/P38/NF-κB signaling were suppressed by treatment with lenvatinib. In addition, lenvatinib also suppressed anti-apoptotic (MCL1, c-FLIP, and XIAP) and metastasis-related factors (Twist, Snail-1, ZEB-1, ZEB-2, and MMP9) and promoted epithelial markers (E-cadherin) while reducing mesenchymal markers (N-cadherin). Conclusion In conclusion, the induction of apoptosis and the inhibition of EGFR/ERK/P38/NF-κB signaling are correlated with lenvatinib’s ability to hinder tumor progression and enhance the cytotoxic effects of cisplatin in bladder cancer. These findings underscore the potential of lenvatinib as a therapeutic option for bladder cancer, either as a standalone treatment or in combination with cisplatin.

Amentoflavone has been shown to be effective against a variety of cancer cells, but its role in bladder cancer remains unclear. Thus, the aim of this study is to evaluate whether amentoflavone may induce toxicity effect of bladder cancer. Herein, we evaluated amentoflavone effects in a human bladder cancer cell line TSGH8301 in vitro. Amentoflavone caused significant cytotoxicity in TSGH8301 cells at a concentration as low as 200 μM. FAS/FASL-dependent extrinsic apoptosis and mitochondria-dependent intrinsic apoptosis were observed in amentoflavone-treated cells in a dose-dependent manner. Levels of several proapoptotic proteins, such as FAS, FAS-ligand and BAX (B-cell lymphoma 2 associated X) were increased following amentoflavone treatment. Meanwhile, anti-apoptotic MCL-1 (myeloid cell leukemia sequence 1) and cellular FLICE-inhibitory protein (C-FLIP) protein levels were reduced. Additionally, angiogenesis and proliferation-related proteins, including matrix metalloproteinase (MMP)-2, -9, vascular endothelial growth factor (VEGF), urokinase-type plasminogen actvator (uPA) and cyclin D1 were diminished by amentoflavone. Amentoflavone induced toxicity of bladder cancer by inhibiting tumor progression and inducing apoptosis signaling transduction.

Temozolomide (TMZ) monotherapy is known to be insufficient for resistant/relapsed glioblastoma (GBM), thus seeking a sensitization agent for TMZ is necessary. It was found that regorafenib may improve the overall survival of relapsed GBM patients. We aimed to discover whether regorafenib can enhance the anti-GBM effects of TMZ, and elucidate underlying mechanism. Our analysis of The Cancer Genome Atlas database revealed that the increased expression of CXCR4 is linked to poor survival of GBM patients. Additionally, TMZ treatment may trigger CXCR4/CXCL12 axis of GBM. We used two GBM cell lines, two primary GBM cells, and animal model to identify underlying mechanism and treatment efficacy of regorafenib combined with TMZ by cytotoxicity, apoptosis, reporter gene and invasion/migration assays, chemokine array, Western blotting, MRI, microarray, and immunohistochemistry. We observed that the chemokine CXCL-12 and its receptor CXCR4 regulate the resistance to TMZ, whereas the inhibition of CXCL-12/CXCR4 signaling sensitizes GBM cells to TMZ. The TMZ-induced CXCL-12/CXCR4 signaling, phosphor-extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), and NF-κB-related proteins can effectively diminish when combining with regorafenib. Regorafenib significantly enhanced the TMZ-induced extrinsic/intrinsic apoptotic pathways, and facilitated the suppression of invasion and migration potential in GBM. Orthotopic tumor experiments demonstrated tumor size reduction and prolonged survival in combination group even with half-dose of TMZ. Our findings provide promising evidence that regorafenib may sensitize GBM to TMZ treatment through inhibition of the CXCL12/CXCR4/ERK/NF-κB signaling.

Nab‐paclitaxel (Abraxane), which is a nanoparticle form of albumin‐bound paclitaxel, is one of the standard chemotherapies for pancreatic ductal adenocarcinoma (PDAC). This study determined the effect of Abraxane in combination with a fusion protein, hIL15‐ABD, on subcutaneous Panc02 and orthotopic KPC C57BL/6 murine PDAC models. Abraxane combined with hIL15‐ABD best suppressed tumour growth and produced a 40%–60% reduction in the tumour size for Panc02 and KPC, compared to the vehicle group. In the combination group, the active form of interferon‐γ (IFN‐γ)‐secreting CD8+ T cells and CD11b+CD86+ M1 macrophages in tumour infiltrating lymphocytes (TILs) were increased. In the tumour drainage lymph nodes (TDLNs) of the combination group, there was a 18% reduction in CD8+IFN‐γ+ T cells and a 0.47% reduction in CD4+CD25+FOXP3+ regulatory T cells, as opposed to 5.0% and 5.1% reductions, respectively, for the control group. Superior suppression of CD11b+GR‐1+ myeloid‐derived suppressor cells (MDSCs) and the induction of M1 macrophages in the spleen and bone marrow of mice were found in the combination group. Abraxane and hIL15‐ABD effectively suppressed NF‐κB‐mediated immune suppressive markers, including indoleamine 2,3‐dioxygenase (IDO), Foxp3 and VEGF. In conclusion, Abraxane combined with hIL15‐ABD stimulates the anticancer activity of effector cells, inhibits immunosuppressive cells within the tumour microenvironment (TME) of PDAC, and produces a greater inhibitory effect than individual monotherapies.

Amentoflavone, an effective compound derived from medicinal plants, has been shown to boost therapeutic efficacy of chemotherapy in non-small cell lung cancer (NSCLC). However, anti-NSCLC effect of amentoflavone is ambiguous. The major purpose of the present study was to verify the inhibitory effects of amentoflavone in NSCLC cells. The effects of amentoflavone on growth and invasion of NSCLC CL-1-5-F4 cells were evaluated by cell viability assay, flow cytometry, colony formation assay, nuclear factor-kappa B (NF-κB) reporter gene assay, immunofluorescence staining, transwell invasion, and western blot assay. Amentoflavone effectively induced cell growth inhibition, G1 cell-cycle arrest, apoptosis, and suppression of invasion. Furthermore, amentoflavone not only triggered expression of p27, cleaved caspase-3, -8 also reduced NF-κB signaling, protein levels of matrix metalloproteinase (MMP)-2, -9, Cyclin-D1, and vascular endothelial growth factor (VEGF). Cell-cycle arrest, apoptosis induction, NF-κB signaling inhibition are associated with amentoflavone-inhibited growth and invasion of NSCLC cells.

Background/Aim: Radiation therapy (RT) for head and neck cancer may cause severe radiation dermatitis (RD) resulting in RT interruption and affecting disease control. A few studies address skin moisture changes during RT for head and neck cancer. The purpose of this study was to explore the effect of moisturized skin care (MSC) on severity of RD. Patients and Methods: The study includes newly diagnosed head and neck cancer patients undergoing RT. Participants were divided into MSC group and routine skin care (RSC) group based on patient’s preferred decision. Skin moisture in the four quadrants of the neck was measured weekly before and after RT. RD was assessed with the Radiation Induced Skin Reaction Assessment Scale (RISRAS) and the Radiation Therapy Oncology Group (RTOG) acute skin toxicity grading criteria. Results: A total of 54 patients were enrolled, of which 49 patients were suitable for the statistical analysis. There was a statistically significant difference in the RISRAS total score since the 5th week after RT between the groups. The severity of RD was less (B=0.814, p=0.021) and the onset was later (B=−0.384, p=0.006) in the MSC group when compared to the RSC group. Skin moisture decreased with cumulative radiation dose. In the upper neck, the MSC group had a slower rate of skin moisture decrease compared to the RSC group (right upper neck: B=0.935, p=0.007; left upper neck: B=0.93, p=0.018). Conclusion: MSC can effectively reduce the severity and delay the onset of RD, while slows down skin moisture decrease during RT.

Hepatocellular carcinoma (HCC) is a primary liver cancer with limited treatment options and poor prognosis. Regorafenib, a multi-kinase inhibitor, has shown promise in HCC treatment; however, its efficacy can be enhanced by combining it with other agents. 18β-glycyrrhetinic acid (18β-gly) is a natural compound with potential anti-cancer properties. The toxicity and mechanism of regorafenib and 18β-gly was assessed on Hep3B cells, Huh7 cells, and Hep3B bearing animal model. The combination of regorafenib and 18β-gly exhibited synergistic toxicity in HCC cells and animal model. Importantly, no significant differences in body weight or major tissue damage were observed after treatment with the combination of two drugs. Furthermore, the combination treatment modulated apoptosis-related markers and the mTOR signaling pathway. The study provides evidence for the synergistic effect of 18β-gly and regorafenib in a HCC model. The combination treatment modulated apoptosis-related markers and the mTOR signaling pathway, highlighting potential mechanisms underlying its therapeutic efficacy.

Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular signal-regulated kinases (ERK) in HCC; however, protein kinase B (AKT) was not affected by it. Targeting AKT in combination with sorafenib could be an important breakthrough point of HCC treatment. Many herbal compounds and composite formulas have been shown to enhance anti-HCC activity of sorafenib. Magnolol is a bioactive compound extracted from the bark of the Magnolia officinalis and has been shown to induce apoptosis and inhibit cell invasion in HCC in vitro. However, whether magnolol sensitizes HCC to sorafenib is ambiguous. In this study, we indicated that magnolol significantly enhanced sorafenib-diminished tumor cell growth, expression of anti-apoptotic proteins, and migration/invasion ability compared to sorafenib alone. Magnolol significantly boosted sorafenib-induced extrinsic/intrinsic dependent apoptosis pathways in HCC. Notably sorafenib could not reduce protein level of AKT (Ser473), but expression of AKT (Ser473) was significantly decreased by magnolol or magnolol combined with sorafenib. LY294002 as specific AKT inhibitor was used to confirm that AKT inactivation may promote anticancer effect of sorafenib. Taken together, AKT inhibition is associated with magnolol-enhanced the therapeutic effect of sorafenib in HCC. We suggested magnolol as the potential adjuvant which may enhance therapeutic benefits of sorafenib in patients with HCC.