TL;DR
HHT and Tan IIA combined therapy synergistically suppressed lymphoma progression by downregulating the Akt/MMP signaling pathway, suggesting their use in treating lymphomas.
T-cell lymphoma (TCL) is a malignant tumor caused by abnormal proliferation of T cells, and its specific pathogenesis remains unclear. Currently, there is still a lack of highly effective therapeutic agents in clinic. As a semi-terpene lactone compound, Alantolactone (ATL) is mainly used to treat diseases such as asthma, and its role in TCL has not been revealed. Here we systematically demonstrated that ATL not only significantly inhibits proliferation, migration, and induces apoptosis in TCL cells in vitro, but also exhibits significant anti-tumor effects in TCL cell line xenograft models with no obvious drug toxicity. Notably, ATL markedly enhance the sensitivity of TCL cells to first-line chemotherapeutic agents such as decitabine. Mechanistically, multi-omics analysis confirmed that ATL restricts TCL progression by negatively regulating the PI3K/AKT and ERK signaling pathway. Additionally, our study also found that ATL-mediated suppression of these pathways leads to significant downregulation of CD47 expression through reducing transcriptional factor c-Myc levels, which in turn enhance the phagocytosis of TCL cells by macrophages. It underscores the potential application of ATL in the immunotherapy of TCL. In summary, our study elucidates that ATL exhibits significant anti-TCL effects both in vitro and in vivo, suggesting its potential as a novel clinical strategy for the treatment of TCL.
INTRODUCTION Glioblastoma multiforme is an extremely deadly, aggressive primary brain tumor, distinguished by poor prognosis, and the rapid development of resistance to temozolomide might be the cause of low survival. Novel adjunctive strategies are needed to enhance therapeutic efficacy. Mumio (Shilajit), rich in fulvic acid and bioactive compounds, has shown antioxidant and anticancer effects, but its role in glioblastoma remains unclear. This study evaluated its anticancer potential and its ability to enhance temozolomide efficacy. METHODS Mumio extract was tested in U87 (sensitive) and LN-18 (resistant) glioblastoma cell lines. Cell viability and clonogenicity were assessed by MTT and colony formation assays. Fluorescent staining evaluated mitochondrial function, reactive oxygen species, and lipid accumulation. Western blotting analyzed apoptotic (PARP, Caspase-3, PTEN), ferroptosis-related (NRF2, FTH1), and Akt signaling proteins. Combination treatments were also examined. RESULTS Mumio reduced cell viability in a dose- and time-dependent manner, with stronger effects in U87 cells. It increased reactive oxygen species, disrupted mitochondrial function, and induced apoptosis, as shown by increased cleaved PARP and Caspase-3. Ferroptosis-related changes, including reduced FTH1 in LN-18 cells, were observed. Mumio also enhanced temozolomide-induced cytotoxicity and reduced clonogenic survival. DISCUSSION These findings suggest that Mumio exerts anticancer effects through oxidative stress-mediated apoptosis and modulation of ferroptosis pathways. Its ability to enhance temozolomide efficacy, particularly in resistant cells, indicates a potential role in overcoming chemoresistance. CONCLUSION Mumio triggers apoptosis in glioblastoma cells and induces changes consistent with ferroptosis, while also chemosensitizing cells to temozolomide, suggesting its potential use alongside standard therapy.
Fibrosarcoma is a rare and aggressive soft tissue sarcoma with limited therapeutic options and poor outcomes in advanced disease. Family with sequence similarity 111 member B (FAM111B) has emerged as a pro-tumorigenic factor associated with dysregulated cell survival and proliferation. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits anticancer activity in multiple malignancies, but its effects on FAM111B expression and downstream pathways in fibrosarcoma remain unclear. The effects of CBD were evaluated in human fibrosarcoma (HT1080) cells and non-cancerous human fibroblasts (FG0). Cell metabolic activity was assessed using an MTT assay. Gene and protein expression were determined by real-time quantitative PCR and Western blotting, respectively. Apoptosis and cell-cycle distribution were assessed by flow cytometry using Annexin V-FITC/propidium iodide (PI) and PI staining alone, respectively. Statistical analyses were performed using an unpaired Student’s t-test or a two-way analysis of variance (ANOVA) followed by Šídák’s post hoc multiple comparisons test, as appropriate. CBD reduced metabolic activity in both HT1080 and FG0 cells in a dose-dependent manner, with comparable IC₅₀ values (28.95 ± 3.15 µM and 30.75 ± 9.12 µM, respectively), indicating limited selectivity based on metabolic activity alone. CBD significantly reduced FAM111B mRNA expression by approximately 3-fold in HT1080 cells and 2-fold in FG0 cells; however, a significant reduction in FAM111B protein expression was observed only in HT1080 cells, CBD treatment was associated with marked downregulation of BAG3 and Cyclin B1 proteins, increased apoptosis (Annexin V-positive cells: 3.55 ± 0.78% vs. 13.20 ± 4.56%), and altered cell-cycle progression characterized by increased Sub-G1 (3.44 ± 1.10% vs. 18.37 ± 0.83%) and G0/G1 (28.30 ± 1.57% vs. 39.17 ± 0.85%) populations, with corresponding reductions in the S- and G2/M-phase populations. These effects were markedly attenuated in non-cancerous fibroblasts. CBD exerts context-dependent anticancer effects in HT1080 fibrosarcoma cells by selectively suppressing FAM111B protein expression, promoting apoptosis, and disrupting cell-cycle progression. These findings identify FAM111B- and BAG3-associated pathways as potential therapeutic vulnerabilities and support further investigation of CBD as a modulator of stress-adaptive and proliferative signaling in preclinical fibrosarcoma models.
DA elicits a biphasic cellular response in U937 leukemia cells, characterized by transient cytoprotective autophagy followed by apoptotic cell death mediated through dysregulation of Bcl-2/Bax and suppression of the PI3K/Akt pathway, indicating that DA is a promising candidate for novel antileukemic therapeutic strategies.
Cancer progression involves intricate interactions between inflammatory signaling, programmed cell death mechanisms, and oxidative stress. Although enoxaparin is widely used for managing cancer-associated thrombosis, its direct cellular effects on tumor biology remain insufficiently characterized. This study aimed to evaluate the impact of enoxaparin on apoptosis, autophagy, inflammatory mediators, and oxidative DNA damage in breast (MDA-MB-231) and liver (HepG2) cancer cell lines. MDA-MB-231, HepG2, and non-cancerous HEK-293 cells were treated with varying concentrations (5, 10, 20, 40, and 80 mg/mL) of enoxaparin for 24 and 48 h. Cell viability was assessed using the MTT assay, while apoptosis was quantified by TUNEL analysis. Immunofluorescence staining was employed to evaluate the expression of NF-κB, IL-6, TNF-α, LC3, and p62. Oxidative DNA damage was determined by measuring extracellular 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels using a competitive ELISA. Statistical analyses were conducted to compare the treated and control groups. Enoxaparin significantly reduced cell viability in MDA-MB-231 and HepG2 cells without inducing cytotoxicity in HEK-293 cells. Apoptosis was markedly increased in both cancer cell lines following treatment. Enoxaparin differentially modulated inflammatory signaling; NF-κB expression was significantly increased in MDA-MB-231 cells, accompanied by suppression of IL-6 and TNF-α, whereas no significant inflammatory changes were observed in HepG2 cells. Enoxaparin treatment was observed to increase LC3 and p62 expression in both MDA-MB-231 and HepG2 cells, triggering autophagy-related pathways. Moreover, enoxaparin significantly reduced extracellular 8-OHdG levels, suggesting a reduction in oxidative DNA damage. Enoxaparin exhibits multifaceted anticancer effects by promoting apoptosis and autophagy, selectively modulating inflammatory pathways, and reducing oxidative DNA damage in breast and liver cancer cells.
Leukemia remains a challenging hematological malignancy, particularly due to treatment resistance and the limited availability of therapies that selectively target cancer cells. Helminth-derived cysteine protease inhibitors (stefins) are mainly known for their roles in host–parasite interactions, but their effects on cancer cells have not been well explored. In this study, we investigated the biological activity of recombinant Fasciola gigantica Stefin-1 (rFgStefin-1) in the human U937 leukemic cell line. Treatment with rFgStefin-1 reduced cell viability in a dose- and time-dependent manner, with an IC₅₀ of approximately 11 µM at 48 h. In contrast, normal peripheral blood mononuclear cells (PBMCs) showed minimal changes under the same conditions. Flow cytometry analysis demonstrated increased apoptotic cell populations together with mitochondrial membrane depolarization following rFgStefin-1 treatment. At the molecular level, rFgStefin-1 treatment was associated with an increased BAX/BCL-2 ratio, increased cleaved caspase-3 expression, reduced AKT-associated signaling, and enhanced PARP cleavage. These findings were supported by both qRT-PCR and Western blot analyses. Overall, these results suggest that rFgStefin-1 promotes apoptosis in leukemic cells while exerting limited effects on normal cells under the tested conditions. Further studies are required to clarify the underlying molecular mechanisms and to evaluate the effects of rFgStefin-1 in additional leukemia models and in vivo systems.
