Search Results (236)

The ataxia–telangiectasia-mutated (ATM) protein plays a crucial role in the DNA damage response, particularly in the homologous recombination (HR) pathway. This study aimed to assess the impact of deleterious ATM variants on homologous recombination deficiency (HRD) and response to PARP inhibitors (PARPi) in melanoma patients, using a cell line established from melanoma tissue of a patient carrying the c.5979_5983del germline ATM variant. Despite proven loss of heterozygosity, lack of ATM activation, and HRD, our model did not show sensitivity to PARPi. We assessed the potential contribution of the Schlafen family member 11 (SLFN11) helicase, whose expression is inversely correlated with PARPi sensitivity in other cancers, to the observed resistance. The ATM mutant cell line lacked SLFN11 expression and featured hypermethylation-mediated silencing of the SLFN11 promoter. While sensitive to the ATR inhibitor (ATRi), the addition of ATRi to PARPi was unable to overcome the resistance. Our findings suggest that ATM mutational status and HRD alone do not adequately account for variations in sensitivity to PARPi in our model. A comprehensive approach is essential for optimizing the exploitation of DNA repair defects and ultimately improving clinical outcomes for melanoma patients. Full article

BGP-15, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor exerts cardioprotective effects; however, the underlying mechanisms remain unclear. Therefore, our study aimed to investigate the effects of BGP-15 on the imatinib (Imtb)-induced cardiac inflammation at the biochemical level. Male rats were divided to control, Imtb-treated (60 mg/kg/day for 14 days), and Imtb + BGP-15-treated animals. In this group Imtb was co-administered with BGP-15 at the dose of 10 mg/kg/day. At the end of the experiment, nuclear factor-kappa B/p65 (NF-κB/p65), nuclear transcription factor erythroid-2 related factor (Nrf2), heme oxygenase-1 (HO-1), high mobility group box 1 (HMGB1), and myeloperoxidase (MPO) were measured by Western blot. Chemokine and interleukins (ILs) were determined by Legendplex. Additionally, cardiac specific changes were visualized by immunohistochemistry. We demonstrated that Imtb increased NF-κB/p65, IL-6, IL-1β, IL-18, MCP-1, HMGB1, as well as the expression and activity of MPO. Conversely, the expressions of antioxidant Nrf2 and HO-1 were decreased. Administration of BGP-15 effectively mitigated these inflammatory alterations by significantly reducing pro-inflammatory cytokines and MPO activity, while simultaneously restoring and enhancing the levels of Nrf2 and HO-1, thereby promoting antioxidant defenses. The immunohistochemical staining further supported these biochemical changes. Our study provides new and comprehensive biochemical insight for managing Imtb-induced inflammatory responses via BGP-15-induced PARP1 inhibition. Full article

Background: As a pivotal point for the development of liver diseases, liver fibrosis (LF) is closely associated with cellular senescence and ferroptosis. However, there is a lack of effective markers that accurately predict LF status. This study aims to identify key genes involved in LF through bioinformatics analysis and experimental validation. Methods: We used bioinformatics analysis of Gene Expression Omnibus (GEO) data to investigate the gene functions, prognostic value, and immune associations of characteristic genes in LF. Functional enrichment analysis of DEGs was performed using GO and KEGG. Immune cell types and their proportions were estimated with CIBERSORTx. In addition, we analyzed the role of NQO1 in LF using IHC, WB, PCR, and flow cytometry. Results: Bioinformatics analysis identified 10 hub genes, including AR, CDKN1A, GJA1, CTSB, HIF1A, HMGB1, NQO1, PARP1, PTEN, and TXN. Among them, NQO1 was strongly correlated with immune cell activity. Experimental validation confirmed that NQO1 is upregulated and promotes αSMA and COL1A1 expression in hepatic stellate cells (HSCs). Knockdown of NQO1 significantly affected the proliferation of HSCs. Conclusions: NQO1 plays a critical role in HSC senescence and ferroptosis, promoting HSC activation and contributing to LF progression. Our findings suggest that NQO1 may serve as a potential biomarker for LF. Full article

Eliciting DNA damage in tumor cells continues to be one of the most successful strategies against cancer. This is the case for classical chemotherapy drugs and radiotherapy. In the modern era of personalized medicine, this strategy tries to identify specific vulnerabilities found in each patient’s tumor, to inflict DNA damage in certain cell contexts that end up in massive cancer cell death. Cells rely on multiple DNA repair pathways to fix DNA damage, but cancer cells frequently exhibit defects in these pathways, many times being tolerant to the damage. Key vulnerabilities, such as BRCA1/BRCA2 mutations, have been exploited with PARP inhibitors, leveraging synthetic lethality to selectively kill tumor cells and improving patients’ survival. In the DNA damage response (DDR) network, kinases ATM, ATR, Chk1, and Chk2 coordinate DNA repair, cell cycle arrest, and apoptosis. Inhibiting these proteins enhances tumor sensitivity to DNA-damaging therapies, especially in DDR-deficient cancers. Several small-molecule inhibitors targeting ATM/Chk2 or ATR/Chk1 are currently being tested in preclinical and/or clinical settings, showing promise in cancer models and patients. Additionally, pharmacological blockade of ATM/Chk2 and ATR/Chk1 axes enhances the effects of immunotherapy by increasing tumor immunogenicity, promoting T-cell infiltration and activating immune responses. Combining ATM/Chk2- or ATR/Chk1-targeting drugs with conventional chemotherapy, radiotherapy or immune checkpoint inhibitors offers a compelling strategy to improve treatment efficacy, overcome resistance, and enhance patients’ survival in modern oncology. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant efficacy in treating BRCA-mutated cancers; however, a significant proportion of patients fail to respond. Emerging evidence highlights the role of PARP in lipid metabolism, suggest-ing its modulation as a novel strategy to regulate tumor progression. Methods: In this study, lipidomics and transcriptomics analyses were conducted to elucidate the mechanisms underlying PARP inhibitor-induced ferroptosis and immune modulation in triple-negative breast cancer (TNBC). Results: We demonstrated that the PARP inhibitor Niraparib significantly reprograms lipid metabolism in TNBC cells, marked by elevated phosphatidylethanolamine (PE) and cholesterol ester (ChE) levels. This metabolic shift was mechanistically linked to upregulation of the cholesterol transporter NPC1L1 via the PARP1-RELA-NPC1L1 signaling axis, which subsequently activated the AKT pathway. Combinatorial treatment with Niraparib and either Ezetimibe (an NPC1L1 inhibitor) or AZD5363 (an AKT inhibitor) synergistically enhanced TNBC cell death by promoting ferroptosis through glutathione depletion and lipid peroxidation. Furthermore, NPC1L1 inhibition amplified PARP inhibitor-induced immune responses, increasing CD8⁺ T cell infiltration and cytotoxicity in tumors. Conclusions: In conclusion, our findings establish NPC1L1 as a critical mediator of PARP inhibitor efficacy and propose dual targeting of lipid metabolism, providing a new therapeutic approach for the combination treatment of TNBC. Full article

Psoriasis, a chronic immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation and inflammatory cell infiltration, involves multiple distinct programmed cell death pathways in its pathogenesis. Following the Nomenclature Committee on Cell Death recommendations, we analyzed the current literature examining diverse modes of cellular death in psoriatic lesions, with particular focus on keratinocyte cell death patterns and their molecular signatures. Analysis revealed several distinct cell death mechanisms: autophagy dysfunction through IL-17A pathways, decreased apoptotic activity in lesional skin, medication targeting anoikis in psoriasis, upregulated necroptosis mediated by RIPK1/MLKL signaling, gasdermin-mediated pyroptosis with enhanced IL-1β secretion, coordinated PANoptotic activation through specialized complexes, PARP1-mediated parthanatos promoting cutaneous inflammation, iron-dependent ferroptosis correlating with Th22/Th17 responses, copper-dependent cuproptosis with elevated MTF1/ATP7B/SLC31A1 expression, and NETosis amplifying immune responses through interaction with the Th17 axis. The intricate interplay between these cell death mechanisms has led to the development of targeted therapeutic strategies, including mTOR inhibitors for autophagy modulation, RIPK1 inhibitors for necroptosis, and various approaches targeting ferroptosis and NETosis, providing new directions for more effective psoriasis treatments. Full article

Background: Programmed cell death (PCD) dynamically influences breast cancer (BC) prognosis through interactions with the tumor microenvironment (TME). We investigated 13 PCD patterns to decipher their prognostic impact and mechanistic links to TME-driven outcomes. Our study aimed to explore the complex mechanisms underlying these interactions and establish a prognostic prediction model for breast cancer. Methods: Using TCGA and METABRIC datasets, we integrated single-sample gene set enrichment analysis (ssGSEA), weighted gene co-expression network analysis (WGCNA), and Least Absolute Shrinkage and Selection Operator (LASSO) to explore PCD-TME interactions. Multi-dimensional analyses included immune infiltration, genomic heterogeneity, and functional pathway enrichment. Results: Our results indicated that high apoptosis and pyroptosis activity, along with low autophagy, correlated with favorable prognosis, which was driven by enhanced anti-tumor immunity, including more M1 macrophage polarization and activated CD8+ T cells in TME. PCD-related genes could promote tumor metastasis and poor prognosis via VEGF/HIF-1/MAPK signaling and immune response, including Th1/Th2 cell differentiation, while new tumor event occurrences (metastasis/secondary cancers) were linked to specific clinical features and gene mutation spectrums, including TP53/CDH1 mutations and genomic instability. We constructed a six-gene LASSO model (BCAP31, BMF, GLUL, NFKBIA, PARP3, PROM2) to predict prognosis and identify high-risk BC patients (for five-year survival, AUC = 0.76 in TCGA; 0.74 in METABRIC). Therein, the high-risk subtype patients demonstrated a poorer prognosis, also characterized by lower microenvironment matrix and downregulated immunocyte infiltration. These six gene signatures also showed prognostic value with significant differential expression in gene and protein levels of BC samples. Conclusion: Our study provided a comprehensive landscape of the cancer survival difference and related PCD-TME interaction axis and highlighted that high-apoptosis/pyroptosis states caused favorable prognosis, underlying mechanisms closely related with the TME where anti-tumor immunity would be beneficial for patient prognosis. These findings highlighted the model’s potential for risk stratification in BC. Full article

Background/Objectives: PARP inhibitors (PARPi) are pivotal to treating homologous recombination repair-deficient (HRD) cancers, particularly BRCA1/2-mutated ovarian and breast cancers. However, most ovarian and breast cancers harbor wild-type (WT) BRCA1/2, limiting PARPi eligibility. This study aims to identify an approved drug that could induce a BRCAness phenotype, thereby sensitizing WT BRCA cancers to PARPi. Methods: Ovarian and breast cancer cell lines with WT BRCA1/2 were treated with ivosidenib. HR repair efficiency was assessed via RAD51 foci formation and reporter assays. Synthetic lethality with PARPi was evaluated using viability and colony formation assays. Mechanistic studies included RNA-binding protein pulldown, co-immunoprecipitation, and functional analyses of DNA repair pathways. YTHDC2′s role in HR was investigated through siRNA knockdown and rescue experiments. Results: Ivosidenib significantly reduced HR repair efficiency and sensitized cells to PARPi, inducing synthetic lethality. Mechanistically, ivosidenib directly bound YTHDC2, an m6A reader critical for HR. This interaction disrupted YTHDC2′s ability to promote DNA double-strand break repair via HR, evidenced by impaired recruitment of repair proteins (e.g., BRCA1, RAD51) and accumulation of DNA damage (γH2AX foci). YTHDC2 knockdown phenocopied ivosidenib effects, while overexpression rescued HR defects. Conclusions: Ivosidenib induces BRCAness in WT BRCA ovarian and breast cancers by targeting YTHDC2, thereby suppressing HR repair and enhancing PARPi sensitivity. This uncovers a novel, metabolism-independent mechanism of ivosidenib, repositioning it as a therapeutic agent for HRD tumors. These findings propose a strategy to expand PARPi eligibility to WT BRCA cancers, addressing a critical unmet need in oncology. Full article

This study investigated whether combining niraparib and trabectedin in BRCA-proficient epithelial ovarian cancer induces deficiencies in ssDNA break repair and dsDNA homologous recombination, leading to synthetic lethality. A2780 and SKOV3 ovarian cancer cell lines were treated with niraparib and trabectedin. Cell viability was assessed using CCK-8 assays, while RT-qPCR and Western blot analyzed the expression of DNA repair and apoptosis-related genes. Apoptosis was evaluated via Annexin V/PI assays. The combination therapy exhibited a synergistic effect on A2780 cells but not on SKOV3 cells. Treatment reduced BRCA1, BRCA2, RAD51, PARP1, and PARP2 expression, indicating impaired DNA repair. γ-H2AX levels increased, suggesting DNA damage. The therapy also upregulated p53, PUMA, NOXA, BAX, BAK, and p21, promoting p53-mediated apoptosis and cell cycle arrest. Apoptosis induction was confirmed via Annexin V/PI assays. Silencing p53 with siRNA abolished all synergistic effects in A2780 cells. Niraparib and trabectedin combination therapy impairs DNA repair in BRCA-proficient ovarian cancer, leading to synthetic lethality through p53-dependent apoptosis. Full article

Cancer remains one of the most formidable diseases globally and continues to be a leading cause of mortality. While chemotherapeutic agents are crucial in cancer treatment, they often come with severe side effects. Furthermore, the development of acquired drug resistance poses a significant challenge in the ongoing battle against cancer. Combining these chemotherapeutic agents with plant-derived phenolic compounds offers a promising approach, potentially reducing side effects and counteracting drug resistance. Phytochemicals, the bioactive compounds found in plants, exhibit a range of health-promoting properties, including anticarcinogenic, antimutagenic, antiproliferative, antioxidant, antimicrobial, neuroprotective, and cardioprotective effects. Their ability to enhance treatment, coupled with their non-toxic, multi-targeted nature and synergistic potential when used alongside conventional drugs, underscores the growing importance of natural therapeutics. In this study, we investigated the anticancer effects of olaparib (OL), a small-molecule PARP inhibitor that has shown promising results in both preclinical and clinical trials, and gallic acid (GA), a phenolic compound, in olaparib-resistant human osteosarcoma U2OS cells (U2OS-PIR). Both parental U2OS and U2OS-PIR cell lines were treated with increasing concentrations of olaparib and gallic acid, and their cytotoxic effects were assessed using the WST-1 cell viability assay. The synergistic potential of OL and GA, based on their determined IC₅₀ values, was further explored in combination treatment. A colony survival assay revealed the combination’s ability to significantly reduce the colony-forming capacity of cancer cells. Additionally, the apoptotic effects of OL and GA, both individually and in combination, were examined in U2OS-PIR cells using acridine orange/ethidium bromide dual staining. The anti-angiogenic properties were assessed through a VEGF ELISA, while the expression of proteins involved in DNA damage and apoptotic signaling pathways was analyzed via Western blot. The results of this study demonstrate that gallic acid effectively suppresses cell viability and colony formation, particularly when used in combination therapy to combat OL resistance. Additionally, GA inhibits angiogenesis and induces DNA damage and apoptosis by modulating key apoptosis-related proteins, including cPARP, Bcl-2, and Bax. These findings highlight gallic acid as a potential compound for enhancing therapeutic efficacy in overcoming acquired drug resistance. Full article

Background and aims: Ginsenoside compound K (CK), a saponin metabolite of ginseng, exerts anticancer effects; however, its molecular mechanisms of action in lung cancer remain unclear. We investigated the involvement of silent information regulator 6 (SIRT6) and poly (ADP-ribose) polymerase 1 (PARP-1) in the anticancer effects of CK in lung cancer. Methods and Results: CK induced PARP-1 activation-mediated parthanatos via sequestosome-1/p62-mediated SIRT6 degradation and inhibited the proliferation of H460 cells. Although CK reduced procaspase-8 levels, no significant apoptotic cleavage of procaspase-3 or PARP-1 was observed. Furthermore, CK upregulated p27, p21, phospho-p53, and gamma-H2AX levels. CK increased LC3-II levels in a p62-independent manner, but p62 was upregulated by autophagy inhibition, indicating that p62 is involved in CK-induced autophagy. CK-treated cells showed typical features of parthanatos, including PARP-1 hyperactivation, intracellular redistribution of poly ADP-ribose and pro-apoptotic factors, and chromatin fragmentation. SIRT6 was degraded in a CK concentration- and time-dependent manner. SIRT6 protein was upregulated by PARP-1 inhibition, nicotinamide adenine dinucleotide (NAD)+ supplementation, antioxidants, and p62 knockdown, but was decreased by autophagy blockade. PARP-1 activation was negatively correlated with SIRT6 levels, indicating that SIRT6 and PARP-1 activation play complementary roles in CK-induced growth inhibition. Immunofluorescence staining, fractionation studies, and immunoprecipitation were used to confirm the colocalization and interaction between p62 and SIRT6. Conclusions: PARP-1 activation is promoted by p62-mediated SIRT6 degradation, which plays an important role in CK-induced growth inhibition. Therefore, SIRT6 is a potential biomarker for the chemopreventive effect of CK in lung cancer cells, but further studies on SIRT6 are needed for the clinical application of CK. Full article

Background: Triple-negative breast cancer (TNBC) represents an aggressive form of breast cancer with few available therapeutic options. Chemotherapy, particularly with drugs like doxorubicin (DOX), remains the cornerstone of treatment for this challenging subtype. However, the clinical utility of DOX is hampered by adverse effects that escalate with higher doses and drug resistance, underscoring the need for alternative therapies. This study explored the efficacy of pentagalloyl glucose (PGG), a natural polyphenol derived from Bouea macrophylla, in enhancing DOX’s anticancer effects and suppressing the epithelial–mesenchymal transition (EMT) in TNBC cells. Methods: This study employed diverse methodologies to assess the effects of PGG and DOX on TNBC cells. MDA-MB231 triple-negative breast cancer cells were used to evaluate cell viability, migration, invasion, apoptosis, mitochondrial membrane potential, and protein expression through techniques including MTT assays, wound healing assays, flow cytometry, Western blotting, and immunofluorescence. Results: Our findings demonstrate that PGG combined with DOX significantly inhibits TNBC cell proliferation, migration, and invasion. PGG enhances DOX-induced apoptosis by disrupting the mitochondrial membrane potential and activating caspase pathways; consequently, the activation of caspase-3 and the cleavage of PARP are increased. Additionally, the study shows that the combination treatment upregulates ERK signaling, further promoting apoptosis. Moreover, PGG reverses DOX-induced EMT by downregulating mesenchymal markers (vimentin and β-catenin) and upregulating epithelial markers (E-cadherin). Furthermore, it effectively inhibits STAT3 phosphorylation, associated with cell survival and migration. Conclusions: These results highlight the potential of PGG as an adjuvant therapy in TNBC treatment. PGG synergizes with DOX, which potentiates its anticancer effects while mitigating adverse reactions. Full article

This study examined the response to cisplatin in BxPC-3, Mia-Paca-2, PANC-1, and YAPC pancreatic cancer lines with different genotypic and phenotypic characteristics, and the mechanisms associated with their resistance. BxPC-3 and MIA-PaCa-2 cell lines were the most sensitive to cisplatin, while YAPC and PANC-1 were more resistant. Consistently, in cisplatin-treated BxPC-3 cells, the cleavage patterns of pro-caspase-9, -7, -3, and PARP-1 demonstrated that they were more sensitive than YAPC cells. The autophagic pathway, promoting cisplatin resistance, was active in BxPC-3 cells, as demonstrated by the time-dependent conversion of LC3-I to LC3-II, whereas it was not activated in YAPC cells. In cisplatin-treated BxPC-3 cells, Bcl-2 decreased, while Beclin-1, Atg-3, and Atg-5 increased along with JNK1/2 phosphorylation. Basal levels of phosphorylated ERK1/2 in each cell line were positively correlated with cisplatin IC50 values, and cisplatin caused the activation of ERK1/2 in BxPC-3 and YAPC cells. Furthermore, ERK1/2 pharmacological inactivation increased cisplatin lethality in both BxPC-3 and YAPC cells, suggesting that p-ERK1/2 may be related to cisplatin resistance of PDAC cells. Different mechanisms and strategies are generally required to acquire drug resistance. Here, we partially explain the other response to cisplatin of BxPC-3 and YAPC cell lines by relating it to the role of ERK pathway. Full article

Background/Objectives: Sarcopenia is characterized by the loss of muscle mass and function, increases in mortality rate, and risk of comorbidities in the elderly. This study evaluated the effects of Alnus japonica hot water extract (AJHW) and its active compound, oregonin, on muscle atrophy and apoptosis in vitro. Methods: AJHW underwent phytochemical analysis. C2C12 cells were subjected to H₂O₂ and dexamethasone to induce oxidative stress and muscle loss, after which AJHW and oregonin were administered to assess their impacts on cell viability, apoptosis, muscle protein synthesis stimulation, and muscle protein degradation inhibition. Cell viability was assessed via an MTT assay, and apoptosis was analyzed by measuring Bcl-2, Bax, cleaved caspase-3, and cleaved PARP through Western blotting. Western blotting and RT-PCR were utilized to analyze MyoD, Myogenin, Atrogin-1, and MuRF1 protein and gene expression in a muscle atrophy model, as well as the Akt/mTOR and FoxO3α pathways. Results: AJHW was confirmed to contain oregonin, an active compound. AJHW and oregonin significantly increased cell viability and reduced apoptosis by upregulating Bcl-2 and downregulating Bax, cleaved caspase-3, and cleaved PARP. They significantly enhanced muscle protein synthesis through the upregulation of MyoD and Myogenin, while diminishing muscle degradation by downregulating Atrogin-1 and MuRF1. The activation of the Akt/mTOR pathway and inhibition of the FoxO3α pathway were also observed. Conclusions: AJHW and oregonin effectively prevented muscle cell apoptosis, promoted muscle protein synthesis, and inhibited muscle protein degradation in vitro. These results suggest that AJHW and oregonin could serve as therapeutic agents to prevent and treat sarcopenia. Full article

Gerbera piloselloides, a plant in the Asteraceae family, is a traditional Chinese medicinal herb known for its unique therapeutic properties, including reported anti-tumor and antioxidant effects. Recent studies suggest that the main constitute of G. piloselloides, coumarins, may have potential anti-tumor activity. Recent research suggests that coumarins, the active compounds in G. piloselloides, may hold potential anti-tumor activity. However, the pharmacodynamic constituents remain unidentified. This study aims to isolate and characterize the bioactive compounds of G. piloselloides and to assess its anti-tumor effects. Initially, seven compounds, including coumarins, a ketone, and a furanolide, were isolated and identified from G. piloselloides by semi-preparative high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) analysis. The anti-tumor effects of these compounds were evaluated across four different cancer cell lines. Among them, the compound cyclobrachycoumarin showed a significant inhibitory effect on colorectal cancer (CRC) cell proliferation and was selected for further investigation. Cyclobrachycoumarin was found to induce CRC cell apoptosis and cell cycle arrest in a dose-dependent manner. This treatment also led to increased levels of ROS and cleaved PARP, along with decreased expressions of survivin, cyclin D1, and CDK1. In vivo studies further demonstrated that cyclobrachycoumarin effectively reduced tumor growth in HT-29 xenograft models by promoting apoptosis and cell cycle arrest, with a favorable tolerability profile. In summary, this study suggests that cyclobrachycoumarin may be a promising candidate for safe and effective CRC therapy. Full article