Anthracyclines such as doxorubicin (DOX) remain central components of breast cancer (BC) chemotherapy, although their efficacy is frequently limited by drug resistance. Myoglobin (MB), an oxygen-binding heme protein expressed in breast tumors, has been implicated in the detoxification of DOX in cardiomyocytes, but its role in BC remains unclear. Using MB-expressing and MB-knockout (MBKO) MDA-MB-468 BC cells, we demonstrate that MB confers hypoxia-dependent resistance to DOX. Under hypoxia, MB-expressing cells exhibited reduced intracellular DOX-associated fluorescence, enhanced superoxide generation, and decreased sensitivity to DOX, findings consistent with altered redox cycling and oxidative processing of the drug. Re-expression of MB in MBKO cells restored resistance, whereas pharmacological modulation of MB function using carbon monoxide-releasing molecule-3 and tert-butoxycarbonyl-alanine reversed MB-dependent reductions in intracellular DOX accumulation. In contrast, aclarubicin, an anthracycline lacking the hydroquinone moiety required for efficient redox cycling, failed to reproduce MB-dependent effects. Analyses of four independent neoadjuvant BC cohorts further demonstrated that elevated MB expression was consistently associated with reduced probability of achieving pathological complete response following anthracycline-containing chemotherapy. Collectively, these findings identify MB as a previously unrecognized modulator of BC response to redox-active anthracyclines and support its potential utility as both a predictive biomarker and therapeutic target.

The activator protein-1 (AP-1) transcription factor is a regulatory dimeric transcription factor complex, that responds to a wide range of intracellular and extracellular stimuli and controls gene expression involved in tumor initiation and progression. Comprised primarily of members of Jun and Fos protein subfamilies, AP-1 is activated downstream of major oncogenic signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway and controls cellular processes including differentiation, invasion, proliferation and apoptosis. In various cancer types, AP-1 contributes to tumor growth by promoting tumor-like phenotypes and facilitating metastatic behavior. Furthermore, AP-1 can affect the tumor microenvironment by modulating inflammation and interaction with immune cells. AP-1 deregulation is linked to tumor heterogeneity and resistance to chemotherapy and radiation. Therefore, AP-1 has emerged as a potential therapeutic target. In preclinical models, direct and indirect targeting via upstream pathways of AP-1 components has demonstrated encouraging results. In addition, combinatorial approaches targeting AP-1 and other regulators may improve the effectiveness of treatment and overcome therapy resistance. In this review, we highlight the AP-1's role as a critical hub in tumorigenesis that links oncogenic signaling to transcriptional regulation. We also focus on its regulation, function in the tumor microenvironment, and therapeutic potential in combating tumors.

Anthraquinone-based intercalating compounds, such as doxorubicin and mitoxantrone, have long been used clinically due to their ability to induce DNA damage. More recently, heteroarene-fused anthraquinones have been developed to further enhance their anticancer activity. Among these compounds, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated as derivative a) was identified as a potent apoptotic inducer. Based on this scaffold, two additional derivatives were synthesized by replacing the sulfur atom within the heterocyclic ring with nitrogen (derivative b) or oxygen (derivative c). Building upon our previous identification of ENOX2 as the primary target of this scaffold, the present study investigated the antiproliferative effects and underlying mechanisms of these derivatives in colon cancer cells with varying p53 statuses. Derivatives a and b effectively induced apoptosis and suppressed proliferation in p53 wild-type HCT116 cells, which was concomitantly accompanied by significant ENOX2 downregulation and the activation of intrinsic apoptotic signaling. In contrast, p53-null HCT116 cells exhibited reduced sensitivity, attenuated apoptotic responses, and minimal ENOX2 downregulation. Notably, derivative c primarily induced G2/M arrest rather than apoptosis regardless of p53 status, indicating a predominantly cytostatic mechanism. Collectively, these findings suggest that the degree of ENOX2 modulation is linked to the distinct anti-proliferative responses induced by heteroarene-fused anthraquinones, and that p53 status serves as a critical molecular switch influencing the transition between cytostatic growth arrest and apoptotic cell death.

Glutathione (GSH)-responsive nanozymes have attracted increasing attention for biosensing and cancer therapy. However, their practical applications are often limited by aggregation and insufficient catalytic activity. Herein, we report a zwitterionic sulfobetaine-modified palladium nanozyme (SH-SB/Pd NPs) that addresses these limitations by integrating high catalytic activity. The zwitterionic ligand simultaneously stabilizes Pd nanoparticles and preserves accessible catalytic sites, resulting in markedly enhanced peroxidase-like activity. SH-SB/Pd NPs efficiently catalyze H2O2 decomposition to generate multiple reactive oxygen species (1O2, O2•- and •OH), enabling favorable affinity for TMB (Km(TMB) = 0.28) and sensitive colorimetric GSH detection with a low detection limit of 0.135 μM. Benefiting from their long-term antifouling properties and ROS-generating capability, SH-SB/Pd NPs also exhibit potent antitumor activity, achieving 76.56% inhibition of HeLa cells under 808 nm laser irradiation. This work establishes a zwitterionic nanozyme platform that improves catalytic activity, stability, and therapeutic performance, offering a promising strategy for biosensing and synergistic cancer therapy.

Histone deacetylases (HDACs) are important epigenetic regulatory enzymes contributing to cancer proliferation, which could be critical targets in cancer therapy. The structural similarities of the existing HDAC inhibitors have resulted in an increase in the drug resistance. In this study, coumarin was employed as the core scaffold for structural derivatisation to develop a novel class of HDAC inhibitors based on computer-aided design (CADD). Their anti-tumor activity was evaluated against esophageal squamous cell lines. The results showed that most compounds exhibited potent anti-proliferative activity against KYSE70 and KYSE150. Among them, compound 4s and 4p exhibited the most potent activity with IC50 values of 3.44 μM and 3.39 μM against KYSE70. To validate the target of the synthesized compounds, transcriptome sequencing was performed and the results revealed that a total of 487 genes were differentially expressed, including 190 up-regulated and 297 down-regulated genes. Among these, 79 genes were associated with the HDAC regulatory network, accounting for 16.2% of the differentially expressed genes. Molecular docking demonstrated that compound 4s could effectively enter the active site of HDAC, engaging with the cap group, zinc-binding group, and linker region. This multiple interaction network provides a structural basis for the potent inhibitory activity of compound 4s. In conclusion, a series of novel HDAC inhibitors with a coumarin scaffold were discovered, and their mode of action was revealed. This provides a valuable guide for the development of novel HDAC-targeting therapeutics.

γ-Tocotrienol (γ-T3), a naturally occurring vitamin E isoform from plant-derived sources, has attracted attention as an antitumour agent. However, whether γ-T3 can enhance antitumour immunity and improve immune checkpoint blockade remains unclear. Here, using colorectal cancer (CRC) models, we found that γ-T3 suppressed tumour growth in immunocompetent MC38 and CT26 mouse models, whereas this effect was markedly weakened in immunodeficient hosts, indicating that its in vivo antitumour activity is closely associated with host immunity. Combination treatment with γ-T3 and programmed cell death protein 1 (PD-1) blockade further improved tumour control, accompanied by enhanced CD8+ T cell effector function, reduced regulatory T cell abundance, and tumour-associated macrophage remodelling towards an antitumour phenotype. Immune cell depletion experiments confirmed that CD8+ T cells are the principal effector cells mediating γ-T3-associated tumour suppression. Mechanistically, HSPA4 was identified as a candidate γ-T3-associated protein potentially linked to MHC-I-related immune-recognition features. γ-T3 promoted the expression of Psmb8 and Tap2 and increased MHC-I surface levels on tumour cells, accompanied by increased sensitivity of tumour cells to activated CD8+ T cell-mediated growth inhibition. These findings support γ-T3 as a naturally derived immune-sensitising agent for improving PD-1 blockade therapy in CRC.

L-asparaginase (L-ASNase) is a key therapeutic enzyme used in the treatment of acute lymphoblastic leukemia and other hematological malignancies. However, its clinical application is limited by a short plasma half-life, significant toxicity, and immunogenicity. To address these limitations, various strategies have been developed, including conjugation of the enzyme with polyethylene glycol and the use of enzymes from alternative sources with lower immunogenicity. Nevertheless, effective targeting of tumor cells, particularly in solid tumors, remains a major challenge. Protein fusion technology has emerged as a promising approach to improve the pharmacological properties of L-asparaginase by enhancing stability, prolonging circulation time, enabling targeted delivery, and integrating multiple functional domains into a single construct, thereby addressing several limitations simultaneously. This review analyzes current strategies for the design of L-asparaginase-based fusion proteins, including the fusion of protein domains to improve pharmacokinetics and the fusion of targeting peptides or proteins to enhance local cytotoxicity. A comparative analysis indicates that elastin-like peptide (ELP)-based constructs primarily enhance the half-life of L-ASNase, whereas albumin-binding domain (ABD)- and heparin-binding domain (HBD)-based fusions provide more pronounced improvements in both half-life extension and in vivo efficacy. However, described strategies require further validation to ensure enhanced selectivity. Overall, fusion protein technology represents a promising avenue for the development of next-generation L-asparaginase therapeutics.

Lung cancer (LC) remains a leading cause of cancer mortality worldwide. Thymoquinone (TQ), a bioactive compound derived from Nigella sativa, possesses anti-inflammatory and antioxidant properties, but its precise mechanisms concerning miRNA regulation in LC are poorly defined. This study investigates the anti-cancer potential of TQ through modulation of microRNA signaling in LC.

Our previous study demonstrated a potent synergistic antitumor effect between 1 nM digoxin and 1 μM cisplatin in cervical cancer cells, which was dependent on the modulation of the signaling pathway involving Na, K-ATPase/Src. Because of the relationship between Na, K-ATPase/Src and the modulation of oxidative stress, the aim of this study was to demonstrate the effect of combined treatment with digoxin and cisplatin on oxidative stress parameters in HeLa cells and the effect of treatment in non-tumor cell lines. Analysis of oxidative stress parameters revealed a significant reduction in cellular antioxidant defense mechanisms, SOD activity, and content of reduced total thiol groups. Additionally, there was an increase in H2O2 content within 24 h, confirming the elevated cellular oxidative stress during the combined treatment. Furthermore, lipid peroxidation and lipid droplet formation levels were evaluated, showing an increase in these parameters after 48 h of treatment, consistent with oxidative stress. Compared to the other tested cell lines, the combined treatment did not significantly alter cell viability compared to the control. Our data demonstrate that the synergistic antitumor effects of digoxin and cisplatin in HeLa cells are tightly associated with increased oxidative stress via activation of the Na, K-ATPase/Src/ROS signaling pathway, may resulting in antiproliferative and pro-apoptotic effects. These findings indicate that oxidative stress is a key component of the cellular response underlying the synergistic antitumor effects of digoxin and cisplatin.

The most challenging aspects of cancer treatment are multi-drug resistance (MDR) and damage to normal, non-malignant cells. Doxorubicin (Dox)-loaded gold nanoparticles (Dox@AuNPs) were developed and evaluated for enhanced anticancer activity. The nanocomposites exhibited spherical morphology (13 ± 3 nm) with a loading efficiency of 52%. In vitro, Dox@AuNPs reduced the IC₅₀ by approximately 50% compared to free Dox in MCF-7 cells. In vivo, treatment significantly suppressed tumor growth and increased median survival (62 days) relative to free Dox (52 days). In addition to conventional efficacy evaluation, Fourier transform infrared (FTIR) spectroscopy was applied to analyze biochemical changes in tumor tissues. Distinct alterations in protein, lipid, and nucleic acid-associated bands were observed, with treated tissues showing partial spectral shifts toward normal profiles. These findings suggest that FTIR may provide additional insight into tissue-level biochemical responses following treatment. While further validation and toxicity assessment are required, the results demonstrate that Dox@AuNPs enhance anticancer efficacy and highlight the potential utility of FTIR as a complementary tool for evaluating therapeutic response.

Cellular and immunological cancer therapies have substantially changed the treatment landscape of malignant diseases. In particular, chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors (CPI) have enabled durable responses in previously refractory malignancies. However, these treatment strategies are associated with distinct immune-mediated toxicities that differ considerably from the toxicity profiles observed with conventional cytotoxic chemotherapy. Hematologic complications represent an important subgroup of these adverse events. Hematologic immune-related adverse events (irAEs) under CPI therapy are rare but may be associated with considerable morbidity and mortality. In contrast, hematologic toxicities are common after CAR T-cell therapy and are summarized under the term ICAHT (immune effector cell-associated hematotoxicity). These cytopenias may present early after therapy due to lymphodepleting conditioning or later as prolonged or biphasic cytopenias associated with inflammatory bone marrow suppression. In addition, severe hyperinflammatory syndromes such as immune effector cell-associated hemophagocytic syndrome (IEC-HS) may occur and require rapid recognition and treatment. A structured diagnostic approach is essential to differentiate therapy-related cytopenias from disease progression, bone marrow infiltration, or secondary hematologic malignancies. Management strategies depend on the severity of the cytopenia and include supportive measures, immunomodulatory therapies, and in selected cases targeted anti-cytokine treatments. Early recognition and interdisciplinary management are crucial to reduce morbidity and improve patient outcomes.

Immune checkpoint inhibitors (ICIs), particularly antibodies targeting PD-1, PD-L1, and CTLA-4, have fundamentally transformed the treatment landscape of numerous malignant diseases. By blocking T-cell inhibitory mechanisms, they enable an enhanced immune response against malignancies, but can also trigger immune-related adverse events (irAEs). Pulmonary irAEs - most notably ICI-associated pneumonitis (ICI-P) - occur in up to 20% of treated patients (with study-reported rates ranging from 1-6%) and may progress to respiratory failure. The clinical presentation is characterized by dyspnea, cough, and hypoxemia; radiologically, organizing pneumonia, NSIP pattern, and bronchiolocentric pattern are most commonly observed. Management is severity-dependent and includes treatment interruption, immunosuppression with corticosteroids, and, where necessary, second-line immunosuppressive therapy. The most important differential diagnoses include infection, tumour progression, and radiation pneumonitis.

Immunotherapies, including checkpoint inhibitors and T-cell-activating therapies (CAR-T cells, BiTE), have transformed oncology but carry risks of severe toxicities. Checkpoint inhibitors may induce immune-related adverse events (irAEs) such as pneumonitis, myocarditis, or neurological syndromes, often requiring intensive care. T-cell therapies frequently cause acute cytokine release syndrome (CRS) and neurotoxicity (ICANS), while late toxicities like hemophagocytic syndrome (IEC-HS) and delayed neurotoxicity (TIAN, Guillain-Barré) are gaining relevance. Management includes grade-adapted immunosuppression, steroids, IL-6/IL-1 inhibitors, and interdisciplinary intensive care. Despite established algorithms, prognosis remains critical in multiorgan involvement or other high-grade toxicities. Early diagnosis and individualized risk-benefit assessment are crucial for treatment success.

Cancer immunotherapies, particularly immune checkpoint inhibitors (ICIs), have proven to be a very effective and well-established type of therapy for advanced malignancies. Although generally considered well tolerated, immune-related adverse events, which can sometimes be severe, do occur. Unlike other types of adverse events, immune-mediated renal toxicity is rare and can occur after significant delay. Diagnosing immune-mediated renal toxicity can often be difficult, due to possible alternative causes of acute kidney injury, especially in this particular patient population. Acute interstitial nephritis is the most common finding in kidney biopsies. In most cases, ICI-mediated nephritis can be treated effectively by discontinuing ICI therapy and initiating corticosteroid therapy. Renal outcomes are generally favorable. Other types of targeted immunotherapy, such as CAR-T-cell or BiTE therapies play a minor role in renal toxicity. However, due to their increase in usage, possible renal adverse effects of these therapies should receive greater attention.

Immune-mediated adverse effects are becoming increasingly common due to the now widespread use of immune checkpoint inhibitor (ICI) therapies in oncology. The gastrointestinal tract and liver are among the most frequently affected sites. Common manifestations include diarrhea, enterocolitis and hepatitis, while gastritis, duodenitis, cholangitis and pancreatitis are less common. Prompt diagnostic evaluation is essential and includes exclusion of infectious causes, stage-based severity classification, endoscopic evaluation for gastrointestinal symptoms, and close laboratory monitoring for hepatic involvement. Histological confirmation should be performed in severe cases. Management follows a stepwise approach according to severity. Mild cases can be treated symptomatically, whereas moderate to severe toxicity requires corticosteroid therapy and a temporary interruption of ICI therapy. In steroid-refractory cases, early escalation to additional immunosuppressants should be considered. Since prolonged corticosteroid exposure can worsen oncological outcomes, steroid-sparing strategies are becoming increasingly important.

Triazole hybrids have emerged as versatile scaffolds exhibiting diverse pharmacological profiles. In this study, four novel xanthine steroid hybrids linked via a 1,2,3-triazole moiety (4-7) were efficiently synthesized through copper(I)-catalyzed azide alkyne cycloaddition. Their bioactive potential was investigated using molecular docking and in vitro assays targeting both metabolic and apoptotic pathways. Docking simulations were performed against the anti-apoptotic protein BCL-2 (isoform 1), associated with human breast adenocarcinoma cells, and α-glucosidase, a key enzyme involved in carbohydrate hydrolysis. Among the series, compound 4 displayed the highest binding affinity toward α-glucosidase and significant affinity toward BCL-2. In vitro assays confirmed that compound 4 exhibited the most potent dual effect, demonstrating α-glucosidase inhibition with an IC50 value of 123.9 µM (95% CI: 119-129 µM) and an antiproliferative effect on MCF-7 cells, reaching a maximum viability reduction of 21% ± 3% at 250 µM. The dual activity is largely attributed to the 1,2,3-triazole linker, which facilitates stacking and critical hydrogen-bonding interactions with its biological targets.

Chemoresistance remains a major barrier to effective treatment of acute myeloid leukemia, partly because resistant leukemic cells reduce intracellular drug exposure and evade apoptosis. FTY720, a sphingosine-1-phosphate receptor modulator, has reported antiproliferative and chemosensitizing activity in several tumor models. However, whether FTY720 increases doxorubicin sensitivity in doxorubicin-resistant acute myeloid leukemia cells, and whether this effect is associated with changes in drug-efflux transporters and protein kinase B/mechanistic target of rapamycin signaling, remains insufficiently defined. This study evaluated the effects of FTY720 alone and in combination with doxorubicin in parental acute myeloid leukemia cell lines (HL60 and K562) and their doxorubicin-resistant derivatives (HL60/A and K562/A). Cell viability was assessed using Cell Counting Kit-8 assays, apoptosis was measured by Annexin V/propidium iodide flow cytometry, intracellular doxorubicin accumulation was quantified by flow cytometry, and P-glycoprotein, multidrug resistance-associated protein 1, protein kinase B/mechanistic target of rapamycin pathway proteins, and apoptosis-related proteins were examined by flow cytometry and Western blotting. FTY720 showed dose-dependent cytotoxicity and increased doxorubicin sensitivity in resistant leukemia cells. Combined treatment reduced cell viability, increased apoptotic cell fractions, enhanced intracellular doxorubicin accumulation, and decreased P-glycoprotein and multidrug resistance-associated protein 1 expression. FTY720 treatment was also associated with reduced phosphorylation of protein kinase B and mechanistic target of rapamycin, whereas the protein kinase B activator SC79 partially reversed the observed changes in signaling, transporter expression, and apoptosis. These findings indicate that FTY720 increases doxorubicin sensitivity in HL60/A and K562/A cells and that this effect is associated with reduced protein kinase B/mechanistic target of rapamycin signaling, decreased drug-efflux transporter expression, enhanced intracellular doxorubicin accumulation, and increased apoptosis. Because this study was limited to in vitro cell-line models, further validation in primary leukemia samples and in vivo systems is required before therapeutic conclusions can be drawn.

Forest tree seeds are mass produced for afforestation and forest restoration programs, but are mostly underutilized beyond propagation. Here, we aimed to evaluate the antioxidant, anti-inflammatory, anticancer, and tyrosinase-inhibitory activities of seed extracts of seven economically important forest tree species in the Republic of Korea to explore their potential as multifunctional natural bioresources. The seed extracts of Alnus japonica, Chamaecyparis obtusa, Cornus kousa, Phellodendron amurense, Pinus densiflora, Prunus sargentii, and Quercus glauca were comparatively assessed using multiple in vitro assays. The results revealed clear species-dependent functional profiles rather than uniform bioactivities across species. Q. glauca exhibited strong antioxidant activity along with significant anti-inflammatory and tyrosinase-inhibitory activities under the present screening conditions, while C. obtusa presented considerable anticancer activity against several cancer cell lines. A. japonica exhibited the highest tyrosinase-inhibitory activity, followed by Q. glauca and C. obtusa; A. japonica extract also showed a strong antioxidant capacity. Overall, the results revealed clear species-dependent differences in bioactivity profiles among the seven seed extracts under the present screening conditions, providing a comparative baseline for further compound-level and mechanistic studies. By focusing on seed resources generated within existing afforestation systems, we highlight a sustainable approach to valorize forest-derived by-products without additional pressure on natural ecosystems. As all assays were performed at single fixed concentrations using crude extracts, the present findings should be interpreted as a comparative screening; dose-response characterization, selectivity profiling, and identification of active compounds and their mechanisms of action are required next steps.

Chemotherapy resistance is a major treatment issue for cervical cancer (CC), contributing to high morbidity and mortality. This study identifies key molecular drivers of CC progression and cisplatin (DDP) resistance, focusing on secreted phosphoprotein 1 (SPP1).

β-Lapachone exhibits potent anticancer activity although its clinical application remains limited by toxicity and mechanisms of resistance. Therefore, structural modifications have been explored to improve its pharmacological profile. This study evaluated the cytotoxic, genotoxic, and toxicological effects of the oxime derivative β-lapachone oxime (Oxβ-Lp), together with its predicted pharmacokinetic properties and potential molecular interactions. Oxβ-Lp displayed cytotoxic activity against all tested cancer cell lines (NCI-H460, PC9, K562, and HepG2) after 72 h of exposure, with the greatest potency and selectivity observed in NCI-H460 non-small cell lung cancer cells (IC₅₀ = 1.88 µM; SI = 13.1). Mechanistic analyses demonstrated reduced cell viability, mitochondrial membrane depolarization, DNA damage, and induction of apoptosis, without significant cell cycle arrest. In Allium cepa, Oxβ-Lp did not alter the mitotic index or induce micronucleus formation but promoted chromosomal aberrations and DNA strand breaks. The Artemia salina assay indicated high acute toxicity (LC₅₀ = 16.80 µg/mL). Molecular docking suggested a potential interaction between Oxβ-Lp and NQO1, with binding energies comparable to those of dicoumarol and similar interaction patterns within the catalytic site. Overall, these findings demonstrate that Oxβ-Lp exhibits selective cytotoxicity against NCI-H460 cells and promotes apoptosis associated with mitochondrial dysfunction and DNA damage. Although the molecular mechanisms underlying its biological activity require further investigation, Oxβ-Lp represents a promising scaffold for developing novel anticancer agents.