Although neoadjuvant chemotherapy is widely used after osteosarcoma (OS) surgery, suboptimal chemotherapy accelerates OS recurrence, and postoperative bone repair remains challenging. Here, we report a selenium-loaded biomimetic calcium phosphate (Se@BioCaP) to provide a long-term therapeutic-dose release for postoperative OS treatment. Sodium selenite was incorporated into a biomimetic calcium phosphate (BioCaP) via a wet biomimetic mineralization protocol. The release kinetics of Se@BioCaP achieved a transition from non-Fickian transport to Fickian diffusion, delivering sustained cytotoxic concentrations under acidic, tumor-like conditions while maintaining biocompatibility with osteoblasts (OBs) under physiological conditions. The reduction in OS cell viability was associated with the disruption of redox homeostasis, including the downregulation of key antioxidant enzymes (SOD2 and GPx1), increased reactive oxygen species (ROS), and acidic vesicular organelle (AVO) formation. Notably, Se@BioCaP200 extracts maintained in vitro anticancer and pro-osteogenic activity at day 42, while antibacterial activity was maintained through day 42. These findings suggest that Se@BioCaP may be a promising candidate for postoperative OS management.

Neuroblastoma is an aggressive pediatric malignancy with limited therapeutic options for high-risk disease, underscoring the need for alternative treatment strategies. Drug repurposing offers a promising approach to accelerate the identification of effective anti-cancer agents. In this study, we investigated the anti-carcinogenic effects of hydroquinidine, a class IA antiarrhythmic ion channel blocker, and spiramide, a dopamine D2/serotonin 5-HT2 receptor antagonist and endoplasmic reticulum stress inducer, in SH-SY5Y human neuroblastoma cells. Cells were treated with increasing concentrations of each compound and evaluated using cell viability, colony formation, wound healing, proliferation, apoptosis, and quantitative gene expression assays. Both compounds induced a dose-dependent reduction in cell viability, with spiramide exhibiting greater potency than hydroquinidine. Functional assays revealed significant suppression of clonogenic survival, cell migration, and DNA synthesis, accompanied by increased oxidative stress and cell death. Molecular analyses demonstrated coordinated transcriptional regulation of apoptosis- and cell cycle-related genes, characterized by upregulation of BAX, CDKN1A, and CDKN1B, and downregulation of BCL-2 and CCND1. Notably, spiramide consistently produced stronger cytotoxic and wound-closure inhibitory effects, suggesting a greater contribution of oxidative stress- and apoptosis-associated pathways. Collectively, these findings indicate that hydroquinidine and spiramide disrupt neuroblastoma cell growth through complementary stress- and cell cycle-associated pathways and identify them as promising candidates for further preclinical evaluation.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by poor prognosis and marked resistance to chemotherapy. In this study, we investigated the cytotoxic and antimigratory effects of a cationic monofunctional organometallic platinum (II) complex containing 1,10-phenanthroline (phen), [Pt(1-hexyl-1H-imidazole)(η1-C2H4OEt)(phen)]Cl, in comparison with cisplatin in the cisplatin-resistant YAPC pancreatic cancer cell line. The complex exhibited a rapid and potent cytotoxic effect, significantly reducing cell viability within a few hours of treatment and showing greater short-term activity than cisplatin. This enhanced efficacy was associated with a markedly higher and faster intracellular accumulation, suggesting improved cellular uptake. Mechanistically, the compound induced apoptosis more effectively than cisplatin, as demonstrated by flow cytometry, and caused an early and pronounced loss of mitochondrial membrane potential (ΔΨM), indicating mitochondrial involvement in cell death. In addition, the complex significantly impaired cell motility in both transwell and 3D spheroid-based assays, confirming a strong antimigratory and anti-dissemination potential. Overall, these findings indicate that [Pt(1-hexyl-1H-imidazole)(η1-C2H4OEt)(phen)]Cl represents a promising candidate for targeting cisplatin-resistant PDAC cells, owing to its rapid cellular uptake, mitochondrial-mediated apoptotic signaling, and combined cytotoxic and antimigratory properties.

Cancer remains a major global health challenge and is the second leading cause of death worldwide. Targeted therapy has emerged as one of the most promising strategies for cancer treatment. However, current targeted therapies highlight the urgent need for novel therapeutic targets and strategies. The provirus integration site for Moloney murine leukemia virus 1 (PIM1) kinase has been identified as a key factor in tumor progression and poor prognosis. This review systematically summarizes and analyzes the diverse mechanisms of PIM1 in promoting tumor progression, including cell programmed death, cell cycle progression, DNA damage response, metastasis, cell stemness, metabolic reprogramming, tumor angiogenesis, anti-cancer immune response and therapeutic resistance, and comprehensively evaluates its potential as a therapeutic target. Moreover, PIM1 contributes to the development of resistance to various anticancer therapies. Based on the advances and limitations in PIM1-targeted cancer therapy, we propose that future research should focus on combination strategies involving PIM1 inhibitors and agents targeting parallel or upstream/downstream pathways regulated by PIM1. Our review highlights the therapeutic value and potential of PIM1 in cancer treatment, providing new insights and theoretical bases for the development of novel anti-tumor strategies targeting PIM1.

Per- and polyfluoroalkyl substances (PFAS) are an emerging group of anthropogenic environmental pollutants frequently detected in human and animal serum. Although several studies have reported adverse health effects associated with exposure to single PFAS, limited information is available concerning the biological and toxicological impact of PFAS mixtures and their potential interactions with chemotherapeutic agents. This study investigated the effects of acute and chronic exposure to PFAS, including perfluorooctanoic acid (PFOA, 3 nmol/L), perfluorooctane sulfonic acid (PFOS, 5 nmol/L), and their binary mixture containing 3 nmol/L of PFOA plus 5 nmol/L of PFOS, using an in vitro model, mouse ovarian surface epithelial cells (MOSEC), and possible interactions with antineoplastic agents. Results showed increased cell proliferation following acute PFOS exposure; this effect was enhanced in the PFOA-PFOS mixture. In contrast, PFOA exposure showed reduced cell proliferation. Acute exposure to PFOA, PFOS, and their mixture was associated with reduced sensitivity to cabazitaxel and docetaxel, while chronically exposed cells demonstrated increased sensitivity. These findings suggest that PFOA, PFOS, and their mixtures present in human serum and tissues may influence cellular proliferation and alter therapeutic response. These findings further highlight the importance of mixture effects and the exposure duration effect in the toxicological evaluation of PFAS toxicity.

Colorectal cancer stem cells (CRC-SCs) contribute to treatment resistance, tumor recurrence and disease progression. Despite therapeutic advances, CRC-SCs frequently evade eradication and sustain tumor propagation. Although multiple molecular pathways have been implicated in this resistance, current preclinical evidence remains fragmented. This systematic review aims to synthesize preclinical evidence on the molecular mechanisms underlying CRC-SC resistance to modern anticancer therapies. A systematic search of PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials was conducted to identify peer-reviewed original studies published between 2015 and 2025. Eligible studies investigated molecular mechanisms of CRC-SC resistance to chemotherapy, targeted therapy, immunotherapy, and other therapeutic modalities. Risk of bias was assessed using QUIN for in vitro studies and SYRCLE for in vivo studies. A total of 26 studies met the inclusion criteria. Synthesis of findings showed that CRC-SC resistance is driven by interconnected mechanisms, including adaptive signaling pathways, epigenetic reprogramming, enhanced DNA damage response, and protective interactions within the tumor microenvironment. Several studies reported that combination treatments targeting these mechanisms attenuated stemness characteristics and restored therapeutic sensitivity. Overall, CRC-SC resistance arises from multiple intrinsic and extrinsic mechanisms, supporting further preclinical and translational evaluation of combination strategies.

Volatile organic compounds (VOCs) reflect cellular metabolic activities and may serve as non-invasive biomarkers in oncology. This study investigated whether acquired oxaliplatin resistance in colorectal cancer is associated with distinct volatilomic alterations. The human colorectal cancer cell line HCT116 and its oxaliplatin-resistant derivative (OXrHCT116) were analyzed under basal conditions and following oxaliplatin exposure. Chemoresistance was confirmed using dose-response, cell viability, and colony formation assays. VOCs were analyzed by headspace needle trap extraction coupled with gas chromatography-mass spectrometry (HS-NTE-GC-MS). OXrHCT116 cells exhibited markedly reduced oxaliplatin sensitivity, increased IC50 values, and reduced proliferative and clonogenic capacity. Volatilomic profiling identified 55 significantly altered VOCs. Parental HCT116 cells displayed broader VOC diversity and higher turnover than OXrHCT116 cells. Hydrocarbons associated with lipid peroxidation and oxidative stress were more abundant in HCT116 cells, whereas resistant cells showed markedly reduced emission of these compounds. Additional alterations in aldehydes, alcohols, and aromatic compounds suggested reduced metabolic flux in resistant cells. Oxaliplatin exposure induced pronounced volatilomic changes in HCT116 cells but only minimal modulation in OXrHCT116 cells. These findings suggest that oxaliplatin resistance may be associated with distinct metabolic reprogramming and support VOC profiling as a promising approach for monitoring chemoresistance.

Antiproliferative activity of pyrrolo[3,4-d]isoxazolines and pyrrolo[2,1-a]isoquinolines derived from them was studied against human erythroleukemia (K562), cervical carcinoma (HeLa), and melanoma (Sk-mel-2) cell lines in vitro by MTS assays followed by study of their effect on actin cytoskeleton and cell motility by confocal microscopy, and apoptotic activity by flow cytometry. Most effective among the screened compounds were bicyclic hydroxylactams 6-9 with a pyrrolo[3,4-d]isoxazoline structure; they showed IC50 values ranging from 12 to 36 μg/mL for all tested cancer cell lines with selectivity indexes up to 12 (as compared to the embryonic kidney HEK293T cell line). Loss of stress fibers with diffuse redistribution of granular actin throughout the cytoplasm in up to 25% of treated cells and a decrease in filopodia-like protrusions up to 69% were observed by confocal microscopy during an actin cytoskeleton study. Such cytoskeletal changes and the proposed altered cell motility were confirmed by scratch-test (revealed a three-fold decrease in cell motility).

Dimethyl fumarate (DMF) is a clinically approved fumarate ester with pleiotropic effects and a promising candidate for drug repurposing in cancer. Here, we investigated whether low-dose DMF could modulate docetaxel (DCT) responses in prostate cancer cells. PC-3, LNCaP, and RWPE-1 cells were exposed to DMF and DCT individually or in combination, and cell viability, drug interaction profiles, apoptosis, oxidative stress, mitochondrial mass, glutathione status, glucose consumption, lactate production, LDHA/SOD2 expression, and oxygen consumption were evaluated. Low-dose DMF and DCT were well-tolerated in RWPE-1 normal prostate cells. In prostate cancer cells, the DMF-DCT combination was cytotoxic and strongly dose- and ratio-dependent, with the most favorable responses at higher exposures and under balanced or DCT-enriched regimens. DMF-DCT-treated LNCaP cells showed reduced viability, decreased lactate production, increased glucose consumption, mitochondrial dysfunction, oxidative stress, downregulation of LDHA and SOD2, and caspase-associated apoptosis. In contrast, PC-3 cells showed greater combinatorial susceptibility, a docetaxel dose-sparing effect, and a low glycolytic profile, with concomitant cytotoxicity and mitochondrial dysfunction. These findings identify DMF as a context-dependent metabolic modulator of docetaxel response, supporting further evaluation of DMF-DCT combinations as a potential therapeutic strategy in prostate cancer.

Lung, breast, colorectal and prostate cancer account for over 41% of global cancer incidence and 39% of mortality, yet durable control of advanced disease remains limited. Plant secondary metabolites are promising multitarget leads, but their polypharmacological mechanisms cannot be captured by single-target approaches, and the evidence across these four cancers has not been synthesised within a unified framework. This review provides an integrated comparative analysis of network-pharmacology studies of plant-derived anticancer compounds across the four cancers, cataloguing phytochemical profiles, identifying shared and cancer-specific targets, quantifying the concordance between computational predictions and experimental validation, and appraising the translational gap. A systematic search of biomedical databases (2016-2026) identified 101 peer-reviewed studies (40 breast, 33 colorectal, 24 lung, and 14 prostate) combining network pharmacology with experimental validation. AKT1, EGFR, TP53, STAT3, MAPK1/3, CASP3, and HSP90AA1 recurred as cross-cancer hub genes, with the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase pathways most frequently implicated. Cancer-specific signatures comprised the androgen receptor in prostate, the oestrogen receptor and human epidermal growth factor receptor 2 in breast, β-catenin/Wnt in colorectal, and the epidermal growth factor receptor/RAS axis with epithelial-to-mesenchymal transition effectors in lung cancer. Flavonoids, terpenoids, alkaloids, and polyphenols predominated. The persistent validation gap remains the principal barrier to translation.

Ovarian cancer stem cells (OvCSCs) are one of the main factors contributing to post-treatment recurrence and the poor prognosis of patients with ovarian cancer. Therefore, the development of therapeutic strategies targeting OvCSCs is needed to improve patient survival. We previously reported the high expression of survivin/BIRC5 in OvCSCs and also that targeting pathways regulating survivin expression effectively suppressed OvCSC survival. In the present study, we tested a panel of agents consisting of FDA-approved drugs and compounds under clinical studies for their ability to suppress survivin expression in OvCSCs and identified clotrimazole (CTZ) as a potent candidate. The effects of CTZ on survivin expression were examined by RT-PCR and Western blot analyses. The effects of CTZ alone or in combination with anticancer agents on OvCSCs were evaluated using WST-8, PI uptake, and colony formation assays. CTZ preferentially impaired OvCSC survival by suppressing the c-myc-survivin axis without affecting normal fibroblasts and enhanced the efficacy of platinum- and taxane-based chemotherapeutic agents. These results suggest that CTZ suppresses survivin expression in OvCSCs and enhances the effects of conventional ovarian cancer chemotherapeutic agents, supporting further investigations of this approach as a potential strategy for ovarian cancer treatment.

We are writing this letter to respond to the letter to the editor regarding the comments that were raised [...].

We are writing this letter to express our significant concerns regarding the experimental design, experimental data, and interpretation of results in a recent publication by AlAsmari et al [...].

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in American men. Most patients with metastatic disease respond initially to androgen deprivation therapy (ADT) but almost inevitably progress to castration-resistant prostate cancer (CRPC). Identification of markers and drivers of Metastatic CRPC (mCRPC) that (a) represent a progenitor-type cancer cell population, (b) persist in castration-resistant disease, (c) are actionable targets expressed on the cell surface, and (d) are induced by hypoxia is required to facilitate the development of novel targeted therapies. We identified prostatic acid phosphatase (PAP), particularly the transmembrane form (TMPAP), as one such potential target. PAP is both a phosphatase and a 5'ectonucleotidase that generates adenosine. PAP is a human tumor marker first described in 1936 and is still used as an important prognostic marker for advanced metastatic prostate cancer. Our group recently reported that the transmembrane form of the protein (TMPAP) is expressed in CRPC and can serve as a potential therapeutic target. We identified a lead human anti-TMPAP antibody clone 3D8 (3D8-Ab). 3D8-ADCs (Antibody Drug Conjugates) and 3D8-Ab were tested for their ability to reduce tumor size/volume in a xenograft model. The human PAP-expressing PCa cell line VCaP, originally derived from a vertebral metastasis from a patient with CRPC, was inoculated subcutaneously into SCID mice. Treatment with either 3D8-Ab or 3D8-ADC significantly reduced tumor size and increased animal survival. These data indicate that targeting PAP with monoclonal antibodies either alone or conjugated to toxins has the potential to treat CRPC.

Chalcones from medicinal plants are attractive starting points for anticancer lead discovery, and this study aimed to improve the anti-NSCLC potential of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) from Syzygium nervosum through targeted structural modification and mechanistic computational analysis. Air-dried seeds were extracted with CH2Cl2, DMC was purified by silica gel chromatography and crystallization, and its structure was confirmed by HRMS, FTIR and NMR; 4'-O-derivatization with meta- or para-[(bromomethyl)phenyl]methyl groups afforded derivatives 2a and 2b (89-92% yield). Antiproliferative activity and cytotoxicity were evaluated by MTT assay in NSCLC cell lines (A549, NCI-H460) and normal lung fibroblasts (MRC-5) with osimertinib as a reference. Derivatives 2a and 2b showed enhanced activity against NCI-H460 (IC50 = 7.97 ± 0.62 µM and 7.91 ± 2.77 µM) while remaining weak against A549, and they were less cytotoxic to MRC-5 (IC50 ≥ 50 µM and 16.08 ± 0.45 µM) than osimertinib (IC50 = 3.43 ± 0.35 µM). DFT/MEP analyses, docking to wild-type EGFR (1M17; redocking RMSD 1.228 Å), and 500 ns × 3 replica MD simulations supported improved EGFR binding stability for 2a/2b, with MM/GBSA indicating favorable binding free energies (-28.78 ± 6.11 and -21.99 ± 9.39 kcal/mol). Overall, 4'-O-functionalization of DMC generated lead derivatives with improved in vitro activity in NCI-H460 and computationally supported target-ligand stabilization.

Melanoma is a highly aggressive malignancy characterized by strong invasive and metastatic potential. CPEB4 has been implicated in melanoma progression and may serve as a potential therapeutic target. Alkannin has previously been reported to exert antitumor activity against melanoma; however, its in vivo efficacy and direct molecular interaction with CPEB4 remain unclear. In this study, a subcutaneous xenograft model using BALB/c nude mice was used to assess the in vivo antitumor effects of alkannin, and CPEB4 expression was analyzed via Western blotting. DARTS, CETSA, and SPR investigations were used to elucidate the interaction between alkannin and CPEB4. In addition, stable CPEB4-knockdown A375 melanoma cells were established to examine the effects of alkannin on cell proliferation, apoptosis, cell cycle progression, migration, invasion, and downstream signaling molecules. Alkannin markedly suppressed tumor growth in the xenograft model and reduced CPEB4 expression in a dose-dependent manner compared with the model group. DARTS and CETSA demonstrated alkannin-induced stabilization of CPEB4, while SPR analysis using purified recombinant CPEB4 showed a direct physical interaction with alkannin, with micromolar affinity. At the molecular level, alkannin downregulated CPEB4 and PRC1 expression (p < 0.05), whereas CPEB4 knockdown markedly suppressed MITF and PRC1 (p < 0.05). Notably, alkannin treatment alone did not significantly alter MITF protein expression under the present experimental conditions. Alkannin exerts antitumor activity against melanoma, while its interaction with CPEB4 and the associated molecular changes may contribute to cellular responses involving proliferation, survival, migration, invasion-related phenotypes, and mitotic regulation.

Hesperidin is a natural flavonoid derived from citrus plants, which can be hydrolyzed into hesperetin in vivo. Both compounds have anti-inflammatory, antioxidant and antitumor activities. At present, there is a lack of reviews focusing on the epigenetic regulation of cancer stem cells (CSCs) mediated by hesperidin and hesperetin. This review summarizes the molecular crosstalk between hesperidin/hesperetin and CSCs mediated via three major epigenetic pathways, including direct regulatory effects, indirect modulatory actions, and mechanistic relationships proposed based on scientific hypotheses. We elaborate their effects on inhibiting the self-renewal, invasion and metastasis of CSCs as well as reversing chemoresistance, and analyze the crosstalk between epigenetic networks and classical signaling pathways of CSCs. Furthermore, we discuss the core bottlenecks restricting the clinical transformation of these two compounds and introduce improvement strategies such as nanodelivery systems. Current research is still confronted with problems including CSC heterogeneity and the potential off-target toxicity of drugs. In conclusion, hesperidin and hesperetin may serve as potential candidate agents for epigenetic regulation targeting CSCs, which can offer novel theoretical basis for comprehensive tumor therapy.

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.