Cancer therapy remains limited by drug resistance and poor selectivity, while inflammation-driven tumor progression further complicates treatment outcomes. Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives due to their multifunctional properties. In this study, we investigated the anticancer and immunomodulatory activities of KI17, a rationally designed peptide derived from GL18, a peptide fragment identified from the talisin protein of Talisia esculenta. KI17 exhibited dose-dependent antiproliferative effects against murine and human melanoma (B16F10-Nex2, SK-MEL-2, A375) and cervical cancer (HeLa) cell lines, while displaying reduced cytotoxicity toward non-tumoral BV-2 microglial cells, resulting in a favorable selectivity index. Mechanistic analyses revealed that KI17 induces morphological alterations, mitochondrial dysfunction, caspase activation, and late-stage apoptosis, together with G0/G1 cell cycle arrest accompanied by accumulation of the Sub-G0 population, indicating coordinated regulation of cell death and cell cycle progression. KI17 effectively suppressed lipopolysaccharide (LPS)-induced microglial activation, markedly reducing pro-inflammatory cytokine and nitric oxide production without compromising cell viability. These biological activities are consistent with the peptide's optimized physicochemical features, including increased cationicity, amphipathicity, and α-helical folding. Overall, our findings demonstrate that KI17 combines selective anticancer activity with potent immunomodulatory effects, highlighting its potential as a bioinspired peptide for further preclinical development in cancer therapy.

Paclitaxel (PTX), a taxane-derived chemotherapeutic agent, is frequently used in the treatment of breast cancer (BC). Its anticancer effects are primarily associated with microtubule stabilization, disruption of cell-cycle progression, and triggering of apoptotic cell death. In the present study, we investigated the effects of PTX on the expression of genes involved in cancer-related pathways, energy metabolism, and drug resistance in four molecularly distinct BC cell lines: MCF-7, BT-474, SK-BR-3, and MDA-MB-231. The half-maximal inhibitory concentrations (IC50) of PTX in BC cell lines and the non-tumorigenic hTERT-HME1 breast epithelial cell line were determined by the MTT assay to assess cell cytotoxicity. BC cells were exposed to nine different concentrations of PTX for 24, 48, and 72 h to evaluate concentration- and time-dependent effects. Following treatment, total RNA was isolated and converted into cDNA, and RT-qPCR analysis was performed to investigate PTX-mediated alterations in the expression of genes associated with cancer-related pathways. The impact of PTX on the cell-cycle phase distribution and apoptotic cell death was evaluated by flow cytometry. Treatment with PTX for 48 h at concentrations of 12.60 nM in MCF-7, 5.09 nM in BT-474, 16.09 nM in SK-BR-3, and 36.66 nM in MDA-MB-231 cells reduced cell viability and increased apoptosis. PTX treatment also altered the expression of genes involved in apoptosis, cell-cycle regulation, angiogenesis, epithelial-mesenchymal transition, hypoxia-related signaling, energy metabolism, telomere maintenance, and therapy resistance. Collectively, these findings demonstrate that PTX elicits heterogeneous molecular and cellular responses across molecularly distinct BC cell lines, particularly in cell viability, apoptosis, metabolic regulation, and treatment response. These in vitro findings suggest potential molecular mechanisms that could explain why some cells are more sensitive to PTX than others, but further experimental and clinical validation is needed to confirm this.

Breast cancer is a highly heterogeneous malignancy with multiple molecular subtypes and variable treatment responses. Despite advances in endocrine therapy, HER2-targeted therapy, chemotherapy, and immunotherapy, treatment resistance and disease recurrence remain major clinical challenges. There is growing evidence that transcriptional plasticity and enhancer relinking contribute to tumor progression and treatment adaptation, highlighting the powerful role of epigenetic regulators. CREB-binding protein (CBP) and E1A-associated protein p300 (EP300) are transcriptional coactivators that regulate breast cancer enhancer activity and lineage-specific gene expression. Emerging research suggests that CBP/p300 is more of a context-dependent vulnerability point than a universal carcinogenic driver. ER-positive tumors exhibit a strong dependence on CBP/p300-mediated transcriptional programs, while the triple-negative breast cancer subgroup, including androgen receptor-positive and immunosuppressive tumors, may rely on CBP/p300-dependent signaling to maintain survival and treatment resistance. This is in contrast to their role in HER2-positive breast cancer. This review summarizes the biological functions of CBP/p300 in breast cancer and discusses subtype-specific vulnerability, biomarker-directed patient stratification, drug resistance mechanisms, rational combination strategies, and current translational challenges, emphasizing the need for precise treatment of breast cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, and the efficacy of conventional chemotherapy is frequently limited by systemic toxicity, chemoresistance, and tumor recurrence. Natural products derived from marine algae and plants have attracted increasing interest as multitarget adjuvant agents capable of modulating apoptosis, oxidative stress, and tumor-associated signaling pathways. In the present study, we evaluated the anticancer activity of commercially available formulations enriched in fucoxanthin, fucoidan, tocotrienols, astaxanthin, and apple polyphenols, either alone or in combination with doxorubicin (DOX), using two-dimensional and three-dimensional colorectal cancer models. Initial IC50 screening in ovarian (OVCAR3), prostate (PC3), colorectal (Caco2 and HT-29), and non-tumorigenic colon epithelial cells demonstrated that formulations 2.1 and 10.0 exhibited the most relevant cytotoxic activity, particularly in colorectal cancer cells. Combined treatments with DOX significantly reduced cell viability compared to individual treatments, particularly in Caco2 cells, where viability decreased to approximately 10% under combined exposure conditions. Mechanistically, combined treatments enhanced caspase-3/7 activation in both Caco2 and HT-29 cells, indicating apoptosis-associated effects. These findings were further supported in three-dimensional spheroid models, where supplement combinations impaired spheroid expansion, induced apoptotic AO/EB staining patterns, and reduced HT-29 spheroid growth by approximately 30-35%, reaching inhibitory effects comparable to DOX alone. Collectively, these results suggest that plant- and algae-derived formulations enriched in antioxidant bioactives may enhance chemotherapy-associated antitumor responses through apoptosis-related mechanisms and modulation of tumor-like growth behavior. The present findings support the further exploration of natural-product-based adjuvant strategies in colorectal cancer therapy using more clinically representative chemotherapeutic schemes and in vivo models.

This study investigates the combined effects of cisplatin (CDDP) and ε-viniferin (ε-VNF), a natural stilbenoid, on oxidative stress and apoptosis in HeLa cells. Cytotoxicity was assessed using the MTT assay, and IC50 values were determined as 28 µM for CDDP and 21 µM for ε-VNF. Synergistic and antagonistic combination ratios of these doses were tested. Oxidative stress was evaluated via Total Oxidant Status (TOS), Total Antioxidant Status (TAS), Oxidative Stress Index (OSI), Superoxide Dismutase (SOD), Reduced Glutathione (GSH), and Malondialdehyde (MDA). Apoptosis was measured using Annexin V-FITC/PI staining and caspase-9 activation assays. TAS levels significantly increased in all combination groups compared to the control (control: 266.7 ± 0.1 µmol/L; 20% combo: 2466.7 ± 1.0 µmol/L). OSI values decreased accordingly (control: 22.5 ± 7.1; 10% combo: 1.6 ± 0.5). GSH levels decreased in the combination groups (e.g., 20%: 0.8 ± 0.2 µM vs. control: 1.4 ± 0.1 µM), while MDA levels increased (20%: 3.8 ± 0.5 µM vs. control: 0.5 ± 0.1 µM). Caspase-9 positive cells increased markedly (20%: 55.0% vs. control: 13.2%), supporting activation of the mitochondrial apoptotic pathway. Annexin V analysis revealed increased late apoptosis (20%: 76.1%) and early apoptosis (20%: 17.0%).

Cancer multidrug resistance (MDR), particularly mediated by ATP-binding cassette (ABC) transporters, can link ABC transporters' ATP-dependent efflux to Nrf2-driven antioxidant defence. This connection reduces the oxidative threshold in MDR cancer cells. Natural or nature-inspired compounds can target this vulnerability and induce collateral sensitivity (CS) by simultaneously modulating the redox balance and ABC transporters' activity in MDR cancer cells. Moreover, natural-origin compounds can act on multiple targets by combining efflux inhibition, redox modulation, and immune evasion into a unique therapeutic strategy. However, many challenges should be addressed in their characterisation and preclinical validation to ensure their usefulness for clinical application. These include poor bioavailability, pharmacokinetic interactions, safe toxicity windows, and tumour heterogeneity. In perspective, adaptive trial designs employing biomarker-guided patient stratification can translate natural-origin compounds from preclinical promise to precision partners in clinical oncology.

Temozolomide (TMZ) remains the cornerstone of chemotherapeutic agent for glioblastoma (GBM), yet intrinsic and acquired resistance severely limits its clinical benefit. While O6-methylguanine-DNA methyltransferase (MGMT)-mediated repair of TMZ-induced O6-methylguanine (O6-meG) lesions has been extensively studied, the DNA mismatch repair (MMR) pathway is increasingly recognized as a key determinant of TMZ cytotoxicity. Canonical MMR, mediated by MutSα (MSH2-MSH6) and MutLα (MLH1-PMS2) complexes, recognizes O6-meG: thymine mispairs generated during replication and initiates futile repair cycles that culminate in replication stress, replication fork collapse, and apoptotic signaling; intact canonical MMR is, therefore, required for TMZ-induced cell death. Disruption of canonical MMR, frequently via acquired MSH6 mutations, confers TMZ tolerance and drives hypermutated recurrent GBM. Beyond mismatch correction, MMR proteins perform non-canonical functions in DNA damage signaling, replication stress responses, transcriptional regulation, chromatin dynamics, and immune modulation. These activities may shift the outcome from cytotoxic futile repair toward replication stress adaptation, Translesion synthesis (TLS)-mediated lesion tolerance, immune remodeling, and therapeutic resistance. Notably, partial attenuation or functional diversion of MMR may decouple lesion recognition from cytotoxic signaling, enabling TLS-mediated lesion tolerance without complete loss of MMR activity. This review integrates current insights into canonical and non-canonical MMR functions in GBM, defines their distinct contributions to TMZ sensitivity and resistance, and highlights therapeutic opportunities to exploit MMR-associated dependencies, including synthetic lethal strategies and immunotherapeutic vulnerabilities linked to MMR deficiency-driven hypermutation.

Epigenetic alterations promote colorectal cancer (CRC) development, plasticity, and drug resistance. Agents have been developed to target epigenetic modifiers; however, they demonstrate limited clinical efficacy. This outcome is the result of the complex interplay within the epigenome, as well as that of the molecular circuits linking these epigenetic vulnerabilities with genetic mutations, oncogenic pathways, and activation of transcription factors. Therefore, current evidence suggests these agents should be assessed in combination with regimens including additional epigenetic drugs, immune checkpoint inhibitors, monoclonal antibodies, and chemotherapeutic drugs. Herein, we highlight recent advances towards epigenome-centered treatment strategies in CRC. We also prioritize potential efforts of epigenetic-associated therapeutic modalities, which should be further developed following integration of respective biomarkers and as tools of therapeutic reprogramming in context-dependent cellular states.

Matrix metalloproteinase-9 (MMP9) is involved in extracellular matrix remodeling, inflammation, and metastasis, and its overexpression is associated with poor prognosis in lung cancer. However, the systems-level effects of MMP9 inhibition remain incompletely understood. We combined systems biology with experimental validation to characterize MMP9-centered signaling in non-small cell lung cancer (NSCLC) and identify downstream pharmacodynamic biomarkers. Network and pathway analyses revealed extracellular matrix- and inflammation-related interaction modules and prioritized an MMP9-associated gene panel. Synthesized compounds were evaluated using purified enzyme assays and A549 NSCLC cells. At 50 μM, compounds M34 and M33 showed the strongest inhibition of MMP9 activity (65.01% and 61.32%, respectively). Seven compounds (M1, M2, M8, M9, M10, M27, and M34) demonstrated antiproliferative activity at 72 h (IC50 = 40-115 μM), suppressed migration and colony formation, induced apoptosis, and reduced MMP9 protein expression. Quantitative PCR confirmed coordinated downregulation of MMP9, VEGFA, APP, and ETV4, with upregulation of CDH1, COL5A1, COL6A2, CCL2, and CCL17. Enrichment analysis linked these changes to inflammatory signaling, immune activation, and extracellular matrix remodeling. These findings establish an experimentally supported eight-gene pharmacodynamic biomarker signature and support biomarker-guided development of MMP9-targeted strategies in NSCLC.

KRAS G12C, long considered an undruggable oncogenic driver, has become one of the most consequential therapeutic targets in non-small cell lung cancer (NSCLC). The discovery of a cryptic binding pocket accessible in the GDP-bound state enabled covalent inhibitors-sotorasib and adagrasib-that have received regulatory approval for previously treated KRAS G12C-mutant NSCLC, with sotorasib demonstrating PFS and OS superiority over docetaxel in CodeBreaK 200 and adagrasib showing meaningful intracranial activity and a progression-free survival benefit over docetaxel in KRYSTAL-12. Yet response durability is limited by on-target switch-II pocket mutations, upstream RTK and SHP2-mediated bypass signaling, downstream MAPK and PI3K-AKT reactivation, phenotypic plasticity, and adverse modulation by co-occurring STK11, KEAP1, and TP53 alterations. Next-generation covalent inhibitors (divarasib, glecirasib, olomorasib), tri-complex RAS(ON) inhibitors (RMC-6291), pan-KRAS agents, and rationally designed combinations with EGFR, SHP2, SOS1, and PD-1 inhibitors are repositioning KRAS-directed therapy toward earlier lines of treatment. This review integrates the structural, signaling, and clinical biology of KRAS G12C with contemporary trial and real-world evidence to examine the emerging case for first-line KRAS G12C inhibition in genomically defined subsets of NSCLC. First-line use nonetheless remains investigational; platinum-based chemoimmunotherapy remains the standard of care outside of clinical trials, and a frontline indication will require confirmation from randomized phase III trials.

The present study investigates the pro- and anti-apoptotic responses of HepG2 liver cancer cells to Ornithogalum sigmoideum (O. sigmoideum) and Smilax excelsa (S. excelsa) extracts, aiming to identify their potential as anti-cancer agents. Methanolic extracts of O. sigmoideum and S. excelsa were prepared, and their phytochemical profiles were analyzed by Gas Chromatography-Mass Spectrometry (GC-MS). Cytotoxicity and IC50 values were determined in HepG2 cells using the MTT assay. The relative mRNA expression of apoptotic genes (BAX, BCL-2, and Caspase-3) was quantified by qPCR, and the treatment effect size was calculated using Cohen's d. GC-MS analysis revealed distinct phytochemical profiles; S. excelsa was rich in phenolic compounds, while fatty acid esters and alcohols dominated Ornithogalum extracts. O. sigmoideum bulb extract exhibited the strongest cytotoxicity (IC50 = 125.57 µg/mL), followed by the leaves (IC50 = 156.43 µg/mL), whereas Smilax showed minimal toxicity (IC50 = 304.15 µg/mL). Mechanistically, the O. sigmoideum leaf extract showed gene expression patterns consistent with pro-apoptotic signaling, including upregulation of BAX and Caspase-3 mRNA. O. sigmoideum extracts, especially from leaf parts, exhibit significant cytotoxicity, and the transcriptomic profile is consistent with apoptotic pathway activation in HepG2 cells, positioning it as a candidate for further mechanistic investigation.

Colon cancer is one of the leading causes of death, requiring advanced therapies that need models for developing new drugs. Conventional cell culture models do not accurately and precisely reproduce the complexity of the tumor microenvironment, limiting their usefulness in research and therapy development. To address this weakness, patient-derived organoids have emerged as promising in vitro models. The implementation of these organoid-based models into more physiologically relevant systems is expected to improve their clinical relevance. Thus, integrating these organoids into microfluidic chips acting as bioreactors will likely improve the predictive response of therapies in personalized medicine. In this article, we report the development of a new colon cancer organoid-on-a-chip model that enables the in vitro culture of patient-derived colon cancer organoids under continuous culture media flow. We demonstrate how the developed organoids were derived from tumor biopsies of patients with colorectal cancer, expanded in standard three-dimensional (3D) culture, and cultured inside the microfluidic chips. The microfluidic chip chambers are designed to house organoids in a controlled environment, allowing the injection of therapies and monitoring by optical microscopy in real time. The in vitro therapies tested were a combination of drugs based on 5-fluorouracil and oxaliplatin at different concentrations. As a result, we demonstrate for the first time that this model proves the capability of this technology for in vitro testing colon cancer therapies.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) represents a compelling pharmacological target for the development of agents designed to circumvent tumor resistance to topoisomerase 1 (TOP1) inhibitors, a major class of clinically relevant antineoplastic drugs. This paper describes the design and synthesis of novel hybrid TDP1 inhibitors combining coumarin and monoterpene moieties via rigid isoxazole and 1,2,3-triazole heterocyclic linkers. The synthesis was accomplished via [3 + 2] cycloaddition of nitrile oxides to alkynes and copper-catalyzed click chemistry. Biological tests have demonstrated the crucial role of linker nature in the activity of the compounds. Isoxazole-linked conjugates showed strong inhibitory effects on TDP1, with IC50 values in the submicromolar to low micromolar range (0.8-3.2 μM). Overall, these values slightly surpassed those of the triazole-linked analogues, whose IC50 values ranged from 1.1 to 23.3 μM. At noncytotoxic doses, compounds 26e and 16b enhanced the sensitivity of human cervical cancer (HeLa) cells to the antitumor agent topotecan, a TOP1 inhibitor, thereby supporting the promise of this structural class as components of combination chemotherapy.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that requires novel therapeutic targets and selective repurposed drugs with low systemic toxicity. Here, we evaluated the clinically approved M3 muscarinic receptor antagonist, Darifenacin (DF), against Jurkat and MOLT-4 T-ALL cells, as well as healthy human T lymphocytes, under identical conditions. DF induced selective, concentration-dependent cytotoxicity with IC50 values of 26.7 ± 1.07 µM (Jurkat) and 30.5 ± 1.54 µM (MOLT-4), whereas healthy T lymphocytes exhibited an apparent IC50 of 197.9 ± 1.29 µM, corresponding to a 6.5-7.4-fold therapeutic window. Mechanistically, DF decreased M3 receptor and choline acetyltransferase expression and increased acetylcholinesterase activity. Convergent multi-assay validation confirmed that this cytotoxicity was driven by activation of the intrinsic mitochondrial apoptotic pathway, as evidenced by increased Bax, decreased Bcl-2, and cleavage of the executioner caspase-3. Furthermore, DF induced glycative stress through the accumulation of methylglyoxal (MG) and advanced glycation end products (AGEs), and selectively inhibited lysosomal Cathepsins B and C. Molecular docking predicted highly favorable molecular binding within the catalytic cavities of these proteases. These findings suggest that DF exhibits selective antileukemic activity by simultaneously disrupting cholinergic signaling, inducing glycative stress, inhibiting cathepsins, and triggering apoptosis. Thus, DF emerges as a promising candidate for multi-target drug repurposing in T-ALL therapy.

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.