Search Results (437)

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor clinical response to gemcitabine, largely due to intrinsic and acquired mechanisms of chemoresistance. Identifying agents capable of enhancing gemcitabine efficacy without increasing cytotoxicity remains an unmet therapeutic need. Here, we characterise a small drug sensitiser molecule, B12, and evaluate its potential to sensitise PDAC cells to gemcitabine. Methods: Gemcitabine’s dose–response was assessed by MTT assay to determine IC₅₀ values and dose-modifying factor (DMF). Phenotypic consequences of co-treatment were examined using colony formation and wound scratch assays. Mitochondrial membrane potential (JC-1) and apoptosis (Annexin V/PI) were measured using flow cytometry. Transcriptomic profiling was performed using mRNA-seq with differential expression analysis and pathway enrichment (KEGG/GSEA). NF-κB activity was assessed by nuclear and cytoplasmic fractionation of p65, and RT-qPCR validation of NF-κB associated target genes. Results: B12 alone displayed minimal cytotoxicity in the PANC-1 cell line and normal pancreatic ductal HPDE cells, yet shifted the gemcitabine dose–response curve in PANC-1 cells, reducing the IC₅₀ and yielding a dose-modifying factor of 1.39. Functionally, B12 enhanced gemcitabine-induced suppression of colony formation and reduced wound closure relative to gemcitabine alone. The co-treatment also increased both mitochondrial depolarisation and apoptotic cell populations, with increased cell proliferation inhibition over time. Transcriptomic profiling identified a set of B12-associated genes downregulated both in B12-treated and B12 + gemcitabine conditions, including factors linked to growth, survival, inflammation, metabolism, and drug inactivation. Gene set enrichment analysis revealed negative enrichment of NF-κB associated pathways during B12 co-treatment. Consistently, nuclear-cytoplasmic fractionation showed that B12 reduced gemcitabine-induced nuclear accumulation of p65, accompanied by decreased expression of NF-κB associated targets such as BCL2L1, CCL20, SLC2A1, and MAP3K14. Conclusions: In PDAC cell models, B12 enhances gemcitabine cytotoxic response while displaying minimal intrinsic toxicity under the conditions tested. The sensitising phenotype is accompanied by increased apoptotic susceptibility and is associated with reduced NF-κB signalling at the pathway, transcript, and p65 nuclear localisation levels. However, to establish causality, the lack of sensitisation in HPDE cells will require further validation. Full article

Background: gemcitabine is a cytidine analog and major anticancer drug functioning as an antimetabolite. However, its administration by systemic route is accompanied by “burst” and side effects. To limit this, drugs are encapsulated in matrices; metal–organic frameworks (MOFs) are coordination polymers with strong potential for drug encapsulation and delayed release. Methods: mechano-chemical synthesis of solid-state binary complex lag(CYCU-3)(Gem) is described from aluminum MOF (Al-MOF) CYCU-3 and gemcitabine free base (Gem). Synthesis is conducted by liquid-assisted grinding (LAG) with dimethyl sulfoxide (DMSO) followed by its outgassing. The alternative “dry” synthesis results in dry(CYCU-3)(Gem). Materials were characterized by FTIR spectroscopy and XRD, and delayed Gem release was tested to phosphate buffered saline (PBS) at 37 °C. The in vitro toxicity to pancreatic cancer PANC−1 and healthy cells hTERT−HPNE E6/E7/K−RasG12D was assessed by fluorometric assay. Results: in lag(CYCU-3)(Gem) interactions MOF-drug are via non-covalent bonds at O-H and COO⁻ groups of CYCU-3 as found by FTIR marker peak shifts and crystal structure is retained, while dry(CYCU-3)(Gem) shows significant amorphization and loss of functional groups. The lag(CYCU-3)(Gem) but not dry(CYCU-3)(Gem) shows delayed Gem release for 6000 min. The suppression of PANC−1 cells by lag(CYCU-3)(Gem) is time-dependent and it correlates with delayed Gem release. For the first time, a concept of ternary stoichiometric complex lag(CYCU-3)₁(Gem)₁(CIT)₂ is tested that also contains natural organic compound citronellol (CIT), and its structure, bonding and release of Gem are compared to those of binary complex. Bonding is at the O-H groups of CYCU-3 and this complex shows delayed Gem release. Conclusions: binary and ternary complexes of Gem with CYCU-3 yield delayed release and cytotoxicity. LAG is promising for synthesis of solid-state complexes of gemcitabine for delayed release and time-dependent suppression of cancer cells. Full article

Background: Pancreatic cancer (PC) and colorectal cancer (CRC) are among the most lethal malignancies, with growing evidence pointing to the gut microbiota’s role in their progression. This study aimed to explore the anticancer potential of two microbiota-derived postbiotics, N-acetylcysteine (NAC) and tetrahydro β-carboline carboxylic acid (THC), in targeting some hallmark traits of PC and CRC, both as standalone agents and in combination with standard chemotherapeutics (gemcitabine for PC and 5-fluorouracil (5-FU) for CRC). Methods: Cell viability assays and IC₅₀ determination was assessed using either the Muse™ Count & Viability Kit or the Sulforhodamine B assay; cell death was determined by Annexin V/Propidium Iodide and cell cycle assessed by Propidium Iodide was analyzed by flow cytometry. Results: Here, we found that NAC selectively reduced the viability of PC cells BxPC-3 without triggering apoptosis, while effectively inducing apoptosis in PC cells Panc-1 and in CRC cell lines. THC exhibited stronger anticancer activity, inhibiting proliferation and promoting apoptosis in all tested PC and CRC cells, even at lower concentrations. Combination treatments yielded promising enhancement effects. NAC enhanced the cytotoxicity of gemcitabine in Panc-1 cells through increased apoptosis. NAC, when combined with 5-FU, also increased apoptosis of CRC cells. THC further potentiated gemcitabine’s impact on Panc-1 cells by increasing apoptosis and by inducing cell cycle changes in BxPC-3. In the CRC model, THC co-treatment with 5-FU reduced cell viability and increased apoptosis in all cells. Conclusions: These findings provide preliminary in vitro evidence supporting the potential of integrating microbiota-derived postbiotics with conventional chemotherapy both in PC and CRC. Full article

Background: Three-dimensional (3D) cancer models are currently essential tools in high-throughput screening (HTS), serving as a bridge between in vitro and in vivo approaches during drug development. Even though spheroids offer many advantages over 2D cultures, analyzing 3D cultures with heterogeneous morphology remains challenging due to the lack of standardized visualization techniques and multiparameter analysis. Methods: In this work, an optimized CellProfiler pipeline and a Python algorithm for weighting morphological features are used to visualize, extract, and analyze morphological data from spheroids derived from colorectal and pancreatic cancer cell lines with diverse morphologies (HCT116, LoVo, PANC-1, and CFPAC-1). Results: We developed a feature weighting process that combines multiple morphological parameters into a single metric using principal component analysis (PCA). There is a strong correlation between this process and a standard Alamar Blue proliferation assay (r = 0.89, ρ = 0.91, p < 0.001). Using this method, we were able to ascertain the IC₅₀ values of substances that did not produce results in cell lines with heterogeneous morphology (LoVo and CFPAC-1) using a standard proliferation assay. Conclusions: By removing the need for tracer dyes, the resulting methodology may lower costs while accelerating preclinical drug development through informative multiparameter analysis of compound efficacy. Full article

MICB-targeting CAR-NK (chimeric antigen receptor-modified natural killer cells) therapy may serve as off-the-shelf immunotherapy. We designed soluble Anti-MICB-scFv blocks tumor immune evasion targeting the MICB antigen, thereby enhancing CAR-NK cytotoxicity while reactivating endogenous immune attacks against malignancies. The Anti-MICB-CAR includes two Anti-MICB-scFv connected by an F2A linker, the CD8 hinge and transmembrane domain, the 4-1BB co-stimulatory domain, the CD3ζ activation domain, and IL-15. The expression efficiency of Anti-MICB-CAR in NK cells was investigated by flow cytometry; ELISA demonstrated that Anti-MICB-CAR-NK secreted free Anti-MICB-scFv and detected IL-15 secretion. Flow cytometry and CCK8 were utilized to study Anti-MICB-CAR-NK on tumor cell viability. The PANC-1 xenograft model was established in order to elucidate the anti-tumor effects of Anti-MICB-CAR-NK in vivo. In vitro investigations have demonstrated that the treatment of tumor cells with Anti-MICB-CAR-NK supernatant + NK cells or Anti-MICB-CAR-NK cells not only significantly increased the cytotoxic activity of tumor cells, but also secreted and produced higher levels of IL-15, IFN-γ, TNF-α, perforin, and granzyme B compared with NK cells. Anti-MICB-CAR-NK cells exhibit strong cytotoxic activity against tumor cells with high MICB expression. In vivo, Anti-MICB-CAR-NK cells exhibited a substantial inhibitory effect on tumor growth. The IHC results reveal that Anti-MICB-CAR-NK cells show a more pronounced ability to infiltrate the tumor. We demonstrated the successful expression of Anti-MICB-CAR in NK cells, which enhances the anti-tumor activity of NK cells both in vitro and in vivo. This stress ligand-targeting approach provides a promising strategy for solid tumors. Full article

Sacha inchi (P. volubilis L.), an ancient oilseed crop native to the Amazon, is gaining attention for its high nutritional value particularly due to its ω-3-, -6-, -9-rich oil. However, most research has focused mainly on oil characterization, neglecting the potential of its by-products, such as the Sacha inchi oil-press cake (i.e., the solid residue after oil extraction). This study explores the chemical composition of Sacha inchi oil press-cake powder, focusing on fatty acid and amino acid profiles, antinutrient factors, total phenolic content, antioxidant activity, and the bioactivity of its extracts on cellular models. Fatty acid analysis revealed a high proportion of polyunsaturated fatty acids, especially α-linolenic acid (42.52%), making it a valuable resource for health-promoting applications. The protein content was also significant (41.86%), with a balanced amino acid composition, including essential amino acids such as leucine, valine, and isoleucine, which are vital for muscle protein synthesis and energy metabolism, in food and/or feed applications. Antinutritional factors were detected, including saponins (1050.1 ± 1.1 mg/100 g), alkaloids (2.1 ± 0.5 mg/100 g), and tannins (6.2 ± 0.9 mg/100 g). While these phytotoxins could limit their use in food applications, their potential antimicrobial activity highlights promising pharmacological opportunities. Total phenolic content (TPC) and antioxidant activity (AO) were evaluated using two extract mixtures differing in composition and polarity, with the acetone/water/acetic acid solvent (80/19/1 v/v/v) showing the highest antioxidant properties. The extract obtained showed cytotoxic effects against Panc-1 cancer cells, highlighting its potential in nutraceutical and pharmaceutical applications. This study underscores the unexploited potential of Sacha inchi by-products, such as the oil press-cake, as a sustainable resource of bioactive compounds for functional products, supporting circular bio-economy strategies by plant-based waste and local biodiversity valorization. Full article

Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A₂ (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed derivatives retaining BE’s backbone while modifying tail groups to improve its properties. A concise total synthesis enabled a versatile late-stage intermediate (compound 17), serving as a platform for efficient diversification of BE analogs via modular click chemistry. This approach introduced a central triazole ring connected by flexible alkyl spacers. Key properties, including lipophilicity, solubility, and Caco-2 permeability, were experimentally determined. These derivatives exhibited reduced lipophilicity and improved solubility but unexpectedly lost cellular activity. Direct target engagement studies using MicroScale Thermophoresis (MST) revealed compound-dependent deactivation mechanisms: certain derivatives retained binding to eEF1A1 with only modestly reduced affinity (e.g., compound 29), while others showed no detectable binding (e.g., compound 31). Microsecond-scale molecular dynamics simulations and free-energy calculations showed that, for derivatives retaining target affinity, tail modifications disrupted the delicate balance of drug–membrane and drug–solvent interactions, resulting in substantially higher transmembrane free-energy penalties (>5 kcal/mol) compared to active compounds (<2 kcal/mol). These insights emphasize the need to simultaneously preserve both target engagement and optimal permeability when modifying side chains in cell-permeable macrocyclic peptides, positioning compound 17 as a robust scaffold for future lead optimization. This work furnishes a blueprint for balancing drug-like properties with therapeutic potency in macrocyclic therapeutics. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, largely due to its dense stromal architecture and poor intratumoral drug penetration. To address this challenge, IMP305 was developed as an ultrasound-sensitive liposome for tumor-localized drug release. In particular, IMP305 is dominantly capable of release by ultrasound-mediated cavitation. Methods: This ultrasound-sensitive liposome integrates tumor-specific drug delivery with cavitation-induced loosening of the stromal architecture in PDAC, thereby enabling more efficient intratumoral drug release using PANC-1 xenografted mouse. Results: The maximal tolerance dose of exatecan was increased by encapsulation into IMP305. Cavitation-triggered structural disruption of IMP305 was 84.68 ± 6.21%, which resulted in a robust release of approximately 84.4 ± 1.95% of the encapsulated exatecan. In PANC-1 xenograft models, IMP305 exhibited a maximal tolerance dose approximately four times higher than that of free exatecan and demonstrated markedly superior antitumor ability. Especially, IMP305 combined with focused ultrasound achieved the most pronounced therapeutic benefit, demonstrating a 49.17 ± 9.00% reduction in tumor volume at day 48 and an 80% survival rate at day 60. Conclusions: In conclusion, these findings demonstrate that ultrasound-activated IMP305 significantly enhances intratumoral accumulation and release of exatecan, resulting in superior tumor suppression while mitigating systemic toxicity. Full article

A promising strategy for pancreatic cancer therapy involves developing nanocarriers capable of simultaneously delivering various antitumor substances with diverse physicochemical properties, often resulting in synergistic effects. In the present work, novel biocomposites were developed using amphiphilic N-vinylpyrrolidone polymer incorporating bortezomib (BTZ) and modified with either the DR5-selective TRAIL cytokine (DR5-B) or its fusion with the iRGD effector peptide (DR5-B-iRGD), resulting in AmphPVP-BTZ-DR5-B and AmphPVP-BTZ-DR5-B-iRGD formulations. The release of BTZ was most extensive at acidic pH 5.6, mimicking endolysosomal compartments, while at near-neutral pH 7.4 and alkaline pH 8.2 the release was slower and less complete, indicating a smart pH-responsive behavior suitable for triggered release in the tumor microenvironment. Both AmphPVP-BTZ-DR5-B and AmphPVP-BTZ-DR5-B-iRGD significantly inhibited the growth of pancreatic adenocarcinoma cell lines PANC-1, BxPC-3, and MIA PaCa-2 and induced more rapid internalization of the DR5 receptor in MIA PaCa-2 cells than unmodified particles and free DR5-B or DR5-B-iRGD. Importantly, AmphPVP-BTZ-DR5-B-iRGD exhibited a more pronounced DR5 internalization rate and cytotoxic effect than AmphPVP-BTZ-DR5-B owing to the presence of fusion protein with internalizing iRGD peptide. Both biocomposites induced cell death via the apoptotic pathway while exhibiting minimal cytotoxic effects on healthy cells. Therefore, biocomposites incorporating BTZ and functionalized with DR5-selective TRAIL variants DR5-B or DR5-B-iRGD represent a promising avenue for future studies in pancreatic cancer animal models. Full article

Background: The combination of manganese porphyrins (MnPs) and ascorbate (ASC) represents a promising redox-based therapeutic approach for selectively targeting cancer cells. We investigated the cytotoxic effects of two structurally distinct MnPs (MnTPPS and MnF₂BMet) with differing lipophilicity and potential membrane permeability in combination with ASC. Methods: Cancer cell lines (MCF-7, PANC-1, U87, T98G, AT-2) and normal human dermal fibroblasts (HDFs) were treated with MnTPPS and MnF₂BMet in the absence or presence of ASC. Viability, migration potential, and intracellular oxidative stress were assessed using single-cell methods. Results: MnPs alone exhibited no intrinsic cytostatic or cytotoxic activity, as confirmed by proliferation, viability, and motility assays. When combined with ASC, both MnTPPS and MnF₂BMet significantly enhanced ASC-induced oxidative stress, leading to lipid peroxidation, glutathione depletion, mitochondrial dysfunction, and cell membrane disruption. Time-lapse microscopy revealed rapid necrotic cell death under co-treatment. Catalase fully abolished cytotoxicity, indicating the essential role of hydrogen peroxide. In contrast, dehydroascorbate (DHA), which increases intracellular ASC levels, did not induce the same toxicity, suggesting that extracellular ROS generation contributes predominantly to the observed effects. Normal fibroblasts were minimally affected, supporting the MnPs–ASC system’s selectivity toward cancer cells. Conclusions: MnTPPS and MnF₂BMet enhance extracellular oxidation of ascorbate and subsequent ROS production, leading to selective oxidative-stress-mediated cancer cell death. This study supports the potential of MnPs–ASC redox catalysis as a complementary oxidative-stress-based anticancer strategy and highlights the need for further mechanistic and structure–activity investigations. Full article

The tumour microenvironment in pancreatic ductal adenocarcinoma (PDA) regulates vascular function and therapeutic response. P21-activated kinases (PAKs) regulate cytoskeletal dynamics and angiogenesis; however, their roles in vascular reprogramming and chemotherapy responses remain unclear. This study examined the effects of a PAK1 knockdown (PAK1KD) and a PAK4 knockout (PAK4KO) on vascular remodelling in PDA. Human PANC-1 wild-type (WT), PAK1KD, and PAK4KO cells were injected subcutaneously into the flanks of SCID mice followed gemcitabine treatment. The tumour growth, vascular density, pericyte coverage, adhesion molecules, and hypoxia were determined. A proteomics study was used to identify the molecular changes involved in the vascular pathways. PAK1KD suppressed tumour growth and angiogenesis, promoted vascular normalisation, reduced hypoxia, and increased stromal ICAM-1. PAK4KO inhibited tumour growth, enlarged vessels, enhanced angiogenesis, and reduced hypoxia. PAK4KO did not affect adhesion molecules in the absence of gemcitabine, but markedly upregulated ICAM-1 and VCAM-1 with gemcitabine. Additionally, PAK4KO promoted vascular mimicry (VM) with a compromised integrity in tumour-derived vessels, but enhanced the integrity in endothelial-derived vessels. The proteomics study confirmed the enrichment of molecules in fibronectin and the VEGF pathway in PAK4KO cancer cells, along with the upregulation of EphA2, RhoA, ROCK1, ROCK2, and components of the EPH-ephrin signalling pathway, linking to enhanced VM. Neither PAK1KD nor PAK4KO increased the gemcitabine efficacy. In conclusion, PAK1KD and PAK4KO suppressed tumour growth with distinct vascular effects, but failed to enhance the gemcitabine responses, suggesting that PAK targeting reprograms the PDA vasculature, but offers limited benefit in chemotherapy-resistant models. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by late-stage diagnosis, dense stromal barriers, and resistance to conventional therapies. The tumor microenvironment (TME), marked by hypoxia, aberrant vasculature, and metabolic reprogramming, supports tumor persistence and immune evasion. Targeting metabolic and oxidative vulnerabilities in the TME offers a promising strategy to improve treatment outcomes. This study evaluated the combined effects of photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA), a precursor to the natural photosensitizer protoporphyrin IX (PpIX), and dichloroacetic acid (DCA), a mitochondrial function modulator, in the KRAS-mutated PANC-1 pancreatic cancer cell line. The combination of 5-ALA–PDT and DCA significantly reduced cell viability compared with either treatment alone. Mechanistic analyses revealed activation of multiple regulated cell death pathways, including mitochondria-mediated apoptosis, immunogenic cell death (ICD), and ferroptosis. This was evidenced by increased reactive oxygen species (ROS), loss of mitochondrial membrane potential (ΔΨm), release of danger-associated molecular patterns (DAMPs) such as ATP, and lipid peroxidation. DCA amplified PDT-induced oxidative stress, overcoming redox defenses and enhancing ferroptotic and immunogenic responses. These findings suggest that combining DCA with PDT enhances multimodal cell death in PDAC, providing a rationale for further in vivo studies to validate this redox–metabolic approach to treating chemoresistant pancreatic tumors. Full article

The Altai Republic remains a geographic region with an uncovered microbial diversity hiding yet undescribed potential species. Here, we describe the strain al37.1^T from the Altai soil. It showed genomic similarity with the Bacillus mycoides strain DSM 2048^T. However, the in silico DNA–DNA hybridization (DDH) was 61.6%, which satisfies the accepted threshold for delineating species. The isolate formed circular, smooth colonies, in contrast to the rhizoidal morphology typical of B. mycoides. The strain showed optimal growth under the following conditions: pH 6.5, NaCl concentration 0.5% w/v, and +30 °C. The major fraction of fatty acids was composed of C_16:0 (34.77%), C_18:1 (15.20%), C_14:0 (9.06%), and C_18:0 (7.88%), which were sufficiently lower in DSM 2048^T (C_16:0–15.6%, C_14:0–3.7%). In contrast to DSM 2048^T, al37.1^T utilized glycerol, D-mannose, and D-galactose, while being unable to assimilate D-sorbitol, D-melibiose, and D-raffinose. The strain contains biosynthetic gene clusters (BGCs) associated with the production of fengycin, bacillibactin, petrobactin, and paeninodin, as well as loci coding for insecticidal factors, such as Spp1Aa, chitinases, Bmp1, and InhA1/InhA2. The comparative analysis with the 300 closest genomes demonstrated that these BGCs and Spp1Aa could be considered core for the whole group. Most of the strains, coupled with al37.1^T, contained full nheABC and hblABC operons orchestrating the synthesis of enteric toxins. We observed a cytotoxic effect (≈19 and 22% reduction in viability) of the strain on the PANC-1 cell line. Given the unique morphological features and genome-derived data, we propose a new species, B. altaicus, represented by the type strain al37.1^T. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with a severe stromal reaction mediated by pancreatic stellate cells (PSCs), leading to increased resistance to chemotherapy and radiotherapy. Following a repurposing concept, this preclinical study investigates the potential of approved drugs, known to be modulators of cellular copper transport, in combination with cisplatin for therapeutic approaches in PDAC. Two major strategies were pursued: (i) inhibiting copper transporters ATP7A and B with tranilast (TR) and omeprazole (OM) to block the cellular copper and, potentially, also cisplatin efflux, and (ii) using the chelator elesclomol (ES) to elevate intracellular copper and cisplatin levels. Human cell lines PanC-1 (PDAC), HPaSteC (PSC), and their co-culture, as well as the hepatocellular carcinoma cell line HepG2 as a reference model, were used. In addition to an analysis of the expression of copper transport proteins, the dynamics of cellular copper uptake and transport were monitored using a [⁶⁴Cu]CuCl₂ radiotracer approach. In vitro, all drugs enhanced cellular copper uptake and/or reduced copper efflux. Moreover, all drugs contributed to the enhanced cellular anticancer activity of cisplatin, with ES being the most effective compound. The results suggest that the targeted modulation of copper transport mechanisms may offer novel adjuvant approaches for the treatment of PDAC. Full article

Tamoxifen is a well-established selective estrogen receptor modulator (SERM) widely used in breast cancer treatment, yet its efficacy varies across tumor types. To enhance its antitumor potential, we previously synthesized and investigated novel ferrocene-linked (T5, T15) derivatives. This publication is a close continuation of this work, introducing a new indene-based (T6) derivative. Objectives: The main aim of this study was to further broaden our knowledge of the mechanism behind the increased antitumor effect of the ferrocene-linked drugs (T5 and T15) and compare it with a new, indene-based tamoxifen derivative, T6. The indene moiety was selected as a rigid, hydrophobic aromatic unit to probe pharmacological effects independent of ferrocene’s redox activity. Methods: The compounds were tested on MCF7, MDA-MB231 and PANC1 cells. Cell viability was assessed with the AlamarBlue assay and the xCELLigence SP system. Reactive oxygen species (ROS) production was measured with the ROS Glo assay. Flow cytometry and RT-qPCR experiments were conducted to assess apoptosis and ROS regulation as well. Results: The modified compounds demonstrated an increased cell-viability-decreasing effect in breast (MCF7, MDA-MB-231) and pancreatic (PANC1) cancer cell lines, influencing both estrogen-receptor-dependent and -independent pathways. T6 led to G2/M phase arrest in PANC1 cells. Beyond cell cycle disruption, these derivatives significantly elevated ROS levels, contributing to apoptosis. Conclusions: Our findings suggest that these structural modifications retain tamoxifen’s pharmacophore properties while expanding its mechanism of action, particularly through universal interactions independent of the ER status of tumor cells. The enhanced antitumor effects highlight the potential of these derivatives as promising candidates for improved cancer therapies. Full article