Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, highlighting the need to identify novel bioactive compounds with antitumor potential. Natural products constitute a valuable source of molecules with anticancer activity. In this study, we performed a comparative analysis of two classes of natural compounds-sesquiterpene lactones (achillin and polymatin A) and naphthoquinones (α, β-lapachone and lapachol)-in human PDAC cell lines on cell proliferation, metabolic activity and cell death induction and early mitochondrial alterations. Achillin showed limited antiproliferative, metabolic, and cytotoxic activity, whereas polymatin A exhibited activity in the micromolar range, yielding LC50 values of 16.11 ± 2.27 μM and 20.00 ± 1.90 μM for PANC-1 and MIAPaCa-2 cells, respectively. The naphtoquinones α- and β-lapachone effectively inhibited proliferation and metabolic activity and triggered cell death in both PDAC cell lines, with β-lapachone consistently displaying the highest activity with an LC50 of 4.00 ± 0.07 μM for PANC-1 cells and 3.89 ± 0.50 μM for MIAPaCa-2. Interestingly, achillin, polymatin A, α- and β-lapachone selectively induced cell death while sparing PBMCs. In contrast, lapachol showed weak activity, failing to achieve 50% inhibition or cell death within the tested concentration range and lacking tumor selectivity. Mechanistically, quinone derivatives promoted early mitochondrial superoxide modulation and membrane depolarization, consistent with a redox-active profile, whereas sesquiterpene lactones induced mitochondrial depolarization with limited mitochondrial superoxide overproduction, suggesting a distinct bioenergetic disruption phenotype. Overall, these findings highlight structure-activity relationships among natural compounds and support further investigation of achillin, polymatin A and α,β-lapachone as promising molecular scaffolds in PDAC research.

Three new Mn(II) complexes with imidazo[1,2-a]pyridine derivatives were synthesized and structurally characterized in a solid state by single crystal X-ray diffraction, FT-IR and Raman spectroscopy, and thermal analyses. The investigated compounds include [Mn(3-Climpy)2Cl2(MeOH)2] (1), [Mn(3-Brimpy)2Cl2(MeOH)2] (2), and a rare double chloro-bridged coordination polymer [Mn(impy)2Cl2]n (3). Spectroscopic studies were used to assess their potential stability in DMEM (Dulbecco's Modified Eagle Medium), and encapsulation in Pluronic P-123 micelles improved their solubility in aqueous solution, as well as cellular uptake and selectivity. Biological evaluation revealed negligible cytotoxicity against most cancer and control cell lines, but unexpectedly high activity against pancreatic adenocarcinoma (PANC-1), exceeding that of cisplatin. Complex 2, bearing a bromine substituent in the imidazole ring, showed the strongest effects, correlating with enhanced intracellular accumulation, reactive oxygen species (ROS) generation, and mitochondrial membrane potential disruption. Molecular docking and protein binding assays demonstrated moderate affinity toward human serum albumin (HSA) and transferrin, whereas DNA interaction was weak and non-damaging. These results highlight the structure-activity relationship of Mn(II) imidazo[1,2-a]pyridine complexes and support their potential as targeted redox-active agents against pancreatic cancer, with polymeric encapsulation providing an effective strategy to enhance biological performance.

The design, production, and study of new poly[ADP-ribose] polymerase 1 (PARP-1) inhibitors have emerged as an interesting exploration area, since PARP-1 is an overexpressed enzyme in several carcinomas. In this sense, menadione, or vitamin K3, is well known for its use in correct blood clotting, and for the generation of reactive oxygen species, but it is important to mention that it has been used as an antineoplastic agent against several cell lines. Related to the last commentary, in this work, four novel molecules (2-5) were produced from menadione through a Michael addition protocol, using 1,2-ethanedithiol, cysteamine, benzene-1,4-dithiol, and 4-aminobenzenethiol as nucleophiles, and menadione (1) as substrate, to evaluate them as plausible candidates to inhibit PARP-1. It is convenient to note that after their production and spectroscopic characterization, both docking and theoretical studies for each compound were conducted, using density functional theory (DFT) with the hybrid method B3LYP with the 6-311G(d,p) basis set. As a complement, the reactivity properties determined by DFT calculations were obtained for all compounds; the results revealed that 2 has the best properties to bind with PARP-1, and 3 offered good results. Hence, the target compounds were evaluated in vitro, determining their activity against PARP-1, using olaparib as a reference. Molecules 2 and 3 displayed the free binding energy values -7.97 and -9.35 kcal/mol, respectively, but 2 has the best IC50 value, 13.76 µM. It is important to highlight that 2 and 3 must be considered as potential new inhibitor agents against PARP-1, exhibiting competitive IC50 values with olaparib.

Breast cancer represents a persistent global health burden, marked by extensive molecular heterogeneity and frequent therapeutic resistance in aggressive subtypes, particularly triple-negative breast cancer (TNBC). These clinical challenges underscore the urgency for alternative therapeutic strategies. Bioactive alkaloids isolated from Nelumbo nucifera, especially the bisbenzylisoquinoline compounds liensinine (LIE), isoliensinine (ISO), and neferine (NEF), have emerged as promising candidates due to their ability to disrupt oncogenic signaling pathways and inhibit malignant cellular transformation. The present study conducted a systematic investigation of LIE, ISO, and NEF across multiple breast cancer cell lines, including highly aggressive TNBC models. Results revealed potent growth-inhibitory effects mediated through apoptosis induction and cell cycle arrest at both the G1 and G2/M phases. Furthermore, transcriptomic profiling and molecular analysis identified LIE as a principal effector, driving extensive transcriptional reprogramming and targeting the MAPK and mTOR pathways as core regulators of its anti-cancer efficacy. Collectively, these findings define a mechanistic framework for the anti-cancer potential of N. nucifera-derived alkaloids and provide a compelling foundation for their development as therapeutic candidates for advanced breast cancer.

Studies of natural products and their semisynthetic derivatives are a valuable source of therapeutic agents. The aim of this work was to obtain new 30-phosphoramidate derivatives of betulin and determine their biological potential. The synthetic approach utilized the Staudinger reaction (the introduction of a phosphoramidate group), the Steglich reaction (the introduction of an alkynyl group), and the Jones reaction (the introduction of a carboxyl group). The structures of the target compounds were determined using spectroscopic methods (1H NMR, 13C NMR, 31P NMR, and HRMS). The new derivatives were tested for antiproliferative activity against MV4-11, A549, MCF-7, PC-3, and HCT116 cancer cells and against normal MCF-10A cells using the MTT and SRB methods. Apoptosis studies were performed for the most active compounds (6B and 7A), potential molecular targets (AutoDock software) were identified, and lipophilicity parameters (RP-TLC method, SwissADME website) were determined. The greatest effect on apoptosis and caspase 3/7 activation was observed for the diester derivative 7A. Compound 7A showed a high lipophilicity parameter in the study group.

Multitarget-directed ligands offer a promising strategy for overcoming tumor complexity through simultaneous modulation of complementary oncogenic pathways. In this work, a novel (E)-6-(3-(4-methyl-2-thioxo-2,3-dihydrothiazol-5-yl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (compound 6) was synthesized and evaluated as a dual inhibitor of tubulin polymerization and tumor-associated carbonic anhydrases (CAs) IX and XII. Compound 6 displayed potent antiproliferative activity, particularly against MDA-MB-231 triple-negative breast cancer cells (IC50 = 0.37 µM), with excellent selectivity toward non-tumorigenic cells. Mechanistic studies demonstrated strong tubulin polymerization inhibition (IC50 = 3.40 ± 0.09 µM) and submicromolar inhibition of CA IX (IC50 = 0.102 ± 0.005 µM) and CA XII (IC50 = 0.213 ± 0.004 µM), accompanied by downregulation of CA-IX and CA-XII protein expression. Cellular investigations revealed pronounced G2/M phase arrest and apoptosis induction via mitochondrial signaling and caspase activation. Anti-angiogenic activity was supported by inhibition of endothelial migration and concentration-dependent suppression of VEGFR-2 (Tyr1175) phosphorylation in HUVEC cells. Human liver microsomal assays indicated measurable metabolic stability, while molecular docking and in silico ADMET predictions supported target engagement and drug-like properties. Collectively, these findings identify compound 6 as a promising multitarget anticancer lead integrating antimitotic, metabolic, and anti-angiogenic mechanisms.

Background: Tamoxifen remains the cornerstone of endocrine therapy for hormone receptor-positive breast cancer across Africa. Understanding the factors that influence tamoxifen tolerability is critical, as treatment-related side effects can reduce adherence and compromise therapeutic outcomes. Yet, the contribution of pharmacogenetic variation to tamoxifen-related toxicity remains poorly characterized in African populations. This study, therefore, investigated whether genetic variation in key pharmacogenes influences the risk of treatment-related side effects in a South African breast cancer cohort. Methods: A total of 166 women of Mixed and African Ancestry treated with 20 mg/day tamoxifen at Groote Schuur Hospital, South Africa, were included in the study. Genetic variation across 28 variants in nine pharmacogenes, including CYP2D6, CYP3A4/5, UGT1A4, UGT2B7/15, SULT1A1/2, and SULT1E1, was assessed using various genotyping methods. Associations between genetic and non-genetic factors and tamoxifen side effects were evaluated with logistic regression. Results: Over 70% of participants reported at least one treatment-related side effect. Overall side-effect burden was associated with SULT1A1 copy number variation (p = 0.030) and SULT1E1 rs3736599 (p = 0.042). Musculoskeletal complaints were the most common (40%) and were associated with UGT2B7 rs7439366 (p = 0.040) and CYP3A4 rs2242480 (p = 0.051). Gynecological symptoms affected more than 20% of participants and were linked to SULT1A2*2 (p = 0.050), SULT1E1 rs3736599 (p = 0.016), and UGT2B15 rs4148269 (p = 0.039). Hot flashes were frequent, affecting 33% of patients, but showed no clear pharmacogenetic associations. Conclusions: This study demonstrates that pharmacogenetic variation is associated with interindividual differences in treatment-related side effects, underscoring the need to expand research in African populations to better inform precision endocrine therapy.

Copper-organic compounds are being investigated as antitumor candidates. Besides their efficacy as cytotoxic agents alone, the oxidative potential of electrochemical Cu2+-to-Cu1+ transition emerges as an attractive approach for elimination of tumor cells otherwise resistant to chemotherapy. To minimize side effects of the potent oxidative burst upon Cu(II) reduction, the metal cations should be delivered to the tumor site. Taking advantage of the ability of bisphosphonates to accumulate in the bone, we synthesized a Cu(II) complex of zoledronic acid (ZA), an FDA-approved drug for prevention of bone destruction. The CuZA complex obtained upon precipitation of ZA and different copper salts (sulfate, chloride or perchlorate) were structurally identical, consisting of two organic moieties coordinated by three metal cations. Combined treatment with water-soluble formulations of CuZA and cysteine triggered rapid death in human cell lines. This effect was achievable with non-toxic concentrations of CuZA and cysteine alone. Importantly, the K562 chronic myelogenous leukemia cells that demonstrated an attenuated response to the 3d generation Bcr-Abl tyrosine kinase inhibitor in the medium conditioned by bone marrow-derived fibroblasts, were readily killed by CuZA-cysteine combination. Thus, oxidative burst upon metal reduction in CuZA complexes emerges as a promising method of eradication of tumor cells in the bone microenvironment.

Heat-shock factor 1 (HSF1) is a multifunctional transcription factor whose overexpression is associated with the development, progression, and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). In the present study, we thoroughly investigated the antitumor activity of NXP800, a recently developed HSF1 inhibitor that is currently tested in clinical trials, on HCC growth. We discovered that NXP800 inhibits the cell growth of human HCC cell lines by reducing proliferation, inducing apoptosis, and causing DNA damage. At the metabolic level, NXP800 significantly decreased mitochondrial respiration, which was associated with extensive structural alterations in the mitochondria, and reduced glycolysis of HCC cells. At the molecular level, NXP800 administration led to the upregulation of the integrated stress response and downregulation of the E2F1 signaling cascade. In addition, NXP800 profoundly constrained the growth of HCC patient-derived organoids. Furthermore, NXP800 antitumor properties were significantly augmented when NXP800 was coupled with the DNA-damaging agent doxorubicin or the PARP inhibitor olaparib. Our investigation indicates that NXP800 has significant antitumor activity and might represent a promising therapeutic agent for the treatment of human HCC.

Glioblastoma is the most aggressive primary malignant tumor of the central nervous system in adults, with a poor prognosis and high resistance to conventional therapies. Platinum drugs like cisplatin are effective but limited by systemic toxicity, poor blood-brain barrier penetration, and resistance. Natural compounds are increasingly studied for their anticancer potential and ability to enhance existing therapies. Based on this rationale, we designed Pt(IV)Ac-GA, a novel platinum(IV) complex obtained by conjugating cisplatin with ganoderic acid A, a triterpenoid from Ganoderma lucidum known for anticancer and immunomodulatory effects. The compound was synthesized, structurally characterized, and showed high stability and favorable pharmacokinetics. In vitro, Pt(IV)Ac-GA strongly reduced the viability of U251 and T98G glioblastoma cells while sparing normal astrocytes. It triggered apoptosis, cell cycle arrest, impaired migration, and increased sensitivity to ferroptosis and mitochondrial dysfunction. These results highlight Pt(IV)Ac-GA as a promising candidate to overcome current limitations in glioblastoma treatment.

Triple-negative breast cancer (TNBC) remains highly aggressive and refractory to conventional treatments, underscoring the need for novel combination strategies. Here, we employed 2D and 3D in vitro models, transcriptomic profiling, and in vivo xenograft studies to evaluate the anticancer efficacy of cannabinoids combined with the terpene β-caryophyllene (BC) in resistant TNBC models. Among the tested cannabinoids, cannabichromene (CBC) exhibited the greatest potency, and its combination with BC at sub-toxic concentrations significantly reduced IC50 values, enhanced cytotoxicity in spheroids, and suppressed colony formation and migration. The combination treatment induced pronounced G1 cell cycle arrest and increased apoptotic cell death. Western blot analyses revealed downregulation of PARP, Survivin, mTOR, Vimentin, Glypican-5, and PD-L1, while RNA sequencing demonstrated suppression of proliferative and migratory signaling pathways alongside activation of apoptosis, autophagy, and ferroptosis-related pathways. In vivo, CBC + BC significantly inhibited tumor growth in MDA-MB-231 xenografts, outperforming single-agent treatments. Collectively, these findings demonstrate that BC synergistically enhances cannabinoid activity, yielding superior antiproliferative and anti-migratory effects, and highlight this combination as a promising therapeutic strategy for resistant TNBC.

Chalcones are compounds containing an α,β-unsaturated carbonyl group that have been studied due to their structural simplicity, ease of synthesis, and broad spectrum of biological activities. Within this family, nitrochalcones have gained relevance due to the influence of the nitro group (-NO2) on the modulation of their electronic properties, chemical reactivity, and pharmacological behavior. This review presents a critical analysis of advances in the biological activities and possible mechanisms of action of nitrochalcones and their derivatives, with an emphasis on their structure-activity relationships and therapeutic potential. The available evidence shows that nitrochalcones and their derivatives act as multitarget molecules, capable of intervening in key biological processes such as oxidative stress, mitochondrial dysfunction, inflammation, and cell signaling pathways associated with proliferation and apoptosis. Several studies report anticancer, anti-inflammatory, antiparasitic, antimicrobial, antifungal, and cardiovascular activities, often with favorable selectivity toward pathological cells over healthy cells.

Non-small cell lung cancer (NSCLC) is the leading cause of lung cancer deaths, with resistance to targeted therapies posing a major clinical challenge. Drug-tolerant persister (DTP) cells are key contributors to resistance, and targeting them offers new strategies to enhance existing treatments. MicroRNAs (miRNAs), particularly the tumour-suppressive miR-15/107 family, offer promise due to their ability to target multiple oncogenic pathways. This study evaluated a synthetic consensus miRNA mimic, conmiR-15/107, in NSCLC cell line models. Dose-response assays showed robust, dose-dependent growth inhibition in both EGFR-mutant (PC9) and KRAS-mutant (H358 and A549) lung adenocarcinoma cells, but not in the human bronchial epithelial cell line BEAS-2B. When combined with EGFR inhibitors (osimertinib and gefitinib) in PC9 cells, the mimics showed a higher rate of growth inhibition compared with the controls and reduced IC50 values. Similarly, conmiR-15/107 enhanced growth inhibition by the KRAS inhibitors sotorasib and adagrasib in H358 cells. RT-qPCR confirmed downregulation of conmiR-15/107 targets, including MEK1, BCL2 and BRCA1, suggesting a multi-target mechanism of action. Long-term assays showed that the mimics reduced the survival and delayed the proliferation of DTPs in osimertinib-treated PC9 cells as well as sotorasib-treated H358 cells. These findings support conmiR-15/107 as a potential adjunct to targeted therapy, capable of enhancing treatment efficacy and delaying resistance in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced hepatocellular carcinoma (HCC), establishing immunotherapy-based combinations as the standard of care. Improved treatment responses have expanded liver transplant eligibility for selected patients with advanced HCC through downstaging or bridging strategies. Such advances have directly influenced transplant candidacy and post-transplant outcomes. However, accumulating evidence indicates that pretransplant exposure to ICIs may disrupt post-transplant immune homeostasis, increasing the risk of acute allograft rejection and graft failure requiring retransplantation. From an immunological perspective, rejection following pretransplant ICI therapy predominantly manifests as T cell-mediated rejection and is characterized by the sustained activation of effector T cells and impairment of regulatory immune pathways. Blockade of immune checkpoint signaling interferes with mechanisms critical for allograft tolerance, including T cell apoptosis and regulatory T cell induction. Recent studies further underscore the importance of the washout period between ICI discontinuation and LT, with longer washout intervals being associated with lower rejection rates. Importantly, timely recognition and appropriate immunosuppressive management can often resolve acute rejection without adversely affecting long-term graft outcomes. This review integrates current immunological insights with emerging clinical evidence to inform optimal transplant timing and management strategies for liver transplant candidates receiving ICIs.

CRISPR screens are a powerful functional genomics approach for identifying genes that confer sensitivity and resistance to anti-cancer therapies. CFI-402257 (luvixasertib, 2257) is a small molecule inhibitor of threonine tyrosine kinase (TTK), a promising therapeutic target in genomically unstable cancers due to its critical role in establishing the spindle assembly checkpoint (SAC) during mitosis. To inform its ongoing development and evaluation in clinical trials, we sought to use CRISPR activation (i.e., gain of function) screens to identify cellular mechanisms of resistance to 2257 in models of triple-negative breast cancer (TNBC). In vitro screens conducted in two TNBC cell lines nominated ABCG2 as the top resistance-conferring gene in both models. Validation studies assessing clonogenic survival and apoptosis confirmed that ABCG2 overexpression enhanced TNBC resistance to 2257 in vitro, while knockdown enhanced sensitivity. These findings suggest that 2257 is a substrate of ABCG2's drug efflux activity. However, overexpression of ABCG2 failed to confer resistance to 2257 in TNBC xenografts grown in mice and treated with a moderately active dose and schedule. Our results highlight the potential impact of drug transporters in in vitro CRISPR screens and the importance of confirming the relevance of drug response mechanisms identified in cultured cells using in vivo models that recapitulate drug pharmacokinetics and pharmacodynamics.

Monoacylglycerol lipase (MAGL) is a key regulator of lipid signaling networks implicated in tumor progression and represents an attractive anticancer target. To combine MAGL inhibition with potentially enhanced uptake by highly glycolytic cancer cells, we designed glycoconjugated analogs of a N-benzoylpiperidine MAGL inhibitor scaffold bearing a glucopyranose unit. An alkyne-functionalized benzoylpiperidine intermediate was prepared and coupled to azido sugars through a CuAAC "click" reaction to afford two triazole-linked glycoconjugates. In a colorimetric assay on human MAGL, the new compounds 17 and 18 inhibited the enzyme with IC50 values of 43.3 and 68.8 μM, respectively, confirming compatibility with MAGL inhibition albeit with reduced potency versus reference triazole-substituted benzoylpiperidine 13 (IC50 = 4.1 μM). In PANC-1 pancreatic cancer cells, both glycoconjugates were inactive in high-glucose medium, but displayed antiproliferative activity under low-glucose conditions (GI5017 = 129 μM; GI5018 = 12 μM), consistent with glucose-dependent uptake/competition. Overall, these first-in-class MAGL-targeting glycoconjugates provide a starting point for optimizing dual MAGL inhibition and metabolically driven cellular selectivity.

Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediates histone H3 lysine 27 trimethylation (H3K27me3), an epigenetic modification associated with transcriptional repression. EZH2 inhibitors (EZH2is) gained attention after the first-in-class drug Tazemetostat received FDA approval for treating epithelioid sarcoma. Preclinical studies suggest that EZH2is could be effective against melanoma, but their general inability to cross the blood-brain barrier (BBB), among others, limits the treatment of secondary brain metastases. Based on these limitations, we designed SG-8, a novel compound derived from TDI-6118 (a known brain-penetrant EZH2i). In silico docking predicted that SG-8 may exhibit high affinity for EZH2 as well as for another PRC2 subunit, Embryonic Ectoderm Development (EED). In addition, in vitro PAMPA assays suggested passive BBB permeability of SG-8. In cell-based assays, SG-8 and the structurally related EZH2i PF-06726304 displayed lower cytotoxicity than Tazemetostat in both primary (A375) and metastatic (Colo-679) human melanoma cells. Western blot analysis showed that SG-8 and PF-06726304 markedly reduced EED protein levels and, to a lesser extent, EZH2 levels, without affecting total H3K27me3, consistent with preserved canonical PRC2 activity. Instead, treatment with both compounds-most prominently SG-8-was associated with reduced phosphorylation levels of EZH2 (Ser21) and its upstream regulator Akt (Ser473), suggesting that modulation of the Akt-EZH2 signaling axis may at least partially contribute to their anti-melanoma activity.

Leucine-rich repeat-containing 8A (LRRC8A; also known as SWELL1), the essential subunit of volume-regulated anion channels (VRACs), is amplified in multiple malignancies and has been implicated in tumor progression and therapeutic resistance. Three-dimensional (3D) cancer spheroids have been well-established as in vitro models that recapitulate characteristics of tumor stemness and intrinsic drug resistance. In the present study, spheroid formation in human breast cancer cell lines, YMB-1 and MDA-MB-468, conferred resistance to multiple anticancer drugs, including doxorubicin (DOX), gemcitabine (GEM), and 5-fluorouracil (5-FU), thereby mimicking the characteristic properties of breast cancer stem-like cells. LRRC8A expression was upregulated in 3D spheroids compared with adherent 2D monolayers, and its pharmacological inhibition induced membrane hyperpolarization accompanied by intracellular Cl- accumulation. Inhibition of LRRC8A significantly sensitized spheroids to DOX, GEM, and 5-FU. Spheroid formation increased the expression of multidrug resistance-related protein 3 (MRP3) and the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4), whereas LRRC8A inhibition suppressed their expression. The transcriptional upregulation of MRP3 and CYP3A4 was mediated through the NRF2-CEBPB/D transcriptional axis. Collectively, these findings suggest that LRRC8A inhibition may represent a therapeutic strategy to overcome chemoresistance by repressing MRP3 and/or CYP3A4 expression in breast cancer stem cells.

Clinical evidence suggests that vitamin C (VitC) may enhance the efficacy of cancer chemotherapy. However, its high oxidating and reducing activity results in low stability in physiological fluids, which may compromise its supportive role in cancer therapies. VitC stability improves when located in a region where water activity is reduced and exposure to a limited amount of ferrous ions. This can be achieved when VitC is encapsulated in liposomes. Here, we present a novel combinatorial effect of a liposomal formulation of vitamin C (LVC, liposomal VitC) and an ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor (ATRi, ceralasertib) on cancer cells. The cytotoxic effects of vitamin C, LVC and ATRi were evaluated using spectrophotometric and spectrofluorimetric assays, flow cytometry and Western blot. Lipid peroxidation was assessed via fluorescence microscopy and quantified by spectrofluorimetric assays. DNA damage was examined by Western blot. The combination has higher efficacy than ceralasertib alone in genetically diverse ovarian cancer cell lines. LVC offers protective effects when used as an adjuvant during anticancer therapy. We found that the inhibition of the ATR pathway in the presence of LVC results in increased intracellular calcium levels, elevated lipid peroxidation, and higher Fe2+ concentrations. The upregulation of ROS, together with the increased expression of long-chain-fatty-acid-CoA ligase 4 (ACSL4) following co-treatment with ATRi and LVC, indicates the activation of ferroptotic pathways. The formation of DNA double-strand breaks suggests replication fork collapse. Our findings demonstrates that this synthetic targeted therapy, combining a novel liposomal formulation of VitC with an ATR inhibitor, not only enhances DNA damage and the cytotoxic efficacy of ceralasertib but also effectively drives ovarian cancer cells toward cell death.

Copper-based nanoparticles (Cu-based NPs) represent a major focus in nanomedicine due to their unique physicochemical properties and excellent biocompatibility. In this paper, we present an interdisciplinary study bridging engineering and biomedical sciences by employing a novel synthesis approach to produce highly stable and uniformly dispersed spherical copper nanoparticles (CuNPs), which were subsequently tested for their cytotoxic effects on SKBR3 and MSC human cells. The synthesis of CuNPs was performed in the presence of the complexing agent trisodium citrate (TSC), while starch was used for the chemical reduction step. Characterization of the Cu-based NPs via UV-Vis, FT-IR, Mie theory, DLS and SEM confirmed their nanoscale structure. The obtained CuNPs were subsequently assessed for their biological effects and cytotoxic responses induced in normal and SKBR3 cancer cell lines. The SKBR3 cell line showed a dose-dependent decrease in the cell index and a higher proportion of apoptotic cells compared to normal MSCs, with apoptosis representing the dominant mode of cell death. Although SKBR3 cells appeared to mount an antioxidant response against CuNP oxidative stress, the response was insufficient to counteract the apoptotic progression. In comparison, MSCs showed a greater resilience to CuNP-induced cellular stress. By promoting oxidative stress and disrupting the antioxidant defense system of cancer cells, CuNPs exhibit promising anti-cancer properties.