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Triple-negative breast cancer (TNBC) is traditionally treated with systemic chemotherapy, often resulting in significant off-target toxicity. In this study, we assess the efficacy of intraductal chemotherapeutic delivery, aimed at reducing systemic side effects. Using an in situ TNBC model, created by intraductal injection of 4T1-luc cells, we identified day 3 post-tumor implantation as an optimal early intervention point. Echocardiographic analysis confirmed that intraductal administration of eribulin (ERI) or doxorubicin (DOX) did not cause cardiac dysfunction or apoptosis. Our results demonstrate that intraductal delivery of ERI and DOX significantly enhances anti-tumor and anti-metastatic effects. Mechanistically, ERI followed by DOX increased intratumoral perfusion, improved drug concentration, reversed epithelial-mesenchymal transition, and inhibited tumor cell invasion and metastasis. Additionally, this approach triggered immunogenic cell death and activated a systemic anti-tumor immune response. These findings underscore the potential of intraductal chemotherapy as a safe, highly effective approach, offering a preclinical foundation for minimally invasive TNBC therapies.

Salinomycin is a polyether ionophore natural product widely studied for its anticancer stem cell properties and well established anti-coccidial activity. However, its complex structure and tendency to isomerise in solution complicates its mass spectrometric analysis. In this study, a combination of high-resolution accurate mass electrospray sequential mass spectrometry, ion mobility spectrometry and computational modelling was employed to analyse salinomycin and its isomers for the first time. Product ions generated from salinomycin and its isomer in the MSn analysis are distinguished, and detailed fragmentation mechanisms are proposed. The novel application of ion mobility mass spectrometry to separate isomeric salinomycins provides revolutionary insight into the chelation positions of sodium by salinomycin (‘ionoforms’). The cation position has a fundamental effect on the fragmentation routes observed. These observations were supported by Gaussian modelling and collision cross-section calculations. The relationship between collision energy and peak intensity of all identifiable forms of salinomycin and respective product ions was visualised by a 3D energy breakdown graph. Results from this study provided firm grounding for understanding complex structures such as salinomycin. The methodology demonstrated here could be applied to a wide range of natural products and in other drug development or metabolomic studies.

In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti–PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti–TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti–PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.

In this study, we present the preparation and characterization of a novel thallium(I) coordination compound of the polyether ionophorous antibiotic salinomycin (SalH). The complex [TlSal(H2O)] exists as two subunits, SalTl1 and SalTl2, which differ slightly in their structural parameters. Salinomycin acts in a pentadentate coordination mode through oxygen donor atoms, and the six-fold arrangement around the metal centers is completed by interaction with a water molecule. In the overall complex structure, the two mononuclear species SalTl1 and SalTl2 are connected via a hydrogen bond network by a third water molecule. The inclusion of the heavy metal ion into the structure of the polyether ionophore reduces its biological activity against Gram-positive microorganisms and cervical cancer cells at in vitro conditions.

Salinomycin (Sal) is an antiparasitic agent used in veterinary medicine and is characterized by low therapeutic index and high toxicity. Among poultry, chickens are resistant to Sal toxicity, but turkeys are considered susceptible. However, underlying mechanisms of Sal toxicity are poorly understood. This comparative transcriptomic study aimed to determine molecular toxicity mechanisms of Sal in both species. We conducted two experiments on chickens and turkeys exposed to Sal (0.9 mg/kg b.w/day) vs. unexposed. Heart and liver (n = 6) were collected post-mortem (chicken 5th; turkey 13th week). RNA was isolated and examined by RNA-seq to identify differentially expressed (DE) genes and pathways. Number of significant DE genes in chicken was 673 (heart) and 3049 (liver), and in turkey, 485 (heart) and 2337 (liver). Enrichment analysis revealed that Sal exposure activated platelet signaling in chicken heart, while it induced cell cycle arrest in turkey heart. In liver, impaired Sal biotransformation was determined as a shared response. In turkey liver, we determined that extracellular matrix pathway was upregulated, which could indicate liver fibrosis. Our findings demonstrate that molecular toxicity of Sal differs between species and turkey confirmed being more susceptible to Sal toxicity also at molecular level via induced cell cycle arrest and fibrosis.

Drug resistance is an important challenge in medical research and clinical practice, posing a serious threat to the effectiveness of current therapeutic strategies. Transcriptomics has played a crucial role in analyzing resistance-related genes and pathways, while the application of machine learning in high-throughput data analysis and prediction has also opened up new avenues in this field. However, existing studies mostly focus on a single drug or specific categories, and their conclusions are limited in applicability across drug categories, while studies on drugs beyond antibacterial and antitumor categories remain limited. In this study, we systematically analyzed the transcriptomic data of resistant cell lines treated with 1738 drugs spanning 82 categories and identified core genes through an integrated analysis of three classical machine learning methods. Using the antibacterial drug salinomycin as an example, we established a resistance prediction model that demonstrated high predictive accuracy, indicating the significant value of the selected core genes in prediction. Meanwhile, some of the core genes identified through the protein–protein interaction (PPI) network overlapped with those derived from machine learning analysis, further supporting the reliability of these core genes. Pathway enrichment analysis of differential genes revealed potential resistance mechanisms. This study provides a new perspective for exploring resistance mechanisms across drug categories and highlights potential directions for resistance intervention strategies and novel drug development.

Salinomycin and monensin represent a class of natural ionophore antibiotics with strong anticancer properties. In this paper we report on chemical modification of these compounds by conjugation with phosphonium cations for targeting conjugates to the mitochondria of cancer cells. Our findings indicate that this approach yields conjugates with enhanced anticancer activity and selectivity, outperforming not only the parent compounds but also the widely used chemotherapeutic agent, doxorubicin. Comprehensive biological and biophysical analyses proved that the conjugates target the mitochondria in cancer cells, with some of the derivatives additionally promoting generation of mitochondrial reactive oxygen species (mtROS). This targeted strategy holds significant promise for the development of effective mitochondrial-targeted novel anticancer agent.

The antibody‐drug conjugate (ADC) MORAb‐202, consisting of farletuzumab paired with a cathepsin B–cleavable linker and eribulin, targets folate receptor alpha (FRA), which is frequently overexpressed in various tumor types. MORAb‐202 was highly cytotoxic to FRA‐positive cells in vitro, with limited off‐target killing of FRA‐negative cells. Furthermore, MORAb‐202 showed a clear in vitro bystander cytotoxic effect in coculture with FRA‐positive/negative cells. In vivo antitumor efficacy studies of MORAb‐202 were conducted with a single administration of MORAb‐202 in triple‐negative breast cancer (TNBC) patient–derived xenograft (PDx) models expressing low and high levels of FRA. MORAb‐202 exhibited durable efficacy proportional to tumor FRA expression. Toxicology studies (Q3Wx2) in nonhuman primates suggested that the major observed toxicity of MORAb‐202 is hematologic toxicity. Overall, these findings support the concept that MORAb‐202 represents a promising investigational ADC for the treatment of TNBC patients. The antibody‐drug conjugate (ADC) MORAb‐202, consisting of farletuzumab with cleavable linker, is the first ADC that carries clinically validated eribulin as a payload and exhibits direct antitumor efficacy and a strong bystander effect. As a result, the therapeutic window of MORAb‐202 is much wider than other nonvalidated payloads. Importantly, its well validated safety profile is minimizes risk in the clinic. Thus, MORAb‐202 represents promising investigational therapeutics for TNBC patients.

Oxaliplatin (OXA) is widely used for colorectal cancer (CRC) as a first-line chemotherapy. However, drug resistance and peripheral neurotoxicity prevail in colorectal cancer therapy. Salinomycin (SAL) makes cancer cells sensitive to ionizing radiation and chemotherapeutic drugs. Chemotherapy regimens that combine more than two drugs can improve the outcome of patients. In the present study, we detected apoptosis and mitochondrial function in CRC cells through MTT assays, Annexin V-FITC/PI staining, colony-forming assays, intracellular reactive oxygen species (ROS) measurements, western blotting and so on. We used CompuSyn software to calculate combination index (CI). The effect of SAL and OXA was synergistic. The combination treatment inhibited cell proliferation, migration and colony formation but increased the expression of proapoptotic proteins and promoted cell apoptosis of CRC cells. In vitro experiments demonstrated that the SAL and OXA cotreatment increased intracellular ROS levels in CRC cell lines, decreased the MMP and activated the mitogen-activated protein kinase (MAPK) pathway, thus inhibiting the proliferation of CRC cells and promoting the apoptosis of CRC cells. Pretreatment with N-acetylcysteine (NAC) reversed this effect. Cotreatment with SAL and OXA increases the apoptotic effects in OXA-treated CRC cell lines. In vivo, combined treatment of SAL and OXA markedly inhibited the tumor growth compared to either drug alone. SAL enhances OXA-induced antitumor effects in CRC both in vitro and in vivo by ROS-mediated mitochondrial apoptosis and activation of the MAPK pathway. These results may provide a rationale for combining SAL with OXA for CRC treatment.