Heat shock proteins have been implicated in the process of carcinogenesis. HSPA14, a member of the heat shock protein family, remains poorly understood in terms of its significance and pathomechanisms in breast cancer.

We analyzed the expression levels of HSPA14 and its prognostic significance in breast cancer using TCGA data. TCGA data was used to investigate the association between HSPA14 expression and clinicopathological features in breast cancer patients. GSEA analysis was conducted to identify the biological function of HSPA14. Spearman's correlation analysis was performed to examine the correlation between HSPA14 expression and immune cell infiltration, as well as immune checkpoint genes. Single cell transcriptomic data from GSE114727 was utilized to calculate the expression of HSPA14 in different cell subpopulations. The data on HSPA14 levels and drug sensitivity were extracted from the CellMiner dataset. The mRNA expression of HSPA14 was validated through cell experiments.

HSPA14 expression is elevated in breast cancer, which is associated with poor overall survival. It can serve as a diagnostic biomarker for breast cancer patients. Pathway analysis revealed that HSPA14-associated differential genes are involved in cell cycle, apoptosis, cellular response to heat stress, and more. Additionally, HSPA14 expression is significantly correlated with the immune microenvironment. The expression of HSPA14 may also indicate drug sensitivity.

Our study elucidates the involvement of HSPA14 in tumorigenesis, particularly in modulating the immune response, shaping the immune microenvironment, and contributing to drug resistance, which are pivotal for the development of personalized breast cancer therapies.

Viewing the hallmarks as a sequence of adaptations captures the "why" behind the "how" of the molecular changes driving cancer. This eco-evolutionary view distils the complexity of cancer progression into logical steps, providing a framework for understanding all existing and emerging hallmarks of cancer and developing therapeutic interventions.

Chemotherapy serves as the primary treatment for cancers, facing challenges due to the emergence of drug resistance. Combination therapy has been developed to combat cancer drug resistance, yet it still suffers from lack of specific targeting of cancer cells and poor accumulation at the tumor site. Consequently, targeted administration of chemotherapy medications has been employed in cancer treatment. Doxorubicin (DOX) is one of the most frequently used chemotherapeutics, functioning by inhibiting topoisomerase activity. Enhancing the anti-cancer effects of DOX and overcoming drug resistance can be accomplished via delivery by nanoparticles. This review will focus on the development of peptide-DOX conjugates, the functionalization of nanoparticles with peptides, the co-delivery of DOX and peptides, as well as the theranostic use of peptide-modified nanoparticles in cancer treatment. The peptide-DOX conjugates have been designed to enhance the targeted delivery to cancer cells by interacting with receptors that are overexpressed on tumor surfaces. Moreover, nanoparticles can be modified with peptides to improve their uptake in tumor cells via endocytosis. Nanoparticles have the ability to co-deliver DOX along with therapeutic peptides for enhanced cancer treatment. Finally, nanoparticles modified with peptides can offer theranostic capabilities by facilitating both imaging and the delivery of DOX (chemotherapy).

Chemoresistance is a multifactorial phenomenon and the primary cause to the ineffectiveness of oncotherapy and cancer recurrence. Membrane drug transporters are crucial for drug delivery and disposition in cancer cells. Changes in the expression and functionality of these transporters lead to decreased intracellular accumulation and reduced toxicity of antineoplastic drugs. As the mechanism has been better understood and genetic engineering technology progressed quickly in recent years, some novel targeting strategies have come to light. This article summarizes the regulatory mechanisms of membrane drug transporters and provides an extensive review of current approaches to address transporters-mediated chemoresistance. These strategies include the use of chemical inhibitors to block efflux transporters, the development of copper chelators to enhance platinum drug uptake, the delivery of genetic drugs to alter transporter expression, the regulation of transcription and post-translational modifications. Additionally, we provide information of the clinical trial performance of the related targeting strategies, along with the ongoing challenges. Even though some clinical trials failed due to unexpected side effects and limited therapeutic efficacy, the advent of targeting membrane drug transporters still presents a hopeful path for overcoming chemoresistance.

Drug resistance poses a major obstacle to the efficient treatment of colorectal cancer (CRC), which is one of the cancers that kill people most often in the United States. Advanced colorectal cancer patients frequently pass away from the illness, even with advancements in chemotherapy and targeted therapies. Developing new biomarkers and therapeutic targets is essential to enhancing prognosis and therapy effectiveness. My goal in this study was to use bioinformatics analysis of microarray data to find possible biomarkers and treatment targets for colorectal cancer. Using an ArrayExpress database, I examined a dataset on colon cancer to find genes that were differentially expressed (DEGs) in tumor versus healthy tissues. Integration of advanced bioinformatics tools provided robust insights into the identification and analysis of EGFR as a key player. STRING and Cytoscape enabled the construction and visualization of protein-protein interaction networks, highlighting EGFR as a hub gene due to its centrality and interaction profile. Functional enrichment analysis through DAVID revealed EGFR's involvement in critical biological pathways, as identified in GO and KEGG analyses. This underscores the power of combining computational tools to uncover significant biomarkers like EGFR. Autodock Vina screening of the NCI diversity dataset identified two potential EGFR inhibitors, ZINC13597410 and ZINC04896472. MD simulation data revealed that ZINC04896472 could be potential anticancer inhibitor. These findings serve as a basis for the creation of novel therapeutic approaches that target EGFR and other discovered pathways in CRC. The suggested strategy may improve the efficacy of CRC therapy and advance personalized medicine.

Colorectal cancer (CRC) is a substantial global health concern due to its limited treatment options, especially for oxaliplatin (L-OHP) regimen resistance. This study used organoid-based screening methodologies to evaluate drug responses in CRC while validating the approach with patient-derived CRC organoids and investigating potential biomarkers.

Patient-derived organoids were created from CRC surgical specimens, and drug screening were performed. Selected organoids with high and low L-OHP sensitivity underwent next-generation sequencing (NGS), and in vivo experiments using xenotransplantation were used to validate in vitro results. Moreover, the clinical application of homologous recombination deficiency (HRD) as a biomarker was investigated.

Organoid drug screening revealed differences in L-OHP sensitivity among 34 patient-derived CRC organoids, and NGS deemed HRD as a potential biomarker. In vivo experiments validated the correlation between HRD status and L-OHP sensitivity, and clinical data suggested the potential of HRD as a biomarker for recurrence-free survival in patients treated with L-OHP. Additionally, HRD exhibited potential as a biomarker for other platinum agents and poly (ADP-ribose) polymerase inhibitors in CRC.

The study underscores HRD as a potential biomarker for predicting L-OHP sensitivity, expanding its application to other drugs in CRC. Organoid screening is reliable, providing insights into the intricate association between genetic features and treatment responses.

The presence of pre-existing or acquired drug-resistant cells within the tumor often leads to tumor relapse and metastasis. Single-cell RNA sequencing (scRNA-seq) enables elucidation of the subtle differences in drug responsiveness among distinct cell subpopulations within tumors. A few methods have employed scRNA-seq data to predict the drug response of individual cells to date, but their performance is far from satisfactory. In this study, we propose SSDA4Drug, a semi-supervised few-shot transfer learning method for inferring drug-resistant cancer cells. SSDA4Drug extracts pharmacogenomic features from both bulk and single-cell transcriptomic data using semi-supervised adversarial domain adaptation. This allows us to transfer knowledge of drug sensitivity from bulk-level cell lines to single cells. We conduct extensive performance evaluation experiments across multiple independent scRNA-seq datasets, demonstrating SSDA4Drug's superior performance over current state-of-the-art methods. Remarkably, with only one or two labeled target-domain samples, SSDA4Drug significantly boosts the predictive performance of single-cell drug responses. Moreover, SSDA4Drug accurately recapitulates the temporally dynamic changes of drug responses during continuous drug exposure of tumor cells, and successfully identifies reversible drug-responsive states in lung cancer cells, which initially acquire resistance through drug exposure but later restore sensitivity during drug holidays. Also, our predicted drug responses consistently align with the developmental patterns of drug sensitivity observed along the evolutionary trajectory of oral squamous cell carcinoma cells. In addition, our derived SHAP values and integrated gradients effectively pinpoint the key genes involved in drug resistance in prostate cancer cells. These findings highlight the exceptional performance of our method in determining single-cell drug responses. This powerful tool holds the potential for identifying drug-resistant tumor cell subpopulations, paving the way for advancements in precision medicine and novel drug development.

Mutations are the ultimate source of biological evolution that creates genetic variation in populations. Mutations can create new advantageous traits but can also potentially interfere with pre-existing organismal functions. Therefore, organisms may have evolved mutation rates to appropriate levels to maintain or improve their fitness. In this study, we aimed to experimentally quantify the relationship between the mutation rate and evolution of antibiotic resistance. We conducted an evolution experiment using 12 Escherichia coli mutator strains with increased mutation rates and five antibiotics. Our results demonstrated that the rate of adaptation generally increased with higher mutation rates, except in a single mutator strain with the highest mutation rate, which exhibited a significant decline in evolutionary speed. To further elucidate these findings, we developed a simple population dynamics model that successfully recapitulated the observed dependence of adaptation speed on mutation rate. These findings provide important insights into the evolution of mutation rate accompanied by the evolution.

Modifying existing drugs to enhance their activity and reduce toxicity is a major focus of drug development. We developed a novel class of dual-action chimeric molecules for cancer therapy, linking known drugs to a DNA-methylating monomethyl triazene moiety (azene) via nucleophilic substitution. In-vitro screening of these chimeras on various leukemia cell lines identified a potent chimera, doxorubizen, a sequel of the known DNA intercalator and topoisomerase 2 (Topo-II) inhibitor doxorubicin (Dox) and azene. Molecular docking and dynamic simulations showed doxorubizen as a more potent Topo-II inhibitor than Dox as it binds to major grooves in DNA. Moreover, the monomethyl triazene portion is positioned favorably through tetracene core intercalation, potentially facilitating methylation at nearby guanine bases. Doxorubizen demonstrated significantly higher cytotoxicity, mitochondrial depolarization, DNA intercalation, and cell death than Dox. A Topo-II activity assay confirmed potent enzyme inhibition by doxorubizen. The mechanism of action of doxorubizen involves the inhibition of DNA repair in proximity to double-strand breaks by guanine methylation, enhanced mitochondrial depolarization, and increased apoptosis. Furthermore, in an acute leukemia xenograft model, doxorubizen significantly reduced the leukemia burden compared to Dox while preserving body weight and liver function. This work underscores the therapeutic potential of doxorubizen in leukemia treatment.

Promiscuous membrane transporters play vital roles across domains of life, mediating the uptake and efflux of structurally and chemically diverse substrates. Although many transporter structures have been solved, the fundamental rules of polyspecific transport remain inscrutable. In recent years, high-throughput genetic screens have solidified as powerful tools for comprehensive, unbiased measurements of variant function and hypothesis generation, but have had infrequent application and limited impact in the transporter field. In this primer, we describe the principles of high-throughput screening methods available for studying polyspecific transporters and comment on the necessity and potential of high-throughput methods for deciphering these transporters in particular. We present several screening approaches which could provide a fundamental understanding of the molecular basis of function and promiscuity in transporters. We further posit how this knowledge can be leveraged to design inhibitors that combat multidrug resistance and engineer transporters as needed tools for synthetic biology and biotechnology applications.

Streptomyces is widely recognized as the "biological factory" of specialized metabolites comprising a huge variety of bioactive molecules with diverse chemical properties. The potential of this Gram-positive soil bacteria to produce such diversified secondary metabolites with significant biological properties positions them as an ideal candidate for anticancer drug discovery. Some of the Streptomyces-derived secondary metabolites include siderophores (enterobactin, desferrioxamine), antibiotics (xiakemycin, dinactin) pigments (prodigiosin, melanin), and enzymes (L-methioninase, L-asperginase, cholesterol oxidase) which exhibit a pronounced anticancer effect on both in vitro and in vivo system. These secondary metabolites are endowed with antiproliferative, pro-apoptotic, antimetastatic, and antiangiogenic properties, presenting several promising characteristics that make them suitable candidates in the battle against this deadly disease. In this comprehensive review, we have dived deep and explored their history of discovery, their role as anticancer agents, underlying mechanisms, the approaches for the discovery of anticancer molecules from the secondary metabolites of Streptomyces (isolation of Streptomyces, characterization of bacterial strain, screening for anticancer activity and determination of in vitro and in vivo toxicity, structure-activity relationship studies, clinical translation, and drug development studies). The hurdles and challenges associated with this process and their future prospect were also illustrated. This review highlights the efficacy of Streptomyces as a "microbial treasure island" for novel anticancer agents, which warrants sustained research and exploration in this field to disclose more molecules from Streptomyces that are unidentified and to translate the clinical application of these secondary metabolites for cancer patients.

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.

Malignant pleural mesothelioma (PM) is a highly aggressive disease of the lung pleura associated with poor prognosis. Despite advances in improving the clinical management of this malignancy, there is no effective chemotherapy for refractory or relapsing PM. The acquisition of resistance to standard and targeted therapy in this disease is a foremost concern; therefore, a deeper understanding of the complex factors surrounding the emergence of drug resistance is deemed necessary. In this review, we will present broad insights into various cellular and molecular concepts, accounting for the recalcitrance of PM to chemotherapy, including signaling networks regulating drug tolerance, drug resistance-associated proteins, genes, and miRNAs, as well as the critical role of cancer stem cells. Identification of the biological determinants and their associated mechanisms may provide a framework for the development of appropriate treatment.

Despite being one of the primary and most effective treatments for advanced stages of lung cancer, chemotherapy drugs like carboplatin have limitations due to their adverse side effects and the development of drug resistance in lung cancer cells. However, recent studies have shown promising results in using small interfering RNAs (siRNAs) as a therapeutic agent for cancer treatment. Hence, this study aimed to investigate the potential of combining siRNA-DLGAP1-AS2 with carboplatin in human lung cancer cell lines. The viability of the cells was assessed using the MTT assay, and apoptosis induction was examined through Annexin V/Pi staining. Additionally, the effect of the combination on cell cycle arrest and colony formation of lung cancer cells was studied. Furthermore, the expression of Bax, Bcl-2, MMP-2, MMP-9, GCLC, and CD44 was evaluated. Our functional analysis revealed that inhibiting the expression of DLGAP1-AS2 increased the sensitivity of lung cancer cells to carboplatin. Moreover, our study demonstrated that the combination of DLGAP1-AS2 inhibition through siRNA-DLGAP1-AS2 transfection and carboplatin treatment had a tumor-suppressive function, inhibiting the progression and proliferation of A549 lung cancer cells. Therefore, it can be concluded that targeting DLGAP1-AS2 using specific siRNA in combination with carboplatin chemotherapy holds promise as a valuable therapeutic approach for lung cancer.

Cardiac cytochrome P450 2J2 (CYP2J2) plays a significant role in cardiovascular homeostasis due to its dual functions in drug metabolism and the epoxidation of polyunsaturated fatty acids. Additionally, the inhibition of CYP2J2 by xenobiotics has been linked to drug-induced cardiotoxicity, warranting further investigation of this critical enzyme in cardiac systems. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are physiologically relevant in vitro models that recapitulate relevant phenotypes important for cardiovascular research. However, no studies have so far characterized CYP2J2 expression and activities in these models. Here, we developed and validated H7 hESC-CMs as suitable in vitro models for investigating CYP2J2 in drug metabolism and cardiotoxicity. We first performed the genotyping and confirmed the presence of wild-type CYP2J2∗1/∗1 alleles in wild-type hESCs. Our optimized cardiomyocyte differentiation protocols yielded virtually pure (93.3% ± 6.8%) hESC-CMs, which exhibited P450 epoxygenase mRNA-expression profiles consistent with human cardiomyocytes, with CYP2J2 as the dominant isozyme and minor contributions from CYP2C8 and CYP2C9. By employing a CYP2J2-selective fluorescent substrate, ER-BnXPI, and astemizole as probe substrates, CYP2J2-mediated demethylation of both substrates exhibited typical Michaelis-Menten kinetics, which confirms functional CYP2J2 activities in vitro. Additionally, we demonstrated the capacity of CYP2J2 for arachidonic acid epoxidation, validating its ability to metabolize polyunsaturated fatty acid substrates. Finally, CYP2J2 activity in hESC-CMs was significantly inhibited by danazol and dronedarone, which are established CYP2J2 inhibitors known to cause cardiotoxicity. Ultimately, our study sheds novel insights on hESC-CMs as a suitable model for investigating CYP2J2-mediated metabolism and its inhibition in vitro. SIGNIFICANCE STATEMENT: H7 human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were developed and validated as an in vitro model for investigating CYP2J2-mediated drug metabolism and its inhibition. By characterizing CYP2J2 transcriptional expression, catalytic activity, and inhibition response to established CYP2J2 inhibitors, our study confirmed functional CYP2J2 in hESC-CMs and ascertained that the model recapitulates the physiology of primary cardiomyocytes. This pioneering research highlights the potential of hESC-CMs in advancing our understanding of CYP2J2-mediated metabolism, its inhibition, and implications in drug-induced cardiotoxicity.

Introduction: Many studies have reported the role of P-glycoprotein (Pgp) in chemoresistance in various pathological conditions such as cancer and neurodegenerative diseases, such as Alzheimer's. In this study, we are reporting the high-performance liquid chromatography (HPLC)-based purification of fluorine-18 [18F]AVT-011 and its preclinical evaluation. Methods: AVT-011 was labeled with 18F using the nucleophilic substitution method by heating the reaction mixture at 110°C for 10 min, followed by purification using preparative HPLC and C18ec cartridge. The in vitro cell uptake study was carried out in U87 cells with and without an inhibitor. The preclinical toxicity was carried out in CD1 mice in three groups, including control, AVT-011 treated, and [18F]AVT-011 treated. The biodistribution study was done in CD1 mice (n = 12) after intravenous injection of 4-6 MBq [18F]AVT-011, and mice were sacrificed at various time intervals. A dose of 3.7 ± 0.7 MBq of [18F]AVT-011 was injected intravenously in the healthy Swiss albino mice, and the whole-body micro-positron emission tomography was acquired at 0-, 30-, 60-, and 120-min postinjection. Results: The radiochemical purity of [18F]AVT-011 was 97 ± 1.5% as evaluated by radio-HPLC with a yield of 14 ± 2% and was stable up to 95% under in vitro conditions in blood and in vivo conditions up to 4 h. The in vitro cell uptake study showed a significant difference in control (27.4 ± 2.1%) and blocked U987 cells (73.2 ± 3.2%) after incubation of 120 min. The tissue distribution in mice showed the highest uptake in the liver (17.3 ± 2.4%), kidneys (16.6 ± 3.1%), lungs (10.4 ± 2.9%), and spleen (5.6 ± 0.8%) at 15 min, and the activity was washed out with time. The radioactivity cleared through the hepatorenal pathway. The animal imaging study also demonstrates a similar biodistribution pattern. Conclusions: [18F]AVT-011 showed higher specific activity than the cartridge-based method but showed similar biological activity.

Osteosarcoma is an aggressive bone malignancy with a high propensity for drug resistance and metastasis, leading to poor clinical outcomes. This study investigates the role of core 1 β1,3-galactosyltransferase 1 (C1GALT1) in osteosarcoma, focusing on its implications in chemoresistance. Our findings reveal that high expression of C1GALT1 is associated with advanced stages, adverse overall survival, and increased recurrence rates. Elevated levels of C1GALT1 were observed in doxorubicin-selected osteosarcoma cells, where its suppression significantly promoted doxorubicin-induced apoptosis and reduced drug efflux. Pharmacological inhibition of C1GALT1 using itraconazole replicated these effects, suggesting a potential therapeutic strategy to overcome chemoresistance. Additionally, we identified the involvement of the ATP-binding cassette (ABC) transporter ABCC1 in the drug-resistance phenotype mediated by C1GALT1. C1GALT1-mediated O-glycan changes were found to influence the cell-surface targeting and lysosomal degradation of ABCC1, thereby modulating its efflux capacity. In vitro and in vivo studies confirmed that C1GALT1 impacts ABCC1 expression and function, further supporting its role in osteosarcoma chemoresistance. These results highlight the clinical relevance of C1GALT1 as a biomarker for prognosis and a potential therapeutic target for osteosarcoma. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Methotrexate is one of the most essential single agents in patients with primary central nervous system lymphoma (PCNSL). However, 25-50% result in relapse with a poor prognosis. Therefore, studies on methotrexate resistance are warranted to explore salvage chemotherapy for recurrent PCNSL. Single-cell sequence analysis enables the characterization of novel cell types and provides a precise understanding of cancer biology.

Single-cell sequence analysis of parental and methotrexate-resistant PCNSL cells was performed. We used a Weighted Gene Co-expression Network Analysis to identify groups of significantly connected genes.

We identified consensus modules in both the HKBML and TK datasets. HLA-DRβ1, HLA-DQβ1,and SNRPG were hub genes those detected in both datasets revealed by network analysis. Cyclosporine A was selected as the candidate drug for treating methotrexate-resistant cells.

The results of the present study characterized the methotrexate resistance-related signaling pathways in cultured PCNSL cells. Overall, these results may account for variations in treatment responses and lead potential novel therapeutic strategies for patients with PCNSL.

Breast cancer is the highest cancer incidence in the world. Chemotherapy is currently one of the main breast cancer treatments besides surgery. It is capable of evolving to become resistant to chemotherapy agents. Chemotherapy also has significant side effects. Rosmarinic acid could become an anti-cancer agent candidate for the treatment of breast cancer, but its molecular mechanism is still unclear.

This study aimed to clarify the molecular mechanism of rosmarinic acid anti-breast cancer properties via an in-silico study.

Web-based screening tools such as SwissTargetPrediction, Similarity Ensemble Approach (SEA), and TargetNet were used as initial screening. From web-based screening, potential proteins that interact with rosmarinic acid could be determined. Intersected proteins from 3 web-based screenings were assessed via literature review. We found 11 intersected proteins, and 6 of 11 proteins are involved in breast cancer development and progression. Those 6 proteins are MMP-1, MMP-2, MMP-9, MMP-12, aldose reductase, and M-phase Inducer Phosphatase 2 (CDC25B). Then molecular docking using Autodock 4.6.2 was used in ligand and protein interaction simulation. Those 6 proteins were selected as macromolecules in the docking study.

Based on the docking result, we found that rosmarinic acid can bind MMP-1, MMP2, MMP-9, and MMP-12 active sites. The binding profile of rosmarinic acid with aldose reductase has similarities with other confirmed inhibitors. Docking with CDC25B showed that rosmarinic acid also binds in the same place as cyclin-dependent kinases (CDKs).

The ability of rosmarinic acid to inhibit MMP-1, MMP-2, MMP-9, aldose reductase, and CDC25B activity may underlie how rosmarinic acid is able to inhibit the development of breast cancer.

The limitations of two-dimensional (2D) models in cancer research have hindered progress in fully understanding the complexities of drug resistance and therapeutic failures. However, three-dimensional (3D) models provide a more accurate representation of in vivo environments, capturing critical cellular interactions and dynamics that are essential in evaluating the efficacy and toxicity of tyrosine kinase inhibitors (TKIs). These advanced models enable researchers to explore drug resistance mechanisms with greater precision, optimizing treatment strategies and improving the predictive accuracy of clinical outcomes. By leveraging 3D models, it will be possible to deepen the current understanding of TKIs and drive forward innovations in cancer treatment. The present review discusses the limitations of 2D models and the transformative impact of 3D models on oncology research, highlighting their roles in addressing the challenges of 2D systems and advancing TKI studies.

Drug resistance is an inherent challenge during cancer chemotherapy. Cancer cells favor fatty acid metabolism through metabolic reprogramming to achieve therapeutic resistance. However, an effective approach to overcoming the switch from glycolysis-dependent to fatty acid beta-oxidation-dependent anabolic and energy metabolism remains elusive. Here, we developed a macromolecular drug (folate-polySia, FpSA) to induce the extracellular microcalcification of cervical cancer cells with cisplatin resistance. Microcalcification attenuated the uptake of fatty acids and the beta-oxidation of fatty acids by mitochondrial dysfunction but boosted the glycolysis pathway. Consequently, cotreatment with Pt and FpSA inhibited cisplatin-resistant tumor growth and improved tumor-bearing mice's survival rates, indicating that FpSA switched fatty acid metabolism to glycolysis to sensitize cisplatin-resistant cells further. Taken together, cancer cell calcification induced by FpSA provides a reprogramming metabolic strategy for the treatment of chemotherapy-resistant tumors.

Brain metastasis represents a significant challenge in oncology, driven by complex molecular and epigenetic mechanisms that distinguish it from primary tumors. While recent research has focused on identifying genomic mutation drivers with potential clinical utility, these strategies have not pinpointed specific genetic mutations responsible for site-specific metastasis to the brain. It is now clear that successful brain colonization by metastatic cancer cells requires intricate interactions with the brain tumor ecosystem and the acquisition of specialized molecular traits that facilitate their adaptation to this highly selective environment. This is best exemplified by widespread transcriptional adaptation during brain metastasis, resulting in aberrant gene programs that promote extravasation, seeding, and colonization of the brain. Increasing evidence suggests that epigenetic mechanisms play a significant role in shaping these pro-brain metastasis traits. This review explores dysregulated chromatin patterns driven by chromatin remodeling, histone modifications, DNA/RNA methylation, and other epigenetic regulators that underpin brain metastatic seeding, initiation, and outgrowth. We provide novel insights into how these epigenetic modifications arise within both the brain metastatic tumor and the surrounding brain metastatic tumor ecosystem. Finally, we discuss how the inherent plasticity and reversibility of the epigenomic landscape in brain metastases may offer new therapeutic opportunities.

Capsaicin (CAPS), a bioactive alkaloid derived from chili peppers, has garnered significant interest for its potential role as a combinatorial and chemosensitizing agent in cancer therapy. Numerous preclinical studies have demonstrated that CAPS enhanced the efficacy of various anticancer agents by promoting apoptosis, modulating autophagy and inhibiting angiogenesis, tumor growth, and metastasis. Additionally, CAPS modulated critical regulators of chemoresistance, such as P-glycoprotein (P-gp), extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB) pathway, and signal transducer and activator of transcription 3 (STAT3) pathway, thereby contributing to the reversal of multidrug resistance (MDR). Moreover, when administered in combination with chemotherapeutic agents, CAPS has been shown to improve treatment efficacy at lower drug concentrations. Given its multitargeted mechanism of action, CAPS represents a promising adjunct to conventional cancer therapies. However, due to its lipophilic nature, the development of optimized formulation strategies is essential to enhance its bioavailability and ensure consistent therapeutic outcomes. In conclusion, CAPS holds significant potential as a combinatorial and chemosensitizing agent, helping to overcome chemoresistance and enhance treatment outcomes across various malignancies. These promising findings warrant further preclinical and clinical investigations.

Most cancer-related deaths result from drug-resistant disease(1,2). However, cancer drug resistance is not a primary focus in drug development. Effectively mitigating and treating drug-resistant cancer will require advancements in multiple fields, including early detection, drug discovery, and our fundamental understanding of cancer biology. Therefore, successfully tackling drug resistance requires an increasingly multidisciplinary approach. A recent workshop on cancer drug resistance, jointly organised by Cancer Research UK, the Rosetrees Trust, and the UKRI-funded Physics of Life Network, brought together experts in cell biology, physical sciences, computational biology, drug discovery, and clinicians to focus on these key challenges and devise interdisciplinary approaches to address them. In this perspective, we review the outcomes of the workshop and highlight unanswered research questions. We outline the emerging hallmarks of drug resistance and discuss lessons from the COVID-19 pandemic and antimicrobial resistance that could help accelerate information sharing and timely adoption of research discoveries into the clinic. We envisage that initiatives that drive greater interdisciplinarity will yield rich dividends in developing new ways to better detect, monitor, and treat drug resistance, thereby improving treatment outcomes for cancer patients.

Over the past decade, circular RNAs (circRNAs) have gained recognition as a novel class of genetic molecules, many of which are implicated in cancer pathogenesis via different mechanisms, including drug resistance, immune escape, and radio-resistance. ExosomalcircRNAs, in particular, facilitatecommunication between tumour cells and micro-environmental cells, including immune cells, fibroblasts, and other components. Notably, micro-environmental cells can reportedly influence tumour progression and treatment resistance by releasing exosomalcircRNAs. circRNAs often exhibit tissue- and cancer-specific expression patterns, and growing evidence highlights their potential clinical relevance and utility. These molecules show strong promise as potential biomarkers and therapeutic targets for cancer diagnosis and treatment. Therefore, this review aimed to briefly discuss the latest findings on the roles and resistance mechanisms of key circRNAs in the treatment of various malignancies, including lung, breast, liver, colorectal, and gastric cancers, as well as haematological malignancies and neuroblastoma.This review will contribute to the identification of new circRNA biomarkers for the early diagnosis as well as therapeutic targets for the treatment of cancer.

Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide, characterised by poor prognosis and limited responsiveness to chemotherapy. There is a need for new and more effective anticancer agents. Antimicrobial peptides (AMPs) represent a promising class of biomolecules for this purpose. Naturally occurring in the innate immune system, these peptides can also exert cytotoxic effects against cancer cells, earning them the designation of "anticancer peptides" (ACPs). They have the potential to be a viable support for current chemotherapy schedules due to their selectivity against cancer cells and minor propensity to induce chemoresistance in cells. Insects are an excellent source of AMPs. Among them, due to its ability to thrive in hostile and microorganism-rich environments, we isolated a peptide fraction from Hermetia illucens L. (Diptera: Stratiomyidae) haemolymph to evaluate a possible anticancer activity. We tested Peptide Fractions (PFs) against AGS and KATO III gastric cancer cell lines. Data obtained indicated that PFs, especially those resulting from Escherichia coli and Micrococcus flavus infection (to boost immune response), were able to inhibit tumour cell growth by inducing apoptosis or cell cycle arrest in a cell line-specific manner. These results support further investigation into the use of antimicrobial peptides produced from insects as possible anticancer agents.

Background/Objectives: Drug resistance (DR) is a major challenge in cancer therapy, contributing to approximately 90% of cancer-related deaths. While alterations in drug metabolism are known to be key drivers of DR, their role-particularly in the early stages of acquired chemoresistance-remains understudied. Phase I drug-metabolizing enzymes (DMEs), especially cytochrome P450s (CYPs), significantly influence the metabolic fate of chemotherapeutic agents, directly affecting drug response. This study aimed to investigate the role of Phase I DMEs in the early metabolic adaptation of breast cancer (BC) MCF-7 cells to doxorubicin (DOX). Methods: Four types of spheroids were generated from MCF-7 cells that were either DOX-sensitive (DOXS) or adapted to low concentrations of the chemotherapeutic agent (DOXA 25, 35, and 45 nM). The expression levels of 92 Phase I DMEs and the activities of specific CYP isoforms were assessed in both DOXS and DOXA spheroids. Results: A total of twenty-four DMEs, including fifteen CYPs and nine oxidoreductases, were found to be differentially expressed in DOXA spheroids. Pathway analysis identified key roles for the differentially expressed DMEs in physiologically relevant pathways, including the metabolism of drugs, arachidonic acid, retinoic acid, and vitamin D. Conclusions: The deconvolution of these pathways highlights a highly dynamic process driving early-stage DOX resistance, with a prominent role of CYP3A-dependent metabolism in DOX adaptation. Our findings provide valuable insights into the underlying molecular mechanisms driving the early adaptation of MCF-7 cells to DOX exposure.

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Currently, irinotecan (CPT-11) is used alone or in combination with other drugs to treat patients with advanced CRC. However, the 5-year survival rate for metastatic CRC remains below 10 %, largely due to chemotherapy resistance. Several genes, including ABCG2, CYP3A4, MCL1, and MLH1 contribute to irinotecan resistance. This study aimed to identify microRNAs that simultaneously regulate the expression of these genes in irinotecan-resistant cell lines and study their effect on resistant colorectal cancer cells.

Irinotecan-resistant colorectal cancer cell lines were developed by intermittently exposing HCT116 and SW480 cell lines to gradually increasing doses of irinotecan over four generations. These resistant cell lines were designated HCT116-R1, HCT116-R2, HCT116-R3, HCT116-R4 and SW480-R1, SW480-R2, SW480-R3, SW480-R4. The induction of resistance was confirmed using MTT assays, by calculating IC50 values for each generation and comparing them to the parental cells. The expression levels of the ABCG2, CYP3A4, MCL1, and MLH1 genes, along with miR-3664-3p, were initially measured in all resistant and parental cell lines using quantitative real-time PCR. Following transfection of HCT116-R3 and SW480-R3 cells with pre-miR-3664-3p, the expression levels of ABCG2, CYP3A4, MCL1, MLH1, and miR-3664-3p were re-evaluated using real-time PCR.

In resistant cell lines derived from HCT116 and SW480, increased expression of the ABCG2, CYP3A4, and MCL1 genes was observed. However, a reduction in CYP3A4 expression was noted in the final resistant lines from both cell lines. Additionally, while MLH1 expression increased in HCT116-derived cell lines, no significant increase was observed in SW480-derived lines. A consistent decrease in miR-3664-3p expression was found across all resistant cell lines. When we transfected HCT116-R3 and SW480-R3 cells with pre-miR-3664-3p, there was an increase in miR-3664-3p expression and a reduction in ABCG2, CYP3A4, MCL1, and MLH1 gene expression. This led to increased sensitivity to irinotecan.

It can be concluded that miR-3664-3p can be considered a regulator of resistance to irinotecan by modulating the expression of ABCG2, CYP3A4, MCL1, and MLH1 genes.

Doxorubicin (DOX), an anthracycline, is widely used in cancer treatment by interfering RNA and DNA synthesis. Its broad antitumour spectrum makes it an effective therapy for a wide array of cancers. However, the prevailing drug-resistant cancer has proven to be a significant drawback to the success of the conventional chemotherapy regime and DOX has been identified as a major hurdle. Furthermore, the clinical application of DOX has been limited by rapid breakdown, increased toxicity, and decreased half-time life, highlighting an urgent need for more innovative delivery methods. Although advancements have been made, achieving a complete cure for cancer remains elusive. The development of nanoparticles offers a promising avenue for the precise delivery of DOX into the tumour microenvironment, aiming to increase the drug concentration at the target site while reducing side effects. Despite the good aspects of this technology, the classical nanoparticles struggle with issues such as premature drug leakage, low bioavailability, and insufficient penetration into tumours due to an inadequate enhanced permeability and retention (EPR) effect. Recent advancements have focused on creating stimuli-responsive nanoparticles and employing various chemosensitisers, including natural compounds and nucleic acids, fortifying the efficacy of DOX against resistant cancers. The efforts to refine nanoparticle targeting precision to improve DOX delivery are reviewed. This includes using receptor-mediated endocytosis systems to maximise the internalisation of drugs. The potential benefits and drawbacks of these novel techniques constitute significant areas of ongoing study, pointing to a promising path forward in addressing the challenges posed by drug-resistant cancers.

Hepatocellular carcinoma (HCC) is the most common cancer worldwide and vascular endothelial growth factor receptor-2 (VEGFR-2) is an important target in the development of inhibitors for the treatment of liver cancer. So far, however, there are no effective drugs targeting VEGFR-2 to achieve complete treatment of liver cancer. In this study, we employed molecular docking, molecular dynamics simulations, molecular mechanics generalized Born surface area (MM-GBSA) method, quantum mechanics/molecular mechanics (QM/MM) calculations and steered molecular dynamics simulations to discover the potential inhibitors from COCONUT database targeting VEGFR-2. The molecular docking analyses of 13 743 natural compounds targeting VEGFR-2 identified 96 molecules as promising candidates. Our molecular dynamics simulations revealed that only 5 candidate-docking systems remained stable over 100 ns of production run. Then, steered molecular dynamics simulations showed that CNP0076764, CNP0028810, CNP0177683 and CNP0107283 had higher mean force values than that of sorafenib, reflecting the high potential of candidate molecules. A detailed analysis of the binding modes revealed that Leu840, Val848, Lys868, Glu885, Leu889, Val899, Val916, Leu1035, Cys1045, Asp1046 and Phe1047 play key roles in binding the inhibitors. Overall, this study shows evidence that the four natural products obtained from the COCONUT database could be further used as anti-cancer inhibitors, which provides theoretical guidance for designing new drugs.

Using in-house computational tools, this work focuses on investigating how the combination of the electric field magnitude (E), bloodstream velocity (λinl) and pharmaco-kinetic profile (PK) impacts the reaction and transport mechanisms of drug (RTMs) arising in electro-chemotherapeutic treatments. The first step implies retrieving the ratios between extracellular, free intracellular, and bound intracellular concentrations from numerical simulations, employing a meshless code developed, calibrated and validated in a previous work. Subsequently, a Boolean model is developed to determine the presence, interaction and rates of RTMs based on the comparison of the spatio-temporal evolution of the drug concentration ratios, being this the main contribution of the present work to the comprehension of the phenomena involved in the systemic administration of chemotherapeutic drugs in cancer tumors. Different combinations of E (0 kV/m, 46 kV/m, 70 kV/m), λinl (1x10-4m/s, 1x10-3m/s, 1x10-2m/s) and PK (One-short tri-exponential, mono-exponential) are examined. In general, results show that both the presence and relative importance of RTMs can differ between both PKs for a given combination of E and λinl. Additionally, for a given PK, radial uniformity of transmembrane transport rate is aversively affected by the increase of E and λinl, whereas radial homogeneity of association/dissociation rate is monotonously affected only by E. Regarding the axial uniformity of transmembrane transport rate, this is benefited by the increase of λinl and, in a lower extent, by the reduction of E.

Currently, there is a growing concern surrounding the treatment of cancer, a formidable disease. Pharmacogenomics and personalized medicine have emerged as significant areas of interest in cancer management. The efficacy of many cancer drugs is hindered by resistance mechanisms, particularly P-glycoprotein (P-gp) efflux, leading to reduced therapeutic outcomes. Efforts have intensified to inhibit P-gp efflux, thereby enhancing the effectiveness of resistant drugs. P-gp, a member of the ATP-binding cassette (ABC) superfamily, specifically the multidrug resistance (MDR)/transporter associated with antigen processing (TAP) sub-family B, member 1, utilizes energy derived from ATP hydrolysis to drive efflux. This review focuses on genetic polymorphisms associated with P-gp efflux and explores various novel pharmaceutical strategies to address this challenge. These strategies encompass SEDDS/SNEDDS, liposomes, immunoliposomes, solid lipid nanoparticles, lipid core nanocapsules, microemulsions, dendrimers, hydrogels, polymer-drug conjugates, and polymeric nanoparticles. The article aims to elucidate the interplay between pharmacogenomics, P-gp-mediated drug resistance in cancer, and formulation strategies to improve cancer therapy by tailoring formulations to genetically susceptible patients.

Multidrug resistance (MDR) refers to the ability of cancer cells to resist various anticancer drugs and release them from the cells. This phenomenon is widely recognized as a significant barrier that must be overcome in chemotherapy. MDR varies depending on the number and expression level of the ATP-binding cassette transporter (ABC transporter), which is expressed differently in various cancer cells. Therefore, the dose of anticancer drugs should be adjusted according to the extent of MDR. The demand for drug screening that considers the differences in MDR is increasing in the process of drug discovery. In this study, three types of tumor spheroids were fabricated from HeLa (MRP1-/BCRP-), HepG2 (MRP1+/BCRP-), and A549 cells (MRP1+/BCRP+) using three-dimensional (3D) bioprinting. The fabricated tumor spheroids maintained their own MDR phenotypes. The EC50 values of doxorubicin (DOX) against the three tumor spheroids were more than 2-fold higher than those against the 2D cells. In addition, the EC50 value of DOX against tumor spheroids was proportional to the number of ABC transporters. The EC50 value of DOX against A549 tumor spheroids had the largest value of 9.5 μM among the three spheroids. In addition, the EC50 values of DOX against HepG2 and A549 tumor spheroids were remarkably reduced when they were treated with ABC transporter inhibitors, such as MK-571 against MRP1 and/or NOV against BCRP. These results demonstrate the successful construction of a 3D bioprinting-based screening platform to quantitatively evaluate the anticancer efficacy of chemodrugs, considering the MDR of cancer cells.

The development of chemo-resistance remains a significant hurdle in effective cancer therapy. NRF1 and NRF2, key regulators of redox homeostasis, play crucial roles in the cellular response to oxidative stress, with implications for both tumor growth and resistance to chemotherapy. This study delves into the dualistic role of NRF2, exploring its protective functions in normal cells and its paradoxical support of tumor survival and drug resistance in cancerous cells. We investigate the interplay between the PERK/NRF signaling pathway, ER stress, autophagy, and the unfolded protein response, offering a mechanistic perspective on how these processes contribute to chemoresistance. Our findings suggest that targeting NRF signaling pathways may offer new avenues for overcoming resistance to chemotherapeutic agents, highlighting the importance of a nuanced approach to redox regulation in cancer treatment. This research provides a molecular basis for the development of NRF-targeted therapies, potentially enhancing the efficacy of existing cancer treatments and offering hope for more effective management of resistant tumors.

One can recognize multidrug resistance (MDR) and residue as a biggest difficulty in cancer specialist. Chemotherapy-resistant cancer may be successfully treated by combining MDR-reversing phytochemicals with anticancer drugs. Though, clinical application of phytochemicals either alone or in conjunction with chemotherapy is still in its early stages or requires more research to determine their safety and efficacy. In this review we highlighted topics related to MDR in cancer, including an introduction to subject, mechanism of action of efflux pump, specific proteins involved in drug resistance, altered drug targets, increased drug metabolism, and potential role of phytochemicals in overcoming drug resistance.

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.

Cancer, a highly deadly disease, necessitates safe, cost-effective, and readily accessible treatments to mitigate its impact. Theabrownin (THBR), a polyphenolic pigment found in Pu-erh tea, has garnered attention for its potential benefits in memory, liver health, and inflammation control. By observing different biological activities of THBR, recently researchers have unveiled THBR's promising anticancer properties across various human cancer types. By examining existing studies, it is evident that THBR demonstrates substantial potential in inhibiting cell proliferation and reducing tumour size with minimal harm to normal cells. These effects are achieved through the modulation of key molecular markers such as Bcl-2, Bax, various Caspases, Poly (ADP-ribose) polymerase cleavage (Cl-PARP), and zinc finger E box binding homeobox 1 (ZEB 1). This review aims to provide in-depth insights into THBR's role in cancer research. This review also elucidates the underlying anticancer mechanisms of THBR, offering promise as a novel anticancer drug to alleviate the global cancer burden.

Acquired resistance poses a significant obstacle to the effectiveness of platinum-based treatment for cancers. As the most abundant antioxidant, glutathione (GSH) enables cancer cell survival and chemoresistance, by scavenging excessive reactive oxygen species (ROS) induced by platinum. Therapeutic strategy targeting GSH synthesis has been developed, however, failed to produce desirable effects in preventing cancer progression. Thus, uncovering mechanisms of rewired GSH metabolism may aid in the development of additional therapeutic strategies to overcome or delay resistance. Here, we identify upregulation of long noncoding RNA (lncRNA) GDIL (GSH Degradation Inhibiting LncRNA) in platinum resistant colorectal cancer (CRC) and ovarian cancer cells compared with parental ones. High expression of GDIL in resistant CRC is associated with poor survival and hyposensitivity to chemotherapy. We demonstrate that GDIL boosted GSH levels and enhances clearance of ROS induced by platinum. Metabolomic and metabolic flux analysis further reveals that GDIL promotes GSH accumulation by inhibiting GSH degradation. This is attributed by downregulation of CHAC1, an enzyme that specifically degrades intracellular GSH. Mechanistically, GDIL binds and re-localizes the nuclear protein XRN2 to the cytoplasm, where GDIL further serve as a scaffold for XRN2 to identify and degrade CHAC1 mRNA. Suppression of GDIL with selective antisense oligonucleotide, restored drug sensitivity in platinum resistant cell lines and delayed drug resistance in cell line- and patient-derived xenografts. Thus, lncRNA GDIL is a novel target to promote GSH degradation and augment platinum therapy.

Chemotherapy is generally given by intravenous (IV) administration which provides higher bioavailability than other systemic routes. However, in the case of lung cancer, the pulmonary (INH) route is the other choice for inhalable formulations. In the study, biochemical and histological parameters of Cabazitaxel (CBZ) free (2 mg kg-1) and nanoparticle (NP) (2 mg kg-1 CBZ equivalent) formulations are investigated after IV and INH administration in rats. The nanoformulation of CBZ is obtained using PEGylated polystyrene (PEG-PST) nanoparticles obtained by PISA. While a nose and head-only device is used for INH administration, a jugular vein is used as the IV route. Blood samples (blank, 24 h, and 48 h) are collected via carotid artery cannulas without handling in metabolism cages. According to biochemical parameters, free CBZ formulation applied via IV or INH route shows higher systemic toxicity. On the other hand, the nanoformulation of CBZ showed no signs of toxicity in both IV or INH routes. Higher and longer retention is observed in the case of inhaled nanoformulation. Histological analysis showed higher alveolar macrophage migration for inhaled nanoformulation due to enhanced retention. Results showed that nanotechnology and the lung defense system gave the advantage to end up with an inhalable nanomedicine formulation for lung cancer.

Osteosarcoma (OS) is one of the most common primary malignant bone tumors, primarily originating from mesenchymal tissue. It is notorious for its high invasiveness, high disability rate, high mortality rate, and poor prognosis. In most primary and metastatic malignant tumors, bone destruction can promote cancer progression, which is closely related to osteoclast activation and the imbalance between osteoblasts and osteoclasts. A large number of studies confirmed that osteoclasts are an important part of OS, which play an active role in destroying bone homeostasis and promoting the progress of OS. Therefore, we conducted a detailed study of osteoclasts at the single cell level, aiming to find new OS therapeutic targets to prevent tumor progression and local spread.

We analyzed the single-cell sequencing data of OS patients and usedMonocle2, Cytotrace, and Slingshot software to analyze the pseudo-sequential trajectory during OS progression. CellChat was used to reveal the communication between cells. PySCENIC was used to identify active transcription factors in osteoclasts. Finally, we further demonstrated the results by RT-qPCR analysis, CCK-8 assay, wound healing assay, Transwell assay, etc.

Through the analysis of single-cell sequencing data in OS, we identified a highly specific subgroup, C2MKI67+ Osteoclast. The key signaling pathway APP and the top 1 transcription factor PPARG in this subgroup played essential roles in osteoclast proliferation and differentiation. Given the pivotal role of osteoclasts in OS progression, we speculated that these signaling pathways and transcription factors could emerge as novel therapeutic targets, offering innovative strategies for OS treatment.

This study enhanced our understanding of OS and osteoclasts through scRNA-seq. Furthermore, we discovered that PPARG amplifies osteoclast activation and proliferation, resulting in excessive bone resorption and degradation of the bone matrix, thereby creating a favorable environment for tumor cell proliferation and growth. By innovatively targeting PPARG, it affected osteoclast proliferation and thus affected tumor progression; this work offered new insights and directions for the clinical treatment of OS patients.

Podophyllotoxin is a natural compound belonging to the lignan family and is well-known for its great antitumor activity. However, it shows several limitations, such as severe side effects and some pharmacokinetics problems, including low water solubility, which hinders its application as an anticancer agent. Over the past few years, antitumor research has been focused on developing nanotechnology-based medicines or nanomedicines which allow researchers to improve the pharmacokinetic properties of anticancer compounds. Following this trend, podophyllotoxin nanoconjugates have been obtained to overcome its biopharmaceutical drawbacks and to enhance its antitumor properties. The objective of this review is to highlight the advances made over the past few years (2017-2023) regarding the inclusion of podophyllotoxin in different nanosystems. Among the huge variety of nanoconjugates of diverse nature, drug delivery systems bearing podophyllotoxin as cytotoxic payload are organic nanoparticles mainly based on polymer carriers, micelles, and liposomes. Along with the description of their pharmacological properties as antitumorals and the advantages compared to the free drug in terms of biocompatibility, solubility, and selectivity, we also provide insight into the synthetic procedures developed to obtain those podophyllotoxin-nanocarriers. Typical procedures in this regard are self-assembly techniques, nanoprecipitations, or ionic gelation methods among others. This comprehensive perspective aims to enlighten the medicinal chemistry community about the tendencies followed in the design of new podophyllotoxin-based drug delivery systems, their features and applications.

The cytotoxicity of four rhenium compounds: fac-[ReO3(impy)CH3] (1) (impy = 2-(1H-imidazole-2-yl)pyridine), fac-[Re(CO)3(bzimpy)Cl] (2) (bzimpy = 2-(2-pyridyl)benzimidazole), fac-[Re(CO)3(bibzimpy)Cl] (3) (bibzimpy = 2,6-bis(2-benzimidazolyl)pyridine) and fac-[Re(CO)3(impy)Cl] (4) was assessed against cancer cell lines, namely, the cervical hormone-responsive HeLa and the triple-negative breast cancer (TNBC) HCC70 lines versus a non-tumorigenic control breast epithelial cell line, MCF12A. A rare facial trioxorhenium(VII) compound 1 was characterized via various physicochemical techniques. The rhenium compounds 1-4 were, in general, more cytotoxic to HeLa cells, compared to the TNBC HCC70 line, displaying half maximal inhibitory concentration (IC50) values in the micromolar range, however, the compounds were not convincingly selective for cancer cells over non-cancerous cells. In particular, compound 4 was highly cytotoxic towards HCC70, HeLa, and MCF12A cells, displaying low micromolar toxicity with IC50 values of 6.57 ± 1.11 μM, 8.88 ± 1.07 and 9.41 ± 1.04 μM in these three cell lines, respectively and was selected for further study as it displayed the greatest cytotoxicity against the highly treatment-resistant HCC70 TNBC cell line. Compound 4 was able to both bind to genomic DNA and act as an intercalator of CT-DNA, however, this did not lead to DNA damage as assessed by a comet assay. In addition, Compound 4 displayed a long-term dose-dependent effect on colony formation and long-term survival as a proxy of in vivo toxicity.

In pancreatic ductal adenocarcinoma cancer (PDAC) drug resistance is a severe clinical problem and patients relapse within a few months after receiving the standard-of-care chemotherapy. One contributing factor to treatment resistance is the desmoplastic nature of PDAC; the tumours are surrounded by thick layers of stroma composing up to 90% of the tumour mass. This stroma, which is mostly comprised of extracellular matrix (ECM) proteins, is secreted by cancer-associated fibroblasts (CAFs) residing in the tumour microenvironment. However, the mechanistic basis by which the tumour stroma directly contributes to chemoresistance remains unclear. Here, we show that CAF-secreted ECM proteins induce chemoresistance by blunting chemotherapy-induced DNA damage. Mechanistically, we identify N-myc downstream regulated gene 1 (NDRG1) as a key protein required for stroma-induced chemoresistance that responds to signals from the ECM and adhesion receptors. We further show that NDRG1 is a novel DNA repair protein that physically interacts with replication forks, maintains DNA replication and functions to resolve stalled forks caused by chemotherapy. More specifically, NDRG1 reduces R-loops, RNA-DNA hybrids that are known to cause genomic instability. R-loops occur during replication-transcription conflicts in S-phase and after chemotherapy treatments, thus posing a major threat to normal replication fork homeostasis. We identify NDRG1 as highly expressed in PDAC tumours, and its high expression correlates with chemoresistance and poor disease-specific survival. Importantly, knock-out of NDRG1 or inhibition of its phosphorylation restores chemotherapy-induced DNA damage and resensitizes tumour cells to treatment. In conclusion, our data reveal an unexpected role for CAF-secreted ECM proteins in enhancing DNA repair via NDRG1, a novel DNA repair protein, directly linking tumour stroma to replication fork homeostasis and R-loop biology, with important therapeutic implications for restoring DNA damage response pathways in pancreatic cancer.

Drug resistance is a severe clinical problem in stroma-rich tumours, such as pancreatic ductal adenocarcinoma (PDAC), and patients often relapse within a few months on chemotherapy 1-9 . The stroma, comprised of extracellular matrix (ECM) proteins, is secreted by cancer-associated fibroblasts (CAFs) residing in the tumour microenvironment 10-13 . Prior work show that ECM proteins provide survival benefits to cancer cells 14,15 . However, the precise role of CAF-secreted ECM in resistance to DNA damaging chemotherapies remains poorly understood. Here, we link ECM proteins to chemoresistance by enhanced DNA damage repair (DDR). Mechanistically, we identify N-myc downstream-regulated gene 1 (NDRG1) as a key effector downstream of ECM and the integrin-Src-SGK1-signalling axis that mediates enhanced DDR. We show that NDRG1 loss, mutation of conserved His194, or inhibition of NDRG1 phosphorylation by SGK1 lead to replication fork stalling, increased R-loops, and higher transcription-replication conflicts, resulting in genomic instability and sensitivity to chemotherapies. Our analysis of PDAC patient cohorts 16 found that high NDRG1 expression correlates with chemoresistance and poor patient survival. In conclusion, we uncover an unexpected role for CAF-secreted ECM proteins in promoting therapeutic resistance by enhancing DDR and establish NDRG1 as a novel DNA repair protein directly linking tumour stroma to DDR.

Cancer remains the second leading cause of death globally, driving the need for innovative therapies. Among natural compounds, maytansinoids have shown significant promise, contributing to nearly 25% of recently approved anticancer drugs. Despite their potential, early clinical trials faced challenges due to severe side effects, prompting advancements in delivery systems such as antibody-maytansinoid conjugates (AMCs). This review highlights the anticancer activity of maytansinoids, with a focus on AMCs designed to target cancer cells specifically. Preclinical and clinical studies show that AMCs, including FDA-approved drugs like Kadcyla and Elahere, effectively inhibit tumor growth while reducing systemic toxicity. Key developments include improved synthesis methods, linker chemistry and payload design. Ongoing research aims to enhance the safety and efficacy of AMCs, integrate nanotechnology for drug delivery, and identify novel therapeutic targets. These advancements hold potential to transform maytansinoid-based cancer treatments in the future.