Search Results (145)

Phthalocyanines (Pcs) are well-established photosensitizers in photodynamic therapy, valued for their strong light absorption, high singlet oxygen generation, and photostability. Recent advances have focused on covalently conjugating Pcs, particularly zinc phthalocyanines (ZnPcs), with a wide range of small bioactive molecules to improve selectivity, efficacy, and multifunctionality. These conjugates combine light-activated reactive oxygen species (ROS) production with targeted delivery and controlled release, offering enhanced treatment precision and reduced off-target toxicity. Chemotherapeutic agent conjugates, including those with erlotinib, doxorubicin, tamoxifen, and camptothecin, demonstrate receptor-mediated uptake, pH-responsive release, and synergistic anticancer effects, even overcoming multidrug resistance. Beyond oncology, ZnPc conjugates with antibiotics, anti-inflammatory drugs, antiparasitics, and antidepressants extend photodynamic therapy’s scope to antimicrobial and site-specific therapies. Targeting moieties such as folic acid, biotin, arginylglycylaspartic acid (RGD) and epidermal growth factor (EGF) peptides, carbohydrates, and amino acids have been employed to exploit overexpressed receptors in tumors, enhancing cellular uptake and tumor accumulation. Fluorescent dye and porphyrinoid conjugates further enrich these systems by enabling imaging-guided therapy, efficient energy transfer, and dual-mode activation through pH or enzyme-sensitive linkers. Despite these promising strategies, key challenges remain, including aggregation-induced quenching, poor aqueous solubility, synthetic complexity, and interference with ROS generation. In this review, the examples of Pc-based conjugates were described with particular interest on the synthetic procedures and optical properties of targeted compounds. Full article

Increased levels of reactive oxygen species (ROS) are a hallmark of cardiovascular disease. ROS impact the function of proteins largely through thiol modification leading to redox signalling. Acute, targeted interference with local ROS levels has been difficult. Therefore, how dynamics in redox signalling impact cardiovascular health is still a matter of current research. An inducible, endothelial cell-specific knock-in mouse model expressing a yeast D-amino acid oxidase enzyme was generated (Hipp11-Flox-Stop-Flox-yDAO-Cdh5-CreERT2^+/0 referred to as ecDAO). DAO releases H₂O₂ as a by-product of the conversion of D-amino acids into imino acids. The D-amino acid treatment of DAO-expressing cells therefore increases their intracellular H₂O₂ production. The induction of yDAO in the ecDAO mice was performed with tamoxifen. Subsequently, the mice received D-Alanine (D-Ala, 0.5 M) through drinking water, and the effects on ROS production and vascular and cardiac function were determined. ecDAO induction increased endothelial ROS production as well as ROS production in the lung, which is rich in endothelial cells. The functional consequences of this were, however limited: After minimally invasive myocardial infarction, there was no difference in the outcome between the control (CTL) and ecDAO mice. With respect to vascular function, three days of D-Ala slightly improved vascular function as demonstrated by an increase in the diameter of the carotid artery in vivo and decreased vessel constriction to phenylephrine. Fifty-two days of D-Ala induced cardiac remodelling, increased peripheral resistance, and overoxidation of peroxiredoxins. In conclusion, acute stimulation of endothelial ROS improves cardiovascular function, whereas prolonged ROS exposure deteriorates it. Full article

Background: Several targeted drugs have been recently approved for the treatment of PIK3CA-mutated hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC). This study aimed at a comprehensive evaluation of the spectrum of PIK3CA alterations in Russian BC patients. Methods: The tumor material from 1872 patients with ER+/HER2− BC was tested by a combination of PCR-based methods. Results: Mutations were detected in 693/1872 (37%) cases, including 46 BC with two PIK3CA lesions. The three most common substitutions (E542K, E545K, and H1047R) were identified in 542/693 (78%) PIK3CA-mutated cases, while as many as 5.5–12% of identified mutations were not potentially detectable by common commercial kits. The study included patients of Slavic and non-Slavic ethnicities residing in regions with different climate conditions, however, these factors did not influence the distribution of PIK3CA mutations. The presence of PIK3CA variants was associated with older patient age at diagnosis (p = 0.0002), smaller tumor size (p = 0.005), lower grade (p = 0.005), Ki67 <20% (p = 0.0001) and progesterone receptor-positive status (p = 0.002) at the initial disease diagnosis, and fewer distant metastases at the time of the detection of BC spread (p = 0.0001). In a subgroup of 413 BC patients who received adjuvant tamoxifen or aromatase inhibitors, PIK3CA mutations were not associated with resistance to either type of treatment. Conclusions: The results of this study highlight the need to extend the PIK3CA testing beyond the hotspot regions of this gene. Although PIK3CA alterations contribute to the pathogenesis of HR+/HER2− BC and represent a target for several novel drugs, they are not intrinsically associated with unfavorable clinical characteristics of this subtype of cancer disease. Full article

Background: As per recent scenarios, drug resistance is a significant challenge in treating breast cancer for several reasons, such as genetic mutations, altered signaling pathways, and tumor microenvironment. Endocrine resistance is one of the biggest significant barriers to treatment, particularly in hormone receptor-positive (HR+) breast cancers, which depends on estrogen or progesterone signaling for growth. While therapies such as tamoxifen, aromatase inhibitors, and selective estrogen receptor degraders (SERDs) have effectively targeted these pathways, many patients develop resistance, rendering them less effective over time, which is driving a need for innovative therapeutics to treat breast cancer and overcome drug resistance and better treatment outcomes. Recent studies suggest that combining the different therapies, including immunotherapy, targeted therapy, chemotherapy, etc., with endocrine therapy, may bypass the endocrine resistance. Methodology: We conducted a comprehensive systematic review and meta-analysis examining the molecular mechanisms of endocrine resistance and evaluating randomized clinical trial outcomes, overall survival and progression-free survival in endocrine-resistant breast cancer patients treated with endocrine therapy, targeted therapy, immunotherapy, or chemotherapy. Results: We have analyzed 35 randomized clinical trial studies for different therapies along with combination therapy, and our results demonstrated that supplementary or additional therapies in endocrine resistance breast cancer patients have better progression-free and overall survival. Conclusions: The current study has demonstrated that combination therapies may have good survival results and patient outcomes in endocrine resistance. Also, This review sheds light on current challenges in drug resistance and the future direction of cancer treatment through a comprehensive analysis of these emerging treatment approaches to improve patient outcomes. Full article

Approximately 70–80% of breast cancers are estrogen receptor-positive (ER+), with 65% of these cases also being progesterone receptor-positive (ER+PR+). In most cases of ER+ advanced breast cancer, endocrine therapy (ET) serves as the first-line treatment, utilizing various drugs that inhibit ER signaling. These include tamoxifen, a selective estrogen receptor modulator (SERM); fulvestrant, a selective estrogen receptor degrader (SERD); and aromatase inhibitors (AIs), which block estrogen synthesis. However, intrinsic or acquired hormone resistance eventually develops, leading to disease progression. The combination of ET with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) has been shown to significantly increase progression-free survival (PFS) and, in some cases, overall survival (OS). CDK4/6is works by arresting the cell cycle in the G1 phase, preventing DNA synthesis, and enhancing the efficacy of ET. This review highlights the key mechanisms of resistance to ET, whether used alone or in combination with biological agents, as well as emerging therapeutic strategies aimed at overcoming resistance. Addressing ET resistance remains a work in progress, and in the near future, better patient selection for different therapeutic approaches is expected through the identification of more precise biological and genetic markers. In particular, liquid biopsy may provide a real-time portrait of the disease, offering insights into mechanisms driving ET resistance and cancer progression. Full article

Globally, breast cancer (BC) is the leading cause of cancer-related death for women. BC is characterized by heterogeneity, aggressive behavior, and high metastatic potential. Chemotherapy, administered as monotherapy or adjuvant therapy, remains a cornerstone of treatment; however, acquired drug resistance is a significant clinical challenge. Deciphering mechanisms of drug resistance will be central to developing more efficient treatment options and improving patient outcomes. The current review examines the multifaceted nature of exosomes in conferring drug resistance in BC through complex communication networks within the tumor microenvironment. We further explore recent advances in understanding how exosomes contribute to resistance against established chemotherapeutic agents such as tamoxifen, paclitaxel, doxorubicin, platinum-based drugs, trastuzumab, and newer immunotherapies, such as immune checkpoint inhibitors. Moreover, we discuss existing systematic approaches to investigating the exosome–drug resistance relationship in BC. Finally, we explore promising therapeutic approaches to overcome exosome-dependent drug resistance in BC, highlighting potential avenues for improved treatment efficacy. Investigating the distinct functions and cargo of exosomes offers potential for developing innovative approaches to overcoming treatment resistance. Full article

Background: Diosgenin, a powerful compound found in fenugreek and Dioscorea villosa, has diverse pharmacological effects. This study examines the anticancer potential of diosgenin nanoparticles (Dio-NPs) against DMBA-induced breast cancer in mice in combination with tamoxifen. Methods: In the current investigation, characterization of Dio-NPs was performed, including their size, shape, zeta potential, UV-vis, and FT-IR spectra. Dio-NPs (120 mg/kg) and tamoxifen (2 mg/kg) were given to mice with DMBA-induced breast cancer, either alone or in combination, over 4 weeks. We measured inflammatory and oxidative stress markers, as well as gene expressions related to apoptosis, using ELISA and qRT-PCR. Additionally, molecular docking studies were conducted to assess the binding affinity of diosgenin with specific proteins. Molecular dynamics simulations were conducted on CDK4, AKT, and CDK6 proteins with diosgenin using GROMACS. The systems were solved, neutralized, and equilibrated under NVT and NPT ensembles. Simulations ran for 100 ns, and trajectories were analyzed for RMSD, RMSF, RG, SASA, and hydrogen bonds. Results: The IC₅₀ of Dio-NPs against MCF-7 cells was 47.96 ± 1.48 µg/mL. Dio-NPs had a zeta potential of −21.8 ± 0.6 mV and a size of 56.85 ± 3.19 nm and were uniform and spherical. The LD₅₀ of Dio-NPs was 2400 mg/kg. DMBA exposure increased WBCs, inflammatory markers, oxidative stress, and gene expression of CDK2, CDK4, CDK6, and Akt, while reducing Hb%, RBCs, PLTs, GSH, superoxide dismutase, and catalase levels. Dio-NPs and tamoxifen, both alone and combined, significantly reduced these effects. The combination treatment was more effective than individual treatments. Histological analyses supported these findings. Molecular docking showed diosgenin had a stronger binding affinity with the target proteins compared to tamoxifen. The simulations revealed that diosgenin effectively binds to CDK4, AKT, and CDK6, maintaining their stability and structural integrity. CDK4, AKT, and CDK6 showed consistent RMSD, RG, and SASA values, with moderate flexibility and stable hydrogen bonding patterns, suggesting their potential as therapeutic targets. Conclusions: Combining diosgenin and tamoxifen effectively inhibits breast cancer progression in DMBA-treated mice. This is primarily due to the reduction in expression of CDK2, CDK4, CDK6, and Akt proteins, which enhances the sensitivity of resistant breast cancer cells to tamoxifen. Full article

Background: CDK4/6 inhibitors (CDK4/6i) combined with hormone therapies have demonstrated clinical benefit in HR+, HER2- breast cancer patients. However, the onset of resistance remains a concern and highlights a need for therapeutic strategies to improve outcomes. The objective of this study was to develop an in vitro model to better understand the mechanisms of resistance to CDK4/6i + hormone therapies and identify therapeutic strategies with potential to overcome this resistance. Methods: The HR+, HER2− T47D breast cancer cell line genetically modified with a Geminin–Venus reporter construct was treated with CDK4/6i (abemaciclib or palbociclib) in combination with 4-hydroxytamoxifen (tamoxifen). Resistant cells were identified by cell sorting for Geminin (%GEM+), a marker of the S/G2/M phases of the cell cycle, and confirmed by treatment with tamoxifen plus the CDK4/6i used to drive resistance. In resistant cells, following treatment with CDK4/6i + ET (tamoxifen or fulvestrant), the effects on cell proliferation (%GEM+) and viability, gene expression, and protein analysis to evaluate CDK4/6–cyclin D complex composition were examined. Results: Palbociclib + tamoxifen-resistant (PTxR) cells treated with abemaciclib + ET showed decreased %GEM+, %Ki67, and colony formation ability, compared to abemaciclib + tamoxifen-resistant (ATxR) cells treated with palbociclib + ET. Additionally, PTxR cells showed increased CDK4-p21 interaction, compared to ATxR. The CDK6 levels were greater in ATxR cells compared to PTxR cells, associated with CDK4/6i resistance. Additionally, abemaciclib + fulvestrant continued to robustly decrease pRb levels in PTxR models compared to palbociclib + fulvestrant in ATxR models. Transcriptome analysis revealed a depression of the cell cycle and E2F- and Rb-related genes in PTxR cells following treatment with abemaciclib + ET, not present in ATxR cells treated with palbociclib + ET. Both resistant models showed increased EGFR-related gene expression. Conclusion: Taken together, we describe CDK4/6i-dependent mechanisms resulting in early-onset resistance to CDK4/6i + ET, using clinically relevant drug concentrations, in preclinical breast cancer cell models. The characterization of these preclinical models post progression on CDK4/6 inhibitor + ET treatment highlights the potential that the specific sequencing of CDK4/6 inhibitors could offer to overcome acquired resistance to CDK4/6i + ET. Abemaciclib + fulvestrant is currently under clinical investigation in patients with HR+, HER2− breast cancer and progression on prior CDK4/6i + ET (NCT05169567, postMONARCH). Full article

Pharmacogenomics, the study of how genetic variations influence drug response, has become integral to cancer treatment as personalized medicine evolves. This review aims to explore key pharmacogenomic biomarkers relevant to cancer therapy and their clinical implications, providing an updated and comprehensive perspective on how genetic variations impact drug metabolism, efficacy, and toxicity in oncology. Genetic heterogeneity among oncology patients significantly impacts drug efficacy and toxicity, emphasizing the importance of incorporating pharmacogenomic testing into clinical practice. Genes such as CYP2D6, DPYD, UGT1A1, TPMT, EGFR, KRAS, and BRCA1/2 play pivotal roles in influencing the metabolism, efficacy, and adverse effects of various chemotherapeutic agents, targeted therapies, and immunotherapies. For example, CYP2D6 polymorphisms affect tamoxifen metabolism in breast cancer, while DPYD variants can result in severe toxicities in patients receiving fluoropyrimidines. Mutations in EGFR and KRAS have significant implications for the use of targeted therapies in lung and colorectal cancers, respectively. Additionally, BRCA1/2 mutations predict the efficacy of PARP inhibitors in breast and ovarian cancer. Ongoing research in polygenic risk scores, liquid biopsies, gene–drug interaction networks, and immunogenomics promises to further refine pharmacogenomic applications, improving patient outcomes and reducing treatment-related adverse events. This review also discusses the challenges and future directions in pharmacogenomics, including the integration of computational models and CRISPR-based gene editing to better understand gene–drug interactions and resistance mechanisms. The clinical implementation of pharmacogenomics has the potential to optimize cancer treatment by tailoring therapies to an individual’s genetic profile, ultimately enhancing therapeutic efficacy and minimizing toxicity. Full article

Background: Breast cancer (BrCa) patients with tumors expressing high interleukin-6 (IL6) levels have poor clinical outcomes. In BrCa, altered occupancy of CCCTC-binding factor (CTCF) within its DNA binding sites deregulates the expression of its targeted genes. In this study, we investigated whether CTCF contributes to the altered IL6 expression in BrCa. Methods/Results: We performed CTCF gain- and loss-of-function assays in BrCa cell lines and observed an inverse correlation between CTCF and IL6 expression levels. To understand how CTCF negatively regulates IL6 gene expression, we performed luciferase gene reporter assays, site-directed mutagenesis assays, and chromatin immunoprecipitation assays. Our findings revealed that CTCF interacted with the IL6 promoter, a form of regulation disrupted in a CpG methylation-independent fashion in MDA-MB-231 and Tamoxifen-resistant MCF7 cells. Data from TCGA and GEO databases allowed us to explore the clinical implications of our results. An inverse correlation between CTCF and IL6 expression levels was seen in disease-free survival BrCa patients but not in patients who experienced cancer recurrence. Conclusions: Our findings provide evidence that the CTCF-mediated negative regulation of the IL6 gene is lost in highly tumorigenic BrCa cells. Full article

In the breast tumor microenvironment (TME), adipocytes exert a selective pressure on the behavior of breast cancer stem cells (BCSCs), which are involved in endocrine therapy resistance. In obesity, adipocytes secrete reduced levels of adiponectin, which promotes the growth and progression of ERα-positive breast cancer (BC). Here, we examined how low adiponectin levels affect the enrichment of the BCSC subpopulation and the mechanisms contributing to the maintenance of endocrine therapy resistance in BC. Flow cytometry, qRT-PCR, and Western blotting analysis were performed to assess stemness, the cell cycle, and apoptosis markers in MCF-7 wild-type (WT) and tamoxifen-resistant (TR) mammospheres. nLC-MS/MS was employed to profile and compare the proteome of BCSCs. Differentially expressed proteins were intersected with data from the Metacore^TM dataset. Our study demonstrated that adiponectin increased the percentage of CD44⁺/CD24⁻/ALDH1⁺ stem-like cells in TR MCF-7 mammospheres. Specifically, adiponectin contributed to the maintenance of BCSC bulk in TR MCF-7 cells through a slow cycling rate, supported by decreased levels of Cyclin D1 and Ki67 and increased p21 and p27 expression, and through escape from apoptosis, sustained by reduced ROS production and preserved maintenance of mitochondrial membrane potential. Our results provide new insights into the contribution of adiponectin to poor ERα-positive BC outcomes. Deeply understanding adiponectin’s role in stemness may disclose novel therapeutic approaches to treat hormone-resistant obese BC patients. Full article

Background/Objectives: Tamoxifen (TAM) is an anti-breast cancer drug suffering from acquired resistance development, prompting cancer relapse. Propranolol (PRO)’s repurposing for cancer therapy has gained interest. This work aimed to investigate combined TAM/PRO therapy for potentiating the anti-breast cancer activity of TAM. The work probed bilosomes versus standard noisome for simultaneous oral and intratumor delivery of TAM and PRO. Methods: Bilosomes comprising Span60, cholesterol, and increasing concentrations of bile salts were prepared together with bile salts containing free standard niosomes. The vesicular size and morphology were characterized. The entrapment and release efficiencies of TAM and PRO from the tailored vesicles were determined. The in vivo investigations of anti-tumor activity of TAM with or without PRO employed the solid Ehrlich carcinoma model. Results: The vesicles of all fabricated dispersions were spherical and negatively charged, with a size ranging from 104 to 182 nm. The entrapment efficiency depended on the nature of the drug, recording values ranging from 87.5% to 97.8% for TAM and from 31.0% to 46.8% for PRO. Incorporation of bile salts into vesicles increased TAM and PRO release compared to standard niosomes. Oral administration of combined TAM/PRO bilosomes showed a significant reduction in tumor growth volume compared to that recorded following naked drug administration. Histopathological investigations reflected a significant decline in tumor giant cells and mitotic figures, implying the in vivo capability of the TAM/PRO combination to interfere with cancer cell proliferation and persistence. Conclusions: The overall results demonstrated the impact of repurposed PRO to enhance the anti-breast cancer activity of TAM when both were co-encapsulated into bilosomes. Full article

Breast cancer treatment has advanced significantly, particularly for estrogen receptor-positive (ER+) tumors. Tamoxifen, an estrogen antagonist, is widely used; however, approximately 40% of patients develop resistance. Recent studies indicate that microRNAs, especially miR-155, play a critical role in this resistance. Our analysis of MCF-7 tamoxifen-sensitive (TAM-S) and tamoxifen-resistant (TAM-R) cells revealed that miR-155 is significantly upregulated in TAM-R cells. Overexpression of miR-155 in TAM-S cells increased resistance to tamoxifen. Additionally, genistein, a natural isoflavone from soybeans, effectively downregulated miR-155 and its targets associated with apoptosis and glucose metabolism, including STAT3 and hexokinase 2 (HK2). Notably, genistein also significantly decreased cell migration, suggesting potential anti-metastatic effects. Furthermore, genistein reduced glucose consumption, indicating its potential to overcome miR-155-mediated tamoxifen resistance and modulate the Warburg effect. These findings highlight genistein as a promising therapeutic agent for overcoming tamoxifen resistance in ER+ breast cancer and merit further investigation. Full article

Ovarian cancer is one of the most prevalent cancers among women. Due to the frequent problems during treatment, such as relapses or the development of resistance to treatment, new methods of treating this disease are being sought. A special attention is directed towards the combination therapies combining several different anticancer agents. The aim of the following study was to examine the effect of combination therapy with mild hyperthermia (temperatures of 39 °C and 40 °C) and anticancer drugs—cisplatin and tamoxifen—on the SKOV-3 ovarian cancer cell line in vitro. Furthermore, the study also assessed the effect of moderate hyperthermia on the anticancer effectiveness of both of these drugs. The cytotoxic effect of the therapy was assessed using MTT assay and fluorescent acridine orange staining. Changes in the expression of genes involved in apoptosis processes were evaluated using RT-qPCR. It has been shown that the use of combination therapy leads to a significant increase in apoptosis processes in SKOV-3 ovarian cancer cells and, consequently, to a decrease in their viability. At the molecular level, mild hyperthermia leads primarily to a decrease in the expression of anti-apoptotic genes, and also, to a small extent, to an increase in the expression of proapoptotic genes. The results also indicate that moderate hyperthermia has a positive effect on the cytotoxic efficacy of both cisplatin and tamoxifen on ovarian cancer cells. This suggests that hyperthermia could be a potential component in combination therapy for ovarian cancer. Full article

Background/Objectives: Estrogen receptor-α coactivator MED1 is overexpressed in 40–60% of human breast cancers, and its high expression correlates with poor disease-free survival of patients undergoing anti-estrogen therapy. However, the molecular mechanism underlying MED1 upregulation and activation in breast cancer treatment resistance remains elusive. Methods: miRNA and mRNA expression analysis was performed using the NCBI GEO database. MED1 targeting and its impact on therapy resistance was evaluated in control and tamoxifen-resistant breast cancer cell lines by miR-205 overexpression and inhibition. Immunoblotting, chromatin immunoprecipitation, and luciferase reporter assays were used to understand the molecular mechanism of MED1-mediated tamoxifen resistance. Mice xenograft models were used to validate treatment efficacy and molecular mechanisms in vivo. Results: miR-205 was found to directly target and suppress the expression of MED1 through bioinformatic analyses and experimental validations. An inverse correlation of miR-205 and MED1 was observed in breast cancer patients with high MED1/low miR-205, indicative of poor prognosis in long-term anti-estrogen treatment. Furthermore, the depletion of miR-205 was observed in tamoxifen-resistant breast cancer cells overexpressing MED1. The restoration of miR-205 expression attenuated MED1 expression and re-sensitized cells to tamoxifen both in vitro and in vivo. Interestingly, miR205 was also found to target another key regulatory gene, HER3, which drives PI3K/Akt signaling and MED1 activation by phosphorylation. Importantly, we found ER target gene transcription and promoter cofactor recruitment by tamoxifen can be reversed by induced miR205 expression. Conclusions: Altogether, miR-205 functions as a negative regulator of MED1 and HER3, affecting the regulation of the HER3-PI3K/Akt-MED1 axis in anti-estrogen resistance, and could serve as a potential therapeutic regime to overcome treatment resistance. Full article