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Keywords = reversal of chemoresistance

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18 pages, 3267 KiB  
Article
Sodium Caseinate Induces Apoptosis in Cytarabine-Resistant AML by Modulating SIRT1 and Chemoresistance Genes, Alone or in Combination with Cytarabine or Daunorubicin
by Daniel Romero-Trejo, Itzen Aguiñiga-Sánchez, Amanda Velasco-García, Katia Michell Rodríguez-Terán, Fabian Flores-Borja, Isabel Soto-Cruz, Martha Legorreta-Herrera, Víctor Manuel Macías-Zaragoza, Ernesto Romero-López, Benny Weiss-Steider, Karen Miranda-Duarte, Claudia Itzel Sandoval-Franco and Edelmiro Santiago-Osorio
Int. J. Mol. Sci. 2025, 26(15), 7468; https://doi.org/10.3390/ijms26157468 - 1 Aug 2025
Viewed by 211
Abstract
Resistance to cytarabine (Ara-C) remains a major obstacle to the successful treatment of acute myeloid leukemia (AML). Therefore, modulating Ara-C resistance is indispensable for improving clinical outcomes. We previously demonstrated that sodium caseinate (SC), a salt derived from casein, the principal milk protein, [...] Read more.
Resistance to cytarabine (Ara-C) remains a major obstacle to the successful treatment of acute myeloid leukemia (AML). Therefore, modulating Ara-C resistance is indispensable for improving clinical outcomes. We previously demonstrated that sodium caseinate (SC), a salt derived from casein, the principal milk protein, inhibits proliferation and modulates the expression of Ara-C resistance-related genes in chemoresistant cells. However, it remains unclear whether the combination of SC with antineoplastic agents enhances apoptosis, modulates chemoresistance-related genes, and prolongs the survival of tumor-bearing mice implanted with chemoresistant cells. Here, we investigated the effects of SC in combination with Ara-C or daunorubicin (DNR) on cell proliferation, apoptosis, the expression of chemoresistance-associated genes, and the survival of tumor-bearing mice. Crystal violet assays, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, flow cytometry, and Kaplan–Meier survival curves were used to evaluate the effects of combinations in chemoresistant cells. We demonstrate that the IC25 concentration of SC, when combined with antileukemic agents, increases the sensitivity of chemoresistant WEHI-CR50 cells to Ara-C by downregulating SIRT1 and MDR1, upregulating the expression of ENT1 and dCK, enhancing apoptosis, and prolonging the survival of WEHI-CR50 tumor-bearing mice. Our data suggest that SC in combination with antileukemic agents could be an effective adjuvant for Ara-C-resistant AML. Full article
(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)
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20 pages, 3053 KiB  
Article
ERRα and HIF-1α Cooperate to Enhance Breast Cancer Aggressiveness and Chemoresistance Under Hypoxic Conditions
by Dimas Carolina Belisario, Anna Sapino, Ilaria Roato, Amalia Bosia, Sophie Doublier and Serena Marchiò
Cancers 2025, 17(14), 2382; https://doi.org/10.3390/cancers17142382 - 18 Jul 2025
Viewed by 389
Abstract
Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl2-treated [...] Read more.
Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl2-treated SK-BR-3 (ER-negative) cells were used to model tumor hypoxia. Protein expression, coimmunoprecipitation, chromatin immunoprecipitation (ChIP), pharmacological inhibition, and siRNA-mediated gene silencing were employed to assess physical and functional interactions. Immunohistochemistry (IHC) on a tissue microarray (TMA) of 168 invasive breast carcinomas was performed to evaluate clinical relevance. Results: ERRα levels remained unchanged under hypoxia, while its coactivator, Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 α (PGC-1α), was upregulated. ERRα physically interacted with HIF-1α and was required for HIF-1 transcriptional activity under hypoxic conditions. ChIP assays showed that ERRα-driven overexpression of Permeability glycoprotein 1 (P-gp) and Vascular Endothelial Growth Factor (VEGF) was mediated by HIF-1α binding to the MDR1 and VEGF promoters. Inhibition or silencing of ERRα reversed P-gp overexpression and restored intracellular doxorubicin. TMA analysis confirmed the clinical correlation between ERRα, HIF-1α, and P-gp expression, highlighting the role of ERRα in hypoxia-induced drug resistance. ERRα expression was independent of ER status, suggesting an estrogen-independent function. Conclusions: This study identifies a novel physical and functional interaction between ERRα and HIF-1α that promotes chemoresistance in hypoxic breast tumors. Targeting ERRα may represent a promising therapeutic strategy to overcome drug resistance in aggressive, ER-independent breast cancer subtypes. Full article
(This article belongs to the Section Cancer Drug Development)
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30 pages, 2884 KiB  
Review
Silibinin Anticancer Effects Through the Modulation of the Tumor Immune Microenvironment in Triple-Negative Breast Cancer
by Shubham D. Mishra, Patricia Mendonca, Sukhmandeep Kaur and Karam F. A. Soliman
Int. J. Mol. Sci. 2025, 26(13), 6265; https://doi.org/10.3390/ijms26136265 - 28 Jun 2025
Viewed by 1038
Abstract
Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), remains a therapeutic challenge due to its aggressive nature, limited treatment options, and high recurrence rates. Current therapies, including chemotherapy [...] Read more.
Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), remains a therapeutic challenge due to its aggressive nature, limited treatment options, and high recurrence rates. Current therapies, including chemotherapy and immune checkpoint inhibitors, face resistance driven by tumor heterogeneity, immunosuppressive signaling, and dysregulated redox pathways. This review explores silibinin’s potential to modulate the tumor immune microenvironment (TIME) and overcome therapeutic resistance in TNBC. Silibinin exerts multifaceted anticancer effects by suppressing PD-L1 expression through the inhibition of JAK/STAT3 signaling and MUC1-C interaction, attenuating NF-κB-driven inflammation, and downregulating CCL2-mediated recruitment of tumor-associated macrophages (TAMs). Additionally, silibinin disrupts redox adaptation by targeting the Nrf2-EGFR-MYC-TXNIP axis, enhancing oxidative stress and chemosensitivity. Preclinical studies highlight its ability to inhibit epithelial–mesenchymal transition (EMT), reduce cancer stem cell (CSC) populations, and synergize with existing therapies like PD-1 inhibitors. Despite its low bioavailability, advanced formulations such as liposomes and nanoparticles show promise in improving delivery and efficacy. By reshaping TIME through dual antioxidant and immunomodulatory mechanisms, silibinin emerges as a viable adjunct therapy to reverse immunosuppression and chemoresistance in TNBC. Full article
(This article belongs to the Special Issue Bioactive Compounds and Their Anticancer Effects)
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24 pages, 6213 KiB  
Article
Transmembrane Protease Serine 11B Modulates Lactate Transport Through SLC16A1 in Pancreatic Ductal Adenocarcinoma—A Functional Link to Phenotype Heterogeneity
by Dinara Baiskhanova, Maike Menzel, Claudia Geismann, Christoph Röcken, Eric Beitz, Susanne Sebens, Anna Trauzold and Heiner Schäfer
Int. J. Mol. Sci. 2025, 26(11), 5398; https://doi.org/10.3390/ijms26115398 - 4 Jun 2025
Viewed by 630
Abstract
Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells [...] Read more.
Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells running the reverse Warburg metabolism. Key drivers of lactate transport are the carrier proteins SLC16A1 (import/export) and SLC16A3 (export). Expression and function of both carriers are controlled by the chaperone Basigin (BSG), which itself is functionally controlled by the transmembrane protease serine 11B (TMPRSS11B). In this study we explored the impact of TMPRSS11B on the phenotype of PDAC cells under reverse Warburg conditions. Amongst a panel of PDAC cell lines, Panc1 and BxPc3 cells were identified to express TMPRSS11B at a high level, whilst other cell lines such as T3M4 did not. ShRNA-mediated TMPRSS11B knock-down in Panc1 and BxPc3 cells enhanced lactate import through SLC16A1, as shown by GFP/iLACCO1 lactate uptake assay, whereas TMPRSS1B overexpression in T3M4 dampened SLC16A1-driven lactate uptake. Moreover, knock-down and overexpression of TMPRSS11B differentially impacted proliferation and chemoresistance under reverse Warburg conditions in Panc1 or BxPc3 and T3M4 cells, respectively, as well as their stemness properties indicated by altered colony formation rates and expression of the stem cell markers Nanog, Sox2, KLF4 and Oct4. These effects of TMPRSS11B depended on both SLC16A1 and BSG as shown by gene silencing. Immunohistochemical analysis revealed a reciprocal expression of TMPRSS11B and BSG together with SLC16A1 in some areas of tumor tissues from PDAC patients. Those regions exhibiting low or no TMPRSS11B expression but concomitant high expression of SLC16A1 and BSG revealed greater amounts of KLF4. In contrast, other tumor areas exhibiting high expression of TMPRSS11B together with BSG and SLC16A1 were largely negative for KLF4 expression. Thus, the differential expression of TMPRSS11B adds to metabolic heterogeneity in PDAC and its absence supports the reverse Warburg metabolism in PDAC cells by the enhancement of BSG-supported lactate uptake through SLC16A1 and subsequent phenotype alterations towards greater stemness. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)
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13 pages, 4321 KiB  
Article
ML210 Antagonizes ABCB1- Not ABCG2-Mediated Multidrug Resistance in Colorectal Cancer
by Yan-Chi Li, Yu-Meng Xiong, Ze-Ping Long, Yi-Ping Huang, Yu-Bin Shu, Ke He, Hong-Yan Sun and Zhi Shi
Biomedicines 2025, 13(5), 1245; https://doi.org/10.3390/biomedicines13051245 - 20 May 2025
Viewed by 766
Abstract
Objectives: ABCB1-mediated multidrug resistance (MDR) compromises chemotherapy efficacy in colorectal cancer (CRC). Despite decades of research, no selective ABCB1 inhibitor has achieved clinical success. This study investigates ML210 as a novel ABCB1-specific inhibitor to reverse ABCB1-driven MDR. Methods: Cytotoxicity assays (MTT) were performed [...] Read more.
Objectives: ABCB1-mediated multidrug resistance (MDR) compromises chemotherapy efficacy in colorectal cancer (CRC). Despite decades of research, no selective ABCB1 inhibitor has achieved clinical success. This study investigates ML210 as a novel ABCB1-specific inhibitor to reverse ABCB1-driven MDR. Methods: Cytotoxicity assays (MTT) were performed on ABCB1-overexpressing HCT-8/V and ABCG2-overexpressing S1-M1-80 CRC cells. Drug accumulation (doxorubicin/mitoxantrone) was quantified via flow cytometry, and cell cycle effects were analyzed using propidium iodide staining. Molecular docking utilized the ABCB1 crystal structure. Results: ML210 selectively reversed ABCB1-mediated resistance to doxorubicin and vincristine in HCT-8/V cells, enhancing intracellular drug accumulation without affecting ABCG2 activity. It induced cell cycle arrest in ABCB1-overexpressing cells and did not alter ABCB1 protein expression. Molecular docking revealed stable binding of ML210 within the ABCB1 substrate pocket through hydrophobic interactions and hydrogen bonding. Conclusions: ML210 is a selective ABCB1 inhibitor that circumvents MDR via direct transport blockade, offering a targeted strategy against ABCB1-mediated chemoresistance in CRC. Its specificity for ABCB1 over ABCG2 highlights potential clinical advantages. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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19 pages, 2974 KiB  
Article
Epigenetic Inactivation of RIPK3-Dependent Necroptosis Augments Cisplatin Chemoresistance in Human Osteosarcoma
by Aditya Sharma, Daniel Pettee, Christine Mella, Catherine Hord, Maximilian Brockwell, Samantha Hardy, Hope C. Ball, Fayez F. Safadi and Steven J. Kuerbitz
Int. J. Mol. Sci. 2025, 26(8), 3863; https://doi.org/10.3390/ijms26083863 - 18 Apr 2025
Viewed by 817
Abstract
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. Unfortunately, drug resistance limits the efficacy of chemotherapeutic treatment and compromises therapeutic outcomes in a substantial proportion of cases. Aberrant CpG island methylation-associated transcriptional silencing contributes to chemoresistance in pediatric [...] Read more.
Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents. Unfortunately, drug resistance limits the efficacy of chemotherapeutic treatment and compromises therapeutic outcomes in a substantial proportion of cases. Aberrant CpG island methylation-associated transcriptional silencing contributes to chemoresistance in pediatric solid tumors. Here, using whole-genome DNA methylation screening on 16 human primary OS specimens, we identify receptor interacting protein kinase-3 (RIPK3), a molecular regulator of the necroptosis programmed cell death pathway, as a gene target of aberrant CpG methylation and demonstrate its role in human OS chemoresistance. We validated these findings via enforced expression and DsiRNA silencing, and evaluated the role of RIPK3 in cisplatin chemosensitivity and necroptosis activation through MLKL phosphorylation. We found that CpG island methylation results in RIPK3 silencing in primary human OS samples and cell lines. Enforced RIPK3 expression significantly enhanced cisplatin cytotoxicity in OS cells and DsiRNA knockdown reversed the cisplatin-sensitive phenotype. In cells with enforced RIPK3 expression, cisplatin treatment significantly increased phosphorylation of both RIPK3 and its target, MLKL, indicative of induction of necroptosis. Here, we identify RIPK3 as an important mediator of chemoresistance in OS and a potential pharmacologic target to improve chemotherapy efficacy in drug-resistant tumors. Full article
(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)
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19 pages, 3612 KiB  
Article
COX-2 Inhibition in Glioblastoma Cells Counteracts Resistance to Temozolomide by Inducing Oxidative Stress
by Francesca Rosaria Augello, Francesca Lombardi, Valeria Ciummo, Alessia Ciafarone, Maria Grazia Cifone, Benedetta Cinque and Paola Palumbo
Antioxidants 2025, 14(4), 459; https://doi.org/10.3390/antiox14040459 - 12 Apr 2025
Cited by 2 | Viewed by 916
Abstract
Oxidative stress critically influences the pathophysiology of glioblastoma (GBM), a deadly and aggressive brain tumor. Reactive oxygen species (ROS) regulate cancer cell homeostasis, influencing the treatment response. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activates antioxidant defenses, protecting GBM cells [...] Read more.
Oxidative stress critically influences the pathophysiology of glioblastoma (GBM), a deadly and aggressive brain tumor. Reactive oxygen species (ROS) regulate cancer cell homeostasis, influencing the treatment response. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activates antioxidant defenses, protecting GBM cells from therapy-induced oxidative stress and contributing to Temozolomide (TMZ) resistance. Cyclooxygenase-2 (COX-2) plays a key role in GBM chemoresistance by modulating the tumor microenvironment and supporting a pro-survival phenotype. The impact of COX-2 inhibition by celecoxib (CXB), a selective COX-2 inhibitor, combined with TMZ on oxidative stress modulation linked to resistance was investigated in GBM primary cultures and cell lines. The drug combination CXB+TMZ was tested on TMZ-sensitive and -resistant cells, and ROS levels and Nrf2 activation were evaluated via a DCFH-DA probe and Western blotting, respectively. The oxidative stress marker malondialdehyde and antioxidant enzymes were assayed using standard methods. COX-2 inhibition combined with TMZ significantly increased ROS, while TMZ alone induced a compensatory antioxidant response, sustaining resistance. Drug combination reduced this response, restoring oxidative stress even in TMZ-resistant cells. Prostaglandin E2 reversed these effects, confirming the role of the COX-2/PGE2 axis in redox balance. Drug combination increased ROS, disrupted redox homeostasis and overcame TMZ resistance, supporting COX-2 inhibition as a promising GBM therapy strategy. Full article
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17 pages, 4186 KiB  
Article
PEGylated Liposomes of Disulfiram and Paclitaxel: A Promising Chemotherapeutic Combination Against Chemoresistant Breast Cancer
by Ammar Said Suliman, Sahrish Rehmani, Benjamin Small, Kate Butcher, Mouhamad Khoder, Vinodh Kannappan, Weiguang Wang, Abdelbary Elhissi and Mohammad Najlah
Pharmaceuticals 2025, 18(4), 487; https://doi.org/10.3390/ph18040487 - 28 Mar 2025
Viewed by 754
Abstract
Background: Steric stabilization of liposomes using PEGylation has been used widely in pharmaceutical research to overcome the limitations of conventional liposomes and to extend circulation time. PEGylation tended to improve the physicochemical stability and reverse the chemoresistance in multidrug-resistant (MDR) breast cancer cell [...] Read more.
Background: Steric stabilization of liposomes using PEGylation has been used widely in pharmaceutical research to overcome the limitations of conventional liposomes and to extend circulation time. PEGylation tended to improve the physicochemical stability and reverse the chemoresistance in multidrug-resistant (MDR) breast cancer cell lines. In this study, PEGylated formulations of disulfiram (DS) and paclitaxel (PAC) were developed using the ethanol-based proliposome technology. Methods: PEGylated liposomal formulations of disulfiram (DS) and paclitaxel (PAC) were developed using the ethanol-based proliposome approach combined with high-pressure homogenization (HPH). The liposomes were characterized for particle size, polydispersity index (PDI), zeta potential, drug loading efficiency (DLE%), and drug entrapment efficiency (DEE%). Cytotoxicity studies were performed on sensitive (MCF7, MDA-MB-231) and chemoresistant (MDA-MB-231PAC10) breast cancer cell lines using the MTT assay to assess the anti-ancer potential of the formulations. Synergistic cytotoxic effects of DS and PAC co-delivery were also evaluated. Results: There was no significant difference in drug loading (DLE%) and drug entrapment efficiency (EE%) between conventional liposomes and the developed PEGylated vesicles. DS demonstrated higher loading in liposomes than PAC, and a greater cytotoxic effect on both sensitive (MCF7 and MDA-MB-231) and chemoresistant (MDA-MB-231PAC10) human breast cancer cell lines. For both DS- and PAC-loaded liposomes, PEGylation did not compromise the cytotoxic effect on both sensitive and chemoresistant cells. Interestingly, the combination of DS- and PAC-loaded PEGylated liposomes had significantly higher cytotoxic effect and lower IC50 than that of each drug alone. Conclusions: Overall, PEGylated liposomal formulation of DS and PAC acted synergistically to reverse the multidrug resistance in breast cancer cells and could serve as a promising system for delivery of PAC and DS simultaneously in one formulation using an alcohol-based proliposome formulation. Full article
(This article belongs to the Section Pharmaceutical Technology)
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14 pages, 5489 KiB  
Article
Naringenin Exhibits Antiglioma Activity Related to Aryl Hydrocarbon Receptor Activity and IL-6, CCL2, and TNF-α Expression
by Monique Reis de Santana, Deivison Silva Argolo, Irlã Santos Lima, Cleonice Creusa dos Santos, Maurício Moraes Victor, Gabriel dos Santos Ramos, Ravena Pereira do Nascimento, Henning Ulrich and Silvia Lima Costa
Brain Sci. 2025, 15(3), 325; https://doi.org/10.3390/brainsci15030325 - 20 Mar 2025
Cited by 1 | Viewed by 726
Abstract
Background: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid cell proliferation, invasive behavior, and chemoresistance. The aryl hydrocarbon receptor (AhR) is implicated in chemoresistance and immune evasion, making it a promising therapeutic target. Natural compounds such as flavonoids have gained [...] Read more.
Background: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid cell proliferation, invasive behavior, and chemoresistance. The aryl hydrocarbon receptor (AhR) is implicated in chemoresistance and immune evasion, making it a promising therapeutic target. Natural compounds such as flavonoids have gained attention for their anti-inflammatory, antioxidant, and anticancer properties. Among them, naringenin, a citrus-derived flavonoid, exerts antiproliferative, pro-apoptotic, and immunomodulatory effects. Objectives: This study investigated the antiglioma effects of the flavonoid naringenin on the viability, growth, and migration of glioma cells and its potential role as an AhR modulator. Methods: Human (U87) and rat (C6) glioma cell lines were exposed to naringenin (10–300 µM) alone or in combination with the AhR agonist indole-3-carbinol (50 µM) for 24 to 48 h. Cell viability, scratch wound, and cell migration assays were performed. The expression of inflammatory markers was also analyzed by RT-qPCR. Results: Naringenin exerted dose- and time-dependent inhibition of cell viability and migration. The treatment decreased the gene expression of interleukin-6 (IL-6) and chemokine (CCL2), alongside increased tumor necrosis factor-alpha (TNF-α) expression, an effect reversed by the AhR agonist. Conclusions: These findings highlight naringenin’s potential as an antiglioma agent and its role in AhR signaling. Full article
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37 pages, 2353 KiB  
Review
Precision Medicine in High-Grade Serous Ovarian Cancer: Targeted Therapies and the Challenge of Chemoresistance
by Sara Polajžer and Katarina Černe
Int. J. Mol. Sci. 2025, 26(6), 2545; https://doi.org/10.3390/ijms26062545 - 12 Mar 2025
Cited by 3 | Viewed by 2014
Abstract
The poor prognosis for high-grade serous ovarian cancer (HGSOC), the dominant subtype of ovarian cancer, reflects its aggressive nature, late diagnosis, and the highest mortality rate among all gynaecologic cancers. Apart from late diagnosis, the main reason for the poor prognosis and its [...] Read more.
The poor prognosis for high-grade serous ovarian cancer (HGSOC), the dominant subtype of ovarian cancer, reflects its aggressive nature, late diagnosis, and the highest mortality rate among all gynaecologic cancers. Apart from late diagnosis, the main reason for the poor prognosis and its unsuccessful treatment is primarily the emergence of chemoresistance to carboplatin. Although there is a good response to primary treatment, the disease recurs in 80% of cases, at which point it is largely resistant to carboplatin. The introduction of novel targeted therapies in the second decade of the 21st century has begun to transform the treatment of HGSOC, although their impact on overall survival remains unsatisfactory. Targeting the specific pathways known to be abnormally activated in HGSOC is especially difficult due to the molecular diversity of its subtypes. Moreover, a range of molecular changes are associated with acquired chemoresistance, e.g., reversion of BRCA1 and BRCA2 germline alleles. In this review, we examine the advantages and disadvantages of approved targeted therapies, including bevacizumab, PARP inhibitors (PARPis), and treatments targeting cells with neurotrophic tyrosine receptor kinase (NTRK), B-rapidly accelerated fibrosarcoma (BRAF), and rearranged during transfection (RET) gene alterations, as well as antibody–drug conjugates. Additionally, we explore promising new targets under investigation in ongoing clinical trials, such as immune checkpoint inhibitors, anti-angiogenic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, Wee1 kinase inhibitors, and ataxia telangiectasia and Rad3-related protein (ATR) inhibitors for platinum-resistant disease. Despite the development of new targeted therapies, carboplatin remains the fundamental medicine in HGSOC therapy. The correct choice of treatment strategy for better survival of patients with advanced HGSOC should therefore include a prediction of patients’ risks of developing chemoresistance to platinum-based chemotherapy. Moreover, effective targeted therapy requires the selection of patients who are likely to derive clinical benefit while minimizing potential adverse effects, underscoring the essence of precision medicine. Full article
(This article belongs to the Special Issue Molecular Pathology and Treatment of Ovarian Cancer)
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38 pages, 2395 KiB  
Review
Therapeutic Approaches with Iron Oxide Nanoparticles to Induce Ferroptosis and Overcome Radioresistance in Cancers
by Dorianne Sant’Angelo, Géraldine Descamps, Valentin Lecomte, Dimitri Stanicki, Sébastien Penninckx, Tatiana Dragan, Dirk Van Gestel, Sophie Laurent and Fabrice Journe
Pharmaceuticals 2025, 18(3), 325; https://doi.org/10.3390/ph18030325 - 26 Feb 2025
Cited by 4 | Viewed by 2181
Abstract
The emergence of nanotechnology in medicine, particularly using iron oxide nanoparticles (IONPs), may impact cancer treatment strategies. IONPs exhibit unique properties, such as superparamagnetism, biocompatibility, and ease of surface modification, making them ideal candidates for imaging, and therapeutic interventions. Their application in targeted [...] Read more.
The emergence of nanotechnology in medicine, particularly using iron oxide nanoparticles (IONPs), may impact cancer treatment strategies. IONPs exhibit unique properties, such as superparamagnetism, biocompatibility, and ease of surface modification, making them ideal candidates for imaging, and therapeutic interventions. Their application in targeted drug delivery, especially with traditional chemotherapeutic agents like cisplatin, has shown potential in overcoming limitations such as low bioavailability and systemic toxicity of chemotherapies. Moreover, IONPs, by releasing iron ions, can induce ferroptosis, a form of iron-dependent cell death, which offers a promising pathway to reverse radio- and chemoresistance in cancer therapy. In particular, IONPs demonstrate significant potential as radiosensitisers, enhancing the effects of radiotherapy by promoting reactive oxygen species (ROS) generation, lipid peroxidation, and modulating the tumour microenvironment to stimulate antitumour immune responses. This review explores the multifunctional roles of IONPs in radiosensitisation through ferroptosis induction, highlighting their promise in advancing treatment for head and neck cancers. Additional research is crucial to fully addressing their potential in clinical settings, offering a novel approach to personalised cancer treatment. Full article
(This article belongs to the Special Issue Radiopharmaceuticals and Nanotechnology)
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14 pages, 789 KiB  
Review
Understanding microRNA-Mediated Chemoresistance in Colorectal Cancer Treatment
by Guillermo Valenzuela, Héctor R. Contreras, Katherine Marcelain, Mauricio Burotto and Jaime González-Montero
Int. J. Mol. Sci. 2025, 26(3), 1168; https://doi.org/10.3390/ijms26031168 - 29 Jan 2025
Cited by 2 | Viewed by 1722
Abstract
Colorectal cancer (CRC) remains the second most lethal cancer worldwide, with incidence rates expected to rise substantially by 2040. Although biomarker-driven therapies have improved treatment, responses to standard chemotherapeutics, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, vary considerably. This clinical heterogeneity emphasizes the [...] Read more.
Colorectal cancer (CRC) remains the second most lethal cancer worldwide, with incidence rates expected to rise substantially by 2040. Although biomarker-driven therapies have improved treatment, responses to standard chemotherapeutics, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, vary considerably. This clinical heterogeneity emphasizes the urgent need for novel biomarkers that can guide therapeutic decisions and overcome chemoresistance. microRNAs (miRNAs) have emerged as key post-transcriptional regulators that critically influence chemotherapy responses. miRNAs orchestrate post-transcriptional gene regulation and modulate diverse pathways linked to chemoresistance. They influence drug transport by regulating ABC transporters and affect metabolic enzymes like thymidylate synthase (TYMS). These activities shape responses to standard CRC chemotherapy agents. Furthermore, miRNAs can regulate the epithelial–mesenchymal transition (EMT). The miR-200 family (e.g., miR-200c and miR-141) can reverse EMT phenotypes, restoring chemosensitivity. Additionally, miRNAs like miR-19a and miR-625-3p show predictive value for chemotherapy outcomes. Despite these promising findings, the clinical translation of miRNA-based biomarkers faces challenges, including methodological inconsistencies and the dynamic nature of miRNA expression, influenced by the tumor microenvironment. This review highlights the critical role of miRNAs in elucidating chemoresistance mechanisms and their promise as biomarkers and therapeutic targets in CRC, paving the way for a new era of precision oncology. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer: 4th Edition)
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18 pages, 6081 KiB  
Article
PLGA-Nano-Encapsulated Disulfiram Inhibits Cancer Stem Cells and Targets Non-Small Cell Lung Cancer In Vitro and In Vivo
by Kate Butcher, Zhipeng Wang, Sathishkumar Kurusamy, Zaixing Zhang, Mark R. Morris, Mohammad Najlah, Christopher McConville, Vinodh Kannappan and Weiguang Wang
Biomolecules 2024, 14(12), 1651; https://doi.org/10.3390/biom14121651 - 23 Dec 2024
Cited by 2 | Viewed by 1366
Abstract
Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study [...] Read more.
Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study demonstrated hypoxia-induced stemness and chemoresistance at levels comparable to those in typical CSC sphere culture. Activation of the NF-κB pathway (by transfection of NF-κB-p65) plays a key role in NSCLC CSCs and chemoresistance. Disulfiram (DS), an anti-alcoholism drug, showed a strong in vitro anti-CSC effect. It blocked cancer cell sphere reformation and clonogenicity, synergistically enhanced the cytotoxicity of four anti-NSCLC drugs (doxorubicin, gemcitabine, oxaliplatin and paclitaxel) and reversed hypoxia-induced resistance. The effect of DS on CSCs is copper-dependent. A very short half-life in the bloodstream is the major limitation for the translation of DS into a cancer treatment. Our team previously developed a poly lactic-co-glycolic acid (PLGA) nanoparticle encapsulated DS (DS-PLGA) with a long half-life in the bloodstream. Intra venous injection of DS-PLGA in combination with the oral application of copper gluconate has strong anticancer efficacy in a metastatic NSCLC mouse model. Further study may be able to translate DS-PLGA into cancer applications. Full article
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16 pages, 8703 KiB  
Article
Disrupted Lipid Metabolism, Cytokine Signaling, and Dormancy: Hallmarks of Doxorubicin-Resistant Triple-Negative Breast Cancer Models
by Radhakrishnan Vishnubalaji and Nehad M. Alajez
Cancers 2024, 16(24), 4273; https://doi.org/10.3390/cancers16244273 - 23 Dec 2024
Cited by 3 | Viewed by 1437
Abstract
Background: Chemoresistance in triple-negative breast cancer (TNBC) presents a significant clinical hurdle, limiting the efficacy of treatments like doxorubicin. This study aimed to explore the molecular changes associated with doxorubicin resistance and identify potential therapeutic targets to overcome this resistance, thereby improving treatment [...] Read more.
Background: Chemoresistance in triple-negative breast cancer (TNBC) presents a significant clinical hurdle, limiting the efficacy of treatments like doxorubicin. This study aimed to explore the molecular changes associated with doxorubicin resistance and identify potential therapeutic targets to overcome this resistance, thereby improving treatment outcomes for TNBC patients. Methods: Doxorubicin-resistant (DoxR) TNBC models (MDA-MB-231 and BT-549) were generated by exposing cells to increasing concentrations of doxorubicin. RNA sequencing (RNA-Seq) was performed using the Illumina platform, followed by bioinformatics analysis with CLC Genomics Workbench and iDEP. Functional assays assessed proliferation, sphere formation, migration, and cell cycle changes. Protein expression and phosphorylation were confirmed via Western blotting. Pathway and network analyses were conducted using Ingenuity Pathway Analysis (IPA) and STRING, while survival analysis was performed using Kaplan–Meier Plotter database. Results: DoxR cells exhibited reduced proliferation, sphere formation, and migration, but showed enhanced tolerance to doxorubicin. Increased CHK2 and p53 phosphorylation indicated cellular dormancy as a resistance mechanism. RNA-Seq analysis revealed upregulation of cytokine signaling and stress-response pathways, while cholesterol and lipid biosynthesis were suppressed. Activation of the IL1β cytokine network was prominent in DoxR cells, and CRISPR-Cas9 screens data identified dependencies on genes involved in rRNA biogenesis and metabolism. A 27-gene signature associated with doxorubicin resistance was linked to worse clinical outcomes in a large breast cancer cohort (HR = 1.76, FDR p < 2.0 × 10−13). Conclusions: This study uncovers potential therapeutic strategies for overcoming TNBC resistance, including dormancy reversal and targeting onco-ribosomal pathways and cytokine signaling networks, to improve the efficacy of doxorubicin-based treatments. Full article
(This article belongs to the Special Issue Molecular Insights into Drug Resistance in Cancer)
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20 pages, 4089 KiB  
Article
Epigenetic and Cellular Reprogramming of Doxorubicin-Resistant MCF-7 Cells Treated with Curcumin
by Paola Poma, Salvatrice Rigogliuso, Manuela Labbozzetta, Aldo Nicosia, Salvatore Costa, Maria Antonietta Ragusa and Monica Notarbartolo
Int. J. Mol. Sci. 2024, 25(24), 13416; https://doi.org/10.3390/ijms252413416 - 14 Dec 2024
Cited by 1 | Viewed by 1397
Abstract
The MCF-7R breast cancer cell line, developed by treating the parental MCF-7 cells with increasing doses of doxorubicin, serves as a model for studying acquired multidrug resistance (MDR). MDR is a major challenge in cancer therapy, often driven by overexpression of the efflux [...] Read more.
The MCF-7R breast cancer cell line, developed by treating the parental MCF-7 cells with increasing doses of doxorubicin, serves as a model for studying acquired multidrug resistance (MDR). MDR is a major challenge in cancer therapy, often driven by overexpression of the efflux pump P-glycoprotein (P-gp) and epigenetic modifications. While many P-gp inhibitors show promise in vitro, their nonspecific effects on the efflux pump limit in vivo application. Curcumin, a natural compound with pleiotropic action, is a nontoxic P-gp inhibitor capable of modulating multiple pathways. To explore curcumin’s molecular effects on MCF-7R cells, we analyzed the expression of genes involved in DNA methylation and transcription regulation, including ABCB1/MDR1. Reduced representation bisulfite sequencing further unveiled key epigenetic changes induced by curcumin. Our findings indicate that curcumin treatment not only modulates critical cellular processes, such as ribosome biogenesis and cytoskeletal dynamics, but also reverses the resistant phenotype, toward that of sensitive cells. This study highlights curcumin’s potential as an adjuvant therapy to overcome chemoresistance, offering new avenues for pharmacological strategies targeting epigenetic regulation to re-sensitize resistant cancer cells. Full article
(This article belongs to the Special Issue The Role of Omics in Cancer Diagnosis and Treatment)
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