Search Results (138)

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Nucleobase and nucleoside analogs are critical components of antimetabolite chemotherapy treatments used to disrupt DNA replication and induce apoptosis in rapidly proliferating cancer cells. However, the development of resistance to these agents remains a major clinical challenge. This review explores the epigenetic mechanisms that contribute to acquired chemoresistance, focusing on DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These epigenetic alterations regulate key processes such as DNA repair, drug metabolism, cell transport, and autophagy, enabling cancer cells to survive and resist therapeutic pressure. We highlight how dysregulation of DNA methyltransferases (DNMTs) and histone acetyltransferases (HATs) modulates expression of transporters (e.g., hENT1, ABCB1), DNA repair enzymes (e.g., Polβ, BRCA1/2), and autophagy-related genes (e.g., CSNK2A1, BNIP3). Furthermore, emerging roles for long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in regulating nucleoside export and DNA damage response pathways underscore their relevance as therapeutic targets. The interplay of these epigenetic modifications drives resistance to agents such as gemcitabine and 5-fluorouracil across multiple tumor types. We also discuss recent progress in therapeutic interventions, including DNMT and HDAC inhibitors, RNA-based therapeutics, and CRISPR-based epigenome editing. Full article

Background/Objectives: Ibrutinib is a selective Bruton’s tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL). This drug exhibits significant variability in response and toxicity profile, possibly due to genetic polymorphisms in drug-metabolizing enzymes and transporters. The aim of this observational study is to address interindividual variability in the efficacy and safety of ibrutinib treatment in 49 CLL patients. Methods: Genotyping of nine polymorphisms was performed by quantitative polymerase chain reaction (qPCR) using a ViiA7^® PCR Instrument and TaqMan assays, and ibrutinib plasma concentrations were determined using high-performance liquid chromatography coupled to a tandem mass spectrometry detector (HPLC-MS/MS). Results: Our study confirmed a high response rate, with 62% of patients achieving complete remission (CR), 9% CR with incomplete hematologic recovery (CRi), and 24% partial remission (PR). The impact of genetic polymorphisms on the CR rate was evaluated, revealing no statistically significant associations for CYP3A4, CYP3A5, ABCB1, ABCG2, and SLCO1B1 variants. However, a tendency was observed for patients carrying ABCB1 rs1128503, rs1045642 T/T, or rs2032582 A/A genotypes to achieve a higher CR rate. Adverse drug reactions (ADRs) were frequent, with vascular disorders (39%) and infections (27%) being the most common. Genetic polymorphisms influenced ibrutinib toxicity, with CYP3A4 *1/*22 appearing to be protective against overall ADRs. Conclusions: The unexpected association between CYP3A4 *1/*22 genotype and lower ADR incidence, as well as the trend toward improved treatment response in patients carrying ABCB1 genotypes, suggests compensatory metabolic mechanisms. However, given the small sample size, larger studies are needed to confirm these findings and their clinical implications, while also aiming to uncover other non-genetic factors that may contribute to a better understanding of the variability in treatment response and toxicity. Full article

Ruxolitinib, a clinically approved JAK1/2 inhibitor used in the treatment of hematologic malignancies and inflammatory conditions, has been shown to interfere with the function of cytotoxic T lymphocytes (CTLs). Previous studies supported the involvement of the multidrug resistance transporter P-glycoprotein (Pgp/ABCB1) in CTL biology; however, the nature of its regulation remains unclear. To address this, we investigated the impact of ruxolitinib on Pgp expression and function in human CD8⁺ T cells. We demonstrate that CD8⁺ T lymphocytes express Pgp dynamically at both the mRNA and protein levels across naïve, short-term, and long-term activation states. Ruxolitinib increased the calcein accumulation in human Pgp-overexpressing NIH-3T3 cells and in CTLs and directly modulated Pgp function by increasing its basal ATPase activity in a concentration-dependent manner (10–100 μM), similar to the effect of the known Pgp substrate/modulator verapamil. Although measurable ATPase stimulation and transport inhibition were observed at supratherapeutic concentrations of ruxolitinib, its Pgp-mediated efflux may also occur at therapeutically relevant concentrations. In contrast, at therapeutically relevant plasma concentrations (1–3 μM), ruxolitinib significantly stabilized the mRNA expression of Pgp during early T-cell receptor (TCR) activation and inhibited the TCR-induced upregulation of Pgp, CD8, and PD-1 surface markers, suggesting its interference with activation-associated differentiation. At these same concentrations, ruxolitinib also impaired CCL19-directed transmigration of CTLs across human umbilical vein endothelial cell (HUVEC) monolayers, indicating disruption of lymphoid homing cues. Collectively, these findings demonstrate that ruxolitinib modulates Pgp at both the transcriptional and functional levels, with distinct concentration dependence. The ability of ruxolitinib to alter CTL activation and migration at clinically relevant plasma concentrations highlights the need for careful evaluation of JAK inhibitor–mediated immunomodulation and its implications for vaccination, transplantation, and T cell-based immunotherapies. Full article

Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between vemurafenib tolerance levels and metabolic plasticity. To determine how vemurafenib endurance levels drive metabolic plasticity, we developed isogenic BRAFV600E VemR melanoma models with variant vemurafenib tolerances and performed an integrative analysis of metabolomic and transcriptome alterations using metabolome, Mitoplate-S1, Seahorse, and RNA-seq assays. Regardless of drug tolerance differences, both VemR models display resistance to MEK inhibitor and sensitivity to Wnt/β-catenin inhibitor, ICG-001. β-catenin, MITF, and ABCB5 levels are upregulated in both VemR models, and ICG-001 treatment restored vemurafenib sensitivity with reductions in MITF, ABCB5, phospho-ERK1/2, and mitochondrial respiration. Whereas β-catenin signaling induced TCA cycle and OXPHOS in highly drug tolerant A2058VemR cells, it activated pentose phosphate pathway in M14VemR cells with low vemurafenib tolerance, both of which are inhibited by ICG-001. These data implicate an important role for Wnt/β-catenin signaling in VemR-induced metabolic plasticity. Our data demonstrate that drug tolerance thresholds play a direct role in driving metabolic shifts towards specific routes, thus providing a new basis for delineating VemR melanomas for metabolism-targeting therapies. Full article

The standard immunosuppressive treatments in heart transplantation are calcineurin inhibitors, corticosteroids, and antimetabolite agents or inhibitors of the mammalian target of rapamycin. Pharmacogenetic studies show the impact on clinical course of genetic variability in genes that encode transporters, metabolizers, or molecular targets of immunosuppressants. The aim of this systematic review is to elucidate the role that pharmacogenetics of immunosuppressant drugs plays in clinical outcomes upon heart transplantation. PubMed, EMBASE, the Cochrane Central Register, and the Database of Abstracts of Reviews of Effects were searched without restrictions. The 64 studies analyzed followed these criteria: (1) were based on clinical data on heart transplantation patients; (2) analyzed the associations between polymorphisms and clinical response; (3) analyzed the impact of polymorphisms on immunosuppressant safety. CYP3A4/5 variants were associated with higher doses of tacrolimus, whereas POR*28 variants with lower doses—ABCB1, ABCC2, SLCO1B1, and SLC13A1—contribute to interindividual variability in drug absorption, distribution, and toxicity. An ABCC2 polymorphism (rs717620) was related to higher risk of graft rejection in pediatrics. Variations in HLA-G, TNF-α and TGF-β genes influence transplant rejection risk and immune response. Implementing pharmacogenetic screening of polymorphisms could enhance therapeutic outcomes by improving drug efficacy, reducing toxicity, and ultimately increasing heart graft survival rates. Strong evidence supports genotyping for CYP3A5 and TPMT, but further research is required for transporter genes and cytokine polymorphisms. Full article

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

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review examines recent advances in combating P-gp-mediated resistance, including the development of novel P-gp inhibitors, innovative drug delivery systems (e.g., nanoparticle-based delivery), and strategies to modulate P-gp expression or activity. These modulation strategies encompass targeting relevant signaling pathways (e.g., NF-κB, PI3K/Akt) and exploring drug repurposing. While progress has been made, overcoming P-gp-mediated resistance remains crucial for improving patient outcomes. Future research directions should prioritize the development of potent, selective, and safe P-gp inhibitors with minimal off-target effects, alongside exploring synergistic combination therapies with existing chemotherapeutics or novel agents to effectively circumvent multidrug resistance in hematological malignancies. Full article

Background/Objectives: Metastatic prostate cancer (PCa) is the leading cause of cancer-related deaths and a major contributor to cancer mortality in men. Most patients with metastatic PCa eventually develop metastatic castration-resistant prostate cancer (mCRPC), characterized by resistance to treatment with androgen-deprivation therapy, and often later the development of resistance to other types of agents. MAGMAS, a 13.8 kDa mitochondrial-associated protein, facilitates the import of nuclear-encoded proteins into the mitochondrial matrix. Overexpression of MAGMAS has been observed in several aggressive cancers, including breast, glioblastoma, and prostate cancer. When overexpressed, MAGMAS acts as a cytoprotective protein by scavenging reactive oxygen species (ROS), maintaining ROS levels that support cell proliferation while avoiding the induction of apoptosis. This study investigates the role of MAGMAS in therapy resistance in PCa cells. Methods/Results: Quantitative immunoblotting revealed that MAGMAS is endogenously upregulated in docetaxel-resistant (DR) PCa cell lines compared to their docetaxel-sensitive parental counterparts. While MAGMAS depletion alone did not affect the survival of DR cells, it significantly sensitized them to docetaxel (DTX), as indicated by a marked reduction in clonogenic potential. Additionally, transient knockdown of MAGMAS in these resistant cells significantly decreased the levels of ABCB1 protein. Consistent with these findings, sub-therapeutic inhibition of MAGMAS using the novel BT#9 inhibitor, in combination with increasing concentrations of DTX, enhanced the sensitivity of DR cells to DTX, as demonstrated by proliferation and clonogenic assays. Lastly, RNA tumor expression predicts overall survival (OS). Conclusions: These results implicate MAGMAS in PCa chemoresistance and suggest that targeting this protein could provide a novel therapeutic strategy for treating DR tumors. Full article

Background/Objectives: Several genetic factors are related to the risk of Alzheimer’s disease (AD) and the response to cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) or memantine. However, findings have been controversial, and, to the best of our knowledge, admixed populations have not been previously evaluated. We aimed to determine the impact of genetic and non-genetic factors on the risk of AD and the short-term response to ChEIs and memantine in patients with AD from Mexico. Methods: This study included 117 patients from two specialty hospitals in Mexico City, Mexico. We evaluated cognitive performance via clinical evaluations and neuropsychological tests. Nineteen variants in ABCB1, ACHE, APOE, BCHE, CHAT, CYP2D6, CYP3A5, CHRNA7, NR1I2, and POR were assessed through TaqMan assays or PCR. Results: Minor alleles of the ABCB1 rs1045642, ACHE rs17884589, and CHAT rs2177370 and rs3793790 variants were associated with the risk of AD; meanwhile, CHRNA7 rs6494223 and CYP3A5 rs776746 were identified as low-risk variants in AD. BCHE rs1803274 was associated with worse cognitive functioning. None of the genetic and non-genetic factors studied were associated with the response to pharmacological treatment. Conclusions: We identified potential genetic variants related to the risk of AD; meanwhile, no factor was observed to impact the response to pharmacological therapy in patients with AD from Mexico. Full article

Background: Inhibitors of cyclin-dependent kinases (CDKs) and epigenetic modifier enhancer of zeste homolog 2 (EZH2) have emerged as promising options in the pharmacotherapy of malignant tumors. Recently, we demonstrated synergistic antitumor effects of the CDK4/6 inhibitor abemaciclib and the EZH2 inhibitors GSK126 or tazemetostat in patient-derived glioblastoma (GBM) models. Importantly, all three drugs are substrates of the two most important plasma membrane multidrug transporters ABCB1 and ABCG2, with abemaciclib and tazemetostat also being inhibitors of these proteins. Methods: To investigate whether increased intracellular accumulation of either of the two drugs used in combination could have contributed to corresponding synergisms, we developed a simple LC-MS/MS method for simultaneous detection of the three substances in cell culture lysates. The method was validated in accordance with the current International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline M10 on bioanalytical method validation and study sample analysis. Results: All acceptance criteria were met. Subsequent analysis of intracellular drug concentrations confirmed increased cellular uptake of tazemetostat in the presence of abemaciclib in both GBM cell lines studied compared to single agent treatment. A comparable pattern was also observed for GSK126, but in only one of the two cell lines used. Conclusions: In conclusion, the observed synergistic antitumor effect could be partly due to increased intracellular accumulation, although this alone is certainly not sufficient to explain it. Overall, the developed method provides a valuable approach for characterizing interactions at the transport level and for predicting the efficiency of both anticancer substance classes in different cell lines. Full article

As an endogenous hormone, auxin plays a crucial role in regulating plants’ growth and development, and also in the responses to abiotic stresses. However, the effects and mechanism of auxin and its inhibitors on plant growth and mineral nutrient absorption in citrus have not been thoroughly studied. Therefore, we used trifoliate orange (citrus’s rootstock, Poncirus trifoliata) as the experimental material to supplement the research content in this area. The trifoliate orange seedlings were treated with exogenous auxin (indolebutyric acid, IBA) and auxin inhibitor (2-naphthoxyacetic acid, 2-NOA) in a sand culture system. The results showed that compared to the control, exogenous auxin (1.0 µmol L⁻¹ IBA) significantly enhanced the taproot length, lateral root length, and lateral root number by 17.56%, 123.07%, and 88.89%, respectively, while also markedly elevating the levels of nitrogen (N), phosphorus (P), potassium (K), copper (Cu), and zinc (Zn) by 14.29%, 45.61%, 23.28%, 42.86%, and 59.80%, respectively. Again compared to the control, the auxin inhibitor (50.0 µmol L⁻¹ 2-NOA) dramatically reduced the taproot length, lateral root length, and lateral root number by 21.37%, 10.25%, and 43.33%, respectively, while also markedly decreasing the levels of N, magnesium (Mg), iron (Fe), Cu, and Zn by 7.94%, 10.42%, 24.65%, 39.25%, and 18.76%, respectively. Furthermore, IBA increased auxin accumulation in the root hair, stele, and epidermal tissues of citrus taproots, and promoted the up-regulation of auxin synthesis genes (TAR2, YUC3, YUC4, YUC6, YUC8) and transport genes (ABCB1, ABCB19, AUX1, LAX1, LAX2, PIN1, PIN3, PIN4). In contrast, 2-NOA decreased auxin levels in the root hair, stele, and epidermal tissues of citrus taproots, and was involved in the down-regulation of auxin synthesis genes (TAR2, YUC3, YUC4, YUC6) and transport genes (ABCB1, AUX1, LAX1, LAX2, LAX3, PIN3). Interestingly, 2-NOA dramatically elevated auxin level specifically in the root tip of citrus taproot. Therefore, 2-NOA disrupts auxin reflux from the root tip to root hair and epidermal tissues in citrus taproot through down-regulation of auxin transport genes, thereby creating localized (i.e., root hair zone and epidermal tissues) auxin deficiencies that compromise root system architecture and nutrient acquisition capacity. According to the results of this study, exogenous auxin analogs could regulate citrus growth and mineral nutrient absorption through the auxin synthesis and transport pathways. Full article

Background/Objectives: The prognosis of acute lymphoblastic leukemia has significantly improved with the incorporation of innovative therapies such as immunotherapy, tyrosine kinase inhibitors, and CAR-T cell-based treatments. Drug resistance, mediated by genes such as ABCB1, has been associated with reduced treatment efficacy in various clinical scenarios. Although measurable residual disease (MRD) is the most reliable tool for monitoring treatment response in acute lymphoblastic leukemia, the relationship between ABCB1 expression and MRD remains unclear. Aims: To evaluate the expression of the ABCB1 resistance gene and explore its potential relationship with measurable residual disease. Methods: Prospective cohort where 57 patients with de novo diagnosis of acute lymphoblastic leukemia were admitted to the Hospital General de México “Dr. Eduardo Liceaga” between 2022 and 2024. Results: A total of 57 patients undergoing chemotherapy-based treatment were included, with a majority being male (n = 30, 52.6%) and a mean age of 32 years (range 18–71 years). Analysis of ABCB1 gene expression revealed that 35.1% (n = 20) had low expression, 40.4% (n = 23) had overexpression, and 24.6% (n = 14) showed absent expression. No statistically significant association was identified between MRD positivity and the presence of the Philadelphia chromosome (p = 0.171, 95% CI) or the ABCB1 high-risk group (high or absent expression) (p = 0.538, 95% CI). Conclusions: Although ABCB1 expression remains a valuable tool for understanding drug resistance in acute lymphoblastic leukemia, this study did not identify a significant relationship with MRD. MRD continues to be the most reliable prognostic factor in chemotherapy-based treatments for acute lymphoblastic leukemia, underscoring its importance in personalized medicine. Full article

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

Gefitinib is a selective inhibitor of the epidermal growth factor receptor that is used to treat advanced and metastatic non-small cell lung cancer (NSCLC). Dermatological adverse reactions are most commonly associated with gefitinib treatment. The cause of adverse reactions in individuals is multifactorial. Pharmacogenetics is an effective tool to detect such adverse reactions. This case report describes a female patient with NSCLC who was administered gefitinib at a dose of 250 mg/day. However, due to severe adverse dermatological reactions, the treatment was interrupted for 15 d and antibiotic therapy was administered to manage the skin rashes, maculopapular rashes, and hyperpigmentation. Treatment adherence was adequate, and no drug interactions were detected. A pharmacogenetic analysis revealed homozygosity in the ATP-binding cassette (ABC)-B1 rs1128503 (c.1236A>G), heterozygosity in ABCG2 rs2231142 (c.421G>T) and rs2622604 (c.-20+614T>C), and a non-functional variant of the cytochrome P450 family 3, subfamily A, member 5 (CYP3A5). The relationship between altered genetic variants and the presence of adverse reactions induced by gefitinib is still controversial. Overall, this case report highlights the importance of continuing to study pharmacogenetics as predictors of adverse drug reactions. Full article