Search Results (956)

Multidrug resistance (MDR) is a central cause of chemotherapy failure and tumor recurrence and metastasis, and its mechanism involves enhanced drug efflux, target mutation, upregulation of DNA repair and remodeling of the tumor microenvironment. ABC transporter protein (P-gp, MRP, and BCRP)-mediated efflux of drugs is the most intensively researched aspect of the study, but the first three generations of small-molecule reversal agents were stopped in the clinic because of toxicity or pharmacokinetic defects. Natural products are considered as the fourth generation of MDR reversal agents due to their structural diversity, multi-targeting and low toxicity. In this paper, we systematically summarize the inhibitory activities of monoterpenes, sesquiterpenes, diterpenes and triterpenes against ABC transporter proteins in in vitro and in vivo models and focus on the new mechanism of reversing drug resistance by blocking efflux pumps, modulating signaling pathways such as PI3K-AKT, Nrf2, NF-κB and remodeling the tumor microenvironment. For example, Terpenoids possess irreplaceable core advantages over traditional multidrug resistance (MDR) reversers: Compared with the first three generations of synthetic reversers, natural/semisynthetic terpenoids integrate low toxicity (mostly derived from edible medicinal plants, half-maximal inhibitory concentration IC₅₀ > 50 μM), high target specificity (e.g., oleanolic acid specifically inhibits the ATP-binding cassette (ABC) transporter subtype ABCC1 without cross-reactivity with ABCB1), and multi-mechanistic synergistic effects (e.g., β-caryophyllene simultaneously mediates the dual effects of “ABCB1 efflux inhibition + apoptotic pathway activation”). These unique characteristics enable terpenoids to effectively circumvent key limitations of traditional synthetic reversers, such as high toxicity and severe drug–drug interactions. Among them, lupane-type derivative BBA and euphane-type sooneuphanone D (triterpenoids), as well as dihydro-β-agarofuran-type compounds and sesquiterpene lactone Conferone (sesquiterpenoids), have emerged as the core lead compounds with the greatest translational potential in current MDR reverser research, attributed to their potent in vitro and in vivo MDR reversal activity, low toxicity, and excellent druggable modifiability. At the same time, we point out bottlenecks, such as low bioavailability, insufficient in vivo evidence, and unclear structure–activity relationship and put forward a proposal to address these bottlenecks. At the same time, the bottlenecks of low bioavailability, insufficient vivo evidence and unclear structure–activity relationship have been pointed out, and future research directions such as nano-delivery, structural optimization and combination strategies have been proposed to provide theoretical foundations and potential practical pathways for the clinical translation research of terpenoid compounds, whose clinical application still requires further in vivo validation and translational research support. Full article

Chemotherapy resistance in colorectal cancer (CRC) represents a critical clinical challenge leading to treatment failure and poor patient prognosis. Artemisinin is a natural product isolated from Artemisia annua, and its clinically relevant derivatives include dihydroartemisinin (DHA) and artesunate. Beyond their established antimalarial efficacy, both artemisinin and its derivatives—collectively referred to as artemisinin-derived compounds (ADs)—have been increasingly recognized for their unique potential to reverse multidrug resistance in cancer. Unlike previous reviews focusing on isolated mechanisms, this review systematically constructs a multidimensional, synergistic attack network centered on ADs to elucidate their integrated actions against chemotherapy-resistant CRC. Mechanistically, ADs suppress cancer stem cell (CSC)-associated resistance phenotypes while concurrently reshaping the tumor immune microenvironment, highlighting a functional coupling between stemness inhibition and immune remodeling. In parallel, this review presents apoptosis reactivation and ferroptosis induction as complementary, dual-track cell death strategies that collectively circumvent apoptosis resistance. Moreover, ADs exert “one-strike–multiple-effects” through coordinated regulation of pro-survival signaling networks and immune-related pathways, including the induction of immunogenic cell death (ICD) and the modulation of immunosuppressive macrophage subsets. Beyond mechanistic insights, this review integrates emerging translational considerations, including clinical pharmacokinetics, safety and tolerability, formulation and delivery strategies, and rational combination therapy paradigms in CRC. Collectively, these findings position ADs as multi-dimensional modulators rather than a single-agent cytotoxic, providing a coherent mechanistic and translational rationale for their further development in chemotherapy-resistant CRC. Full article

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism. Full article

Background/Objectives: Cancer is a major health concern involving abnormal cell growth. Combining anticancer agents can enhance efficacy and overcome resistance by targeting multiple pathways and creating synergistic effects. Methods: This study used in silico approaches to evaluate the physicochemical and pharmacokinetic profiles of the innovative organoselenium nucleoside analog Di3a, followed by the design of two nanocarriers. Di3a-loaded PLGA nanocapsules and nanostructured lipid carriers based on compritol were prepared and evaluated alone and combined with doxorubicin (DOX) and docetaxel (DTX) for a synergistic effect. Results: Di3a subtly violated some of Lipinski’s rules, but still showed suitable pharmacokinetic properties. Both nanoparticles presented nanometric size, negative zeta potential and polydispersity index values < 0.20. Hemolysis assay suggested a pH-dependent pattern conferred by the surfactant 77KL, and evidenced the biocompatibility of the formulations, aligning with the results observed in the nontumor L929 cell line. The lack of drug release studies under varying pH conditions constitutes a limitation and warrants further investigation to validate the pH-responsive properties of the nanocarriers. MTT assay revealed that both formulations exhibited significant cytotoxic effects in the A549 cell line. However, neither formulation exhibited marked toxicity toward NCI/ADR-RES, a resistant tumor cell line. Conversely, when combined with DOX or DTX, the treatments were able to sensitize these resistant cells, achieving expressive synergistic antitumor activity. Conclusions: Despite the limitations in the in silico studies, the study highlights the potential of combining the proposed nanocarriers with conventional antitumor drugs to sensitize multidrug-resistant cancer cells and emphasizes the safety of the developed nanoformulations. Full article

P-glycoprotein (P-gp) is an ATP-driven transporter that effluxes a wide range of xenobiotics from cells, and its overexpression is a primary cause of multidrug resistance (MDR) in cancer. It is well-established that P-gp functions through conformational changes, yet its large-scale structural dynamics at work have been unexplored. Here, we directly visualized single P-gp molecules reconstituted in nanodiscs using high-speed atomic force microscopy (HS-AFM). The HS-AFM movies revealed that P-gp is intrinsically dynamic in its apo state, with its nucleotide-binding domains (NBDs) undergoing large, spontaneous opening and closing motions. However, addition of ATP stabilized a conformation characterized by NBD proximity with a strong tendency toward closure. We then leveraged this dynamic viewpoint to elucidate the relationship between Elacridar’s function and the resulting structural dynamics of P-gp. Elacridar is designed to overcome multidrug resistance (MDR) in cancer and acts as a potent dual inhibitor of both P-gp and the Breast Cancer Resistance Protein (BCRP), effectively blocking the drug efflux function of these transporters. This inhibitor has suggested concentration-dependent function: it is effluxed as a substrate at low concentrations and acts as an inhibitor at high concentrations. Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms. Full article

Background: Equisetum hyemale L., commonly known as scouring rush or horsetail, is a perennial plant with significant applications in traditional medicine. Methods: The aerial parts of E. hyemale L. were macerated with hexane, chloroform, and ethyl acetate. The phytochemical profile of the extracts was investigated using chromatography approaches. The biological performance of the extracts was determined using antibacterial, antioxidant, anticancer, and toxicity in vitro and in vivo models. Molecular docking and ADMET analyses were employed to determine interactions with structural components of multidrug resistant bacteria and assess potential toxicological risks. Results: The extracts exert high scavenging activity against ABTS radicals (IC₅₀ 2.57–2.68 μg/mL), but poor antibacterial activity. It was evidenced that treatment with extracts exerts in moderate cytotoxicity on hepatocellular and colorectal cancer cell lines. Toxicity assays unveiled that the extracts decrease the survival rate of C. elegans nematodes after 2 h of exposure to treatment. In silico studies evidenced a high affinity of campesterol and calcitriol towards the DNA gyrase, and the oral bioavailability of farnesol and limonene. Conclusions: Our findings demonstrated the presence of biologically active secondary metabolites in hexane, chloroform, and ethyl acetate extracts from E. hyemale L. This work also demonstrated the biological performance of these extracts in in vitro and in vivo models, and validated the potential pharmacokinetic and pharmacodynamic profile of their phytoconstituents. Full article

Multidrug resistance (MDR) remains a major obstacle in the treatment of ovarian cancer. MDR is often mediated by the overexpression of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). In this study, we evaluated the ability of elacridar, a dual P-gp and BCRP inhibitor, to overcome MDR in W1, an ovarian cancer cell line sensitive to Paclitaxel (PAC) and its PAC-resistant variants. Cells were cultured under both two-dimensional (2D) and three-dimensional (3D) conditions to account for differences in tumor-like microenvironments. The MDR1 gene and P-gp protein expression were determined for the analyzed model; P-gp activity was measured by flow-cytometry and fluorescent observation, with and without elacridar. The MTT tests were carried out to evaluate how elacridar, combined with chemotherapeutics, affects cell viability. Our results demonstrate that elacridar effectively inhibited transporter activity and increased cellular sensitivity to PAC and DOX. The inhibitory effect was observed in both 2D and 3D cultures, although the re-sensitization effect in 3D conditions was less pronounced, reflecting the complexity of tumor-specific resistance mechanisms. These findings highlight elacridar as a promising compound for reversing MDR in ovarian cancer and emphasize the importance of 3D models in preclinical drug evaluation. Further studies in advanced in vitro and in vivo models are required to assess the potential of elacridar better. Full article

Antimicrobial resistance (AMR) has become a major health crisis worldwide, and it is expected to surpass cancer as one of the leading causes of death by 2050. Conventional antibiotics are struggling to keep pace with the rapidly evolving resistance trends, underscoring the urgent need for novel antimicrobial therapeutic strategies. Antimicrobial peptides (AMPs) function through diverse, often membrane-disrupting mechanisms that can address the latest challenges to resistance. However, the identification, prediction, and optimization of novel AMPs can be impeded by several issues, including extensive sequence spaces, context-dependent activity, and the higher costs associated with wet laboratory screenings. Recent developments in artificial intelligence (AI) have enabled large-scale mining of genomes, metagenomes, and quantitative species-resolved activity prediction, i.e., MIC, and de novo AMPs designed with integrated stability and toxicity filters. The current review has synthesized and highlighted progress across different discriminative models, such as classical machine learning and deep learning models and transformer embeddings, alongside graphs and geometric encoders, structure-guided and multi-modal hybrid learning approaches, closed-loop generative methods, and large language models (LLMs) predicted frameworks. This review compares models’ benchmark performances, highlighting AI-predicted novel hybrid approaches for designing AMPs, validated by in vitro and in vivo methods against clinical and resistant pathogens to increase overall experimental hit rates. Based on observations, multimodal paradigm strategies are proposed, focusing on identification, prediction, and characterization, followed by design frameworks, linking active-learning lab cycles, mechanistic interpretability, curated data resources, and uncertainty estimation. Therefore, for reproducible benchmarks and interoperable data, collaborative computational and wet lab experimental validations must be required to accelerate AI-driven novel AMP discovery to combat multidrug-resistant Gram-negative pathogens. Full article

Cancer therapy resistance emerges from highly integrated molecular systems that enable tumor cells to evade cell death and survive cytotoxic therapeutic stress. High Mobility Group Box 1 (HMGB1) is increasingly gaining recognition as a central coordinator of these resistance programs. This review delineates how HMGB1 functions as a molecular switch that dynamically redistributes between cellular compartments in response to stress, with each localization enabling a distinct layer of resistance. In the nucleus, HMGB1 enhances chromatin accessibility and facilitates the recruitment of DNA repair machinery, strengthening resistance to radio- and chemotherapeutic damage. Cytosolic HMGB1 drives pro-survival autophagy, maintains redox stability, and modulates multiple regulated cell death pathways, including apoptosis, ferroptosis, and necroptosis, thereby predominantly shifting cell-fate decisions toward survival under therapeutic pressure. Once released into the extracellular space, HMGB1 acts as a damage-associated molecular pattern (DAMP) that activates key pro-survival and inflammatory signaling pathways, establishing microenvironmental circuits that reinforce malignant progression and therapy escape. HMGB1 further intensifies resistance through upregulation of multidrug resistance transporters, amplifying drug efflux. Together, these compartmentalized functions position HMGB1 as a central node in the networks of cancer therapy resistance. Emerging HMGB1-targeted agents, ranging from peptides and small molecules to receptor antagonists and nanoformulations, show promise in reversing resistance, but clinical translation will require precise, context- and redox-informed HMGB1 targeting to overcome multifactorial resistance program in refractory cancers. Full article

Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants. Full article

The development of antibiotic resistance has become a global health challenge, resulting in approximately 800,000 deaths per year. The rapid rise in multidrug-resistant (MDR) pathogens has prompted an urgent need for antimicrobial alternatives. Punica granatum L. peel has long been valued for its rich bioactive polyphenols with potent antimicrobial properties. In this study, P. granatum L. peel extract (PGPE) was integrated with chitosan nanoparticles (CH-PGPE) to enhance antimicrobial efficacy while minimizing potential cytotoxicity. The antimicrobial potential of PGPE and CH-PGPE was evaluated with agar well diffusion, disk diffusion, and minimum inhibitory concentration (MIC) analyses against standard ATCC and clinical MDR strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. MTT assay evaluated the biocompatibility and anti-proliferative potential of PGPE on ARPE-19 (normal retinal pigment epithelial), HeLa (human cervical cancer), and A549 (human lung carcinoma) cell lines. PGPE exhibited antibacterial activity, and CH-PGPE reduced MIC values by approximately two-fold. Both PGPE and CH-PGPE demonstrated comparable or superior inhibition compared to several conventional antibiotics, particularly against MDR strains. The MTT assay revealed that PGPE was non-cytotoxic to normal ARPE-19 cells, while exhibiting the highest antiproliferative potency against A549 cells and a moderate inhibitory response in HeLa cells. The nanoparticle-supported formulation enhanced the antimicrobial efficacy of PGPE and also exhibited selective anti-proliferative activity against cancer cells without affecting normal cells. Full article

Glyoxal (GO) and methylglyoxal (MGO) are highly toxic metabolic byproducts that induce carbonyl stress in bacteria and eukaryotes. Their accumulation in cells is linked to non-enzymatic glycosylation (glycation) of proteins, nucleic acids, and lipids, leading to the formation of advanced glycation end products (AGEs). In humans, AGEs are associated with several health problems, such as diabetes, Alzheimer’s disease, cancer, and aging. Recent studies indicate that, despite their short lifespan, bacteria are also affected by AGEs formation. In this review, we summarize the pathways and mechanisms that help bacteria cope with GO, MGO, and AGEs. We also discuss the impact of dietary AGEs on gut microbiota and the antibacterial activity of host-derived GO/MGO. Recent studies highlight three main areas for future research: the role of AGEs in dysbiosis, the regulation of protein activities by MGO/GO-dependent modifications, and the potential use of glyoxalase pathway inhibitors to combat pathogens. This last point is especially important due to the rising prevalence of multidrug-resistant strains and the failure of antibiotic therapies. Full article

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with therapeutic efficacy often hindered by the development of multidrug resistance. Consequently, alternative strategies to slow down tumor progression warrant rigorous investigation. Bioactive molecules derived from tissues and organs have shown potential therapeutic properties for several diseases. We investigated the biological role of soluble bioactive factors derived from lyophilized porcine freeze-dried lung tissue (FDLT), as they may contain tumor-suppressing components involved in the progression of non-small cell lung cancer (NSCLC). NSCLC H1975 and PC9 cell lines were treated with FDLT at concentrations of 0.25 mg/mL and 0.5 mg/mL. Cell cycle analysis and mitochondrial membrane potential (MMP) assays were performed to assess cell proliferation and cell death activation. In parallel, epithelial–mesenchymal transition (EMT) markers were detected by qRT-PCR. Our findings showed that FDLT treatment reduced the viability of H1975 and PC9 cells in a dose-dependent manner, along with significant suppression of cell proliferation and colony formation. Moreover, FDLT treatment altered the cell cycle phases and determined a concomitant reduction of cyclin D1 levels as well as induction of mitochondria depolarization by suppressing MMP. Finally, qRT-PCR revealed significant downregulation of EMT-related genes vimentin and N-cadherin, along with the EMT transcription factor Twist. These findings highlight soluble FDLT-derived biomolecules as a potential tool to design alternative treatment strategies for NSCLC. Full article

Background: Paclitaxel (PTX), a taxane chemotherapy drug, is widely regarded as one of the most potent and clinically effective treatments for advanced and resistant cancers. However, paclitaxel’s poor bioavailability is attributed to its unfavorable physicochemical properties, including low solubility and permeability. Nanosizing and multidrug combination strategies have emerged as key approaches to enhance the formulation of such compounds. Pterostilbene (PTE), a polyphenolic compound, possesses extensive anti-cancer properties and favorable hydrogen bond formation sites. In this study, PTE was employed to co-assemble with PTX to improve its physicochemical properties and enhance therapeutic efficacy. Methods: Paclitaxel-pterostilbene nanoparticles (PTX-PTE NPs) were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Results: PTX-PTE nanoparticles significantly improved the water solubility (7fold increase) and cytotoxicity of paclitaxel in tumor cells. The enhanced antitumor efficacy was achieved through P-gp and CDK1 protein downregulation, increased drug accumulation, and cell cycle inhibition. Conclusions: These improvements are attributed to the nanoparticles’ amorphous structure and nanoscale properties. In addition, the combined use of PTX and PTE significantly enhanced the cytotoxicity against human non-small cell lung cancer A549 cells. PTX-PTE nanoparticles show promise for improving drug delivery and overcoming multidrug resistance in A549 cells. Full article

The lysosome is no longer viewed as a simple degradative “trash can” of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical “microreactor” that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5–5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective “safe house,” yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome’s broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody–drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine–thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies. Full article