Efficacy of pumpkin seed oil on paclitaxel-induced tongue mucosal injury in rat: Structural and biochemical insights.

Amygdalar calcitonin gene-related peptide driven effects of cold sensitivity induced by peripheral neuropathy in mice.

Paclitaxel (PTX) is broadly prescribed to treat various malignancies. However, it induces negative impacts on many organs, including testes. This study explored the beneficial role of sitagliptin (SIT) in PTX-provoked testicular damage and the underlying mechanisms. Rats were allocated into four groups: (I) control, (II) PTX, (III) PTX + SIT5, and (IV) PTX + SIT10. Histopathological and ultrastructural analyses were conducted along with sperm analysis. Immunohistochemical examinations of NOD-like receptor protein 3 (NLRP3), cleaved caspase-3, caspase-3, cytochrome c (Cyt.c), and interleukin-1 beta (IL-1β) were assessed. Serum testosterone and testicular 17β-hydroxy steroid dehydrogenase (17β-HSD), sestrin2, phosphorylated protein kinase R-like ER kinase (pPERK), and C/EBP homologous protein (CHOP) were determined. SIT induced a remarkable increase in sperm count, motility, and viability, with a pronounced decline in sperm abnormality compared to PTX group. SIT increased testosterone and 17β HSD levels. SIT elevates sestrin2, reduced glutathione (GSH), and catalase, and reduces malondialdehyde (MDA), reflecting its antioxidant action. SIT mitigates ER stress via diminishing pPERK and CHOP. SIT reduces NLRP3 and IL-1β levels, clarifying its anti-inflammatory action. SIT decreases cleaved caspase-3, caspase-3, and Cyt.c levels, verifying its anti-apoptotic features. Overall, SIT ameliorated PTX-provoked testicular dysfunction via mediating PERK/CHOP/NLRP3/Sestrin2 signaling pathway.

Triple-negative breast cancer (TNBC) is a highly invasive subtype characterized by high recurrence rates and the absence of specific therapeutic targets, resulting in limited treatment efficacy and immune insensitivity. Nanoparticle-based photothermal therapy holds promise due to its selective tumor heating and minimal invasiveness; however, its effectiveness is constrained by limited biocompatibility and localized heat transfer. To address these challenges, a multifunctional therapy utilizing CaO@C@PTX@TG nanoparticles was developed for TNBC treatment. This platform combines multiple mechanisms, with the CaO@C core enabling photothermal and chemothermal conversion while simultaneously releasing calcium ions. In parallel, paclitaxel (PTX) enhances chemotherapy synergy. The TG modification improves nanoparticle biocompatibility and supports efficient drug release within target cells. Under light activation, the platform induces calcium-overload, generating synergistic effects with photothermal therapy, promoting apoptosis and enhancing the antitumor immune response through immunogenic cell death (ICD). In vivo and in vitro experiments demonstrated that the CaO@C@PTX@TG system effectively inhibited tumor growth and metastasis. This approach integrates thermotherapy, photothermal therapy, chemotherapy, calcium-overload and immune activation, presenting an effective treatment strategy for TNBC.

Traditional chemotherapy and radiotherapy for glioma are challenging due to the hypoxia in tumor microenvironment and the inability of chemotherapeutic agents to enter into tumor cells. Phototherapy is a novel therapeutic approach against varioustumors in recent years. When combined with chemotherapy, the antitumor efficacy of phototherapyis superior than each alone. However, the combination of chemotherapy and phototherapy is still hampered by the hypoxic tumor microenvironment which upregulates the expression of hypoxia-inducible factor 1 (HIF-1) and its downstream pathways, as well as the thermoresistance caused by the overexpression of heat shock proteins (HSPs). To solve this, the biocompatible albumin-based nanoparticles (NPs) are developed to co-deliver IR780 iodine (IR780) and paclitaxel (PTX) simultaneously at an optimized ratio (IR780-PTX NPs)for synergistic photochemotherapy. Moreover, acriflavine (ACF), a chemical inhibitor of HIF-1, is formulated into intratumorally formed hydrogels to reinforce synergistic photochemotherapy. The continuously released ACF from hydrogel not only relieves the impact of photodynamic therapy-exacerbated tumor hypoxia by suppressing HIF-1 activity, but also efficiently attenuates HSP70 upregulation. The collaboration between IR780-PTX NPs and ACF hydrogels leads to an extraordinary antitumor effect in vitro and in vivo. The reinforced synergistic photochemotherapy via a single molecule by overcoming HIF-1 activity and HSP overexpression provides an effective therapeutic example to treat tumors, especially in those undergone severe hypoxia and/or therapy-induced thermoresistance.

Melanoma is aggressive with limited treatment options. Paclitaxel (PTX) is effective but limited by poor solubility, systemic toxicity, and insufficient intratumoral retention. Here, we report an in situ needle-free platform that amplifies local PTX exposure via multiretention nanoscale mixed polymeric micelles composed of Soluplus and a dipotassium glycyrrhizinate-PEG-folic acid conjugate (DG-pp-FA). Needle-free intratumoral jet injection at the tumor site reduces needle-related barriers and discomfort. The micelles integrate thermoenabled local deposition and physical retention, pH-responsive stabilization and release in acidic tumor microenvironments, and folate-receptor targeting for enhanced uptake and selectivity. Central composite design optimization yielded stable micelles with a hydrodynamic size of 68 ± 3.8 nm, PDI of 0.08 ± 0.01, and 98 ± 0.11% PTX encapsulation efficiency, showing sustained release. Compared with free PTX, NF#PTX@Soluplus/DG-pp-FA improved tumor retention, increased cellular uptake, and more strongly inhibited melanoma proliferation, migration, and invasion. Single-cell sequencing, spatial transcriptomics, and proteomics revealed dual actions of direct tumor suppression and immune microenvironment remodeling, including increased leukocyte infiltration, extracellular matrix (ECM) reprogramming to improve penetration, enhanced immune activation, and reduced fibrosis. In vivo studies confirmed improved tumor localization, prolonged retention, lower toxicity, and good biocompatibility.

Nanostructured lipid carriers (NLCs) and lipid-polymeric hybrid nanoparticles (H-NPs) were developed for the local administration of paclitaxel (PTX) and breast cancer therapy. Here, we investigated how nanoparticle type and composition influence the molecular effects and in vivo antiangiogenic activity of PTX. Elevated BAX expression and PARP-1 cleavage in MCF-7 and MDA-MB-231 breast cancer cells treated with nanoencapsulated PTX indicate that apoptosis is the primary mechanism of cell death, regardless of the nanocarrier type. However, distinct molecular effects were observed for other markers. Both unloaded nanocarriers increased α-tubulin acetylation in MCF-7 cells, indicating an intrinsic ability of the carriers to modulate cytoskeletal organization. Upon PTX loading, these effects became carrier-dependent: NLC-PTX induced higher α-tubulin acetylation than H-NP-PTX compared to the PTX solution. Moreover, in MCF-7 cells, NLC-PTX, but not H-NP-PTX, markedly enhanced drug-induced DNA damage, increasing γH2AX expression by 13.4-fold compared to PTX as a solution. These findings suggest that the nanocarriers not only act as delivery systems but may also confer additional biological effects that may contribute to PTX cytotoxicity. In the chicken chorioallantoic membrane model, nanoencapsulation reduced PTX-induced irritation from moderately irritant (irritation score 6) to nonirritant while preserving its antiangiogenic activity, achieving a 6.1-7.8-fold inhibition of vessel growth at subcytotoxic doses. Collectively, these results highlight nanoencapsulation as a promising strategy to potentiate PTX activity while improving safety for local breast cancer therapy. The distinct molecular responses of lipid and hybrid systems demonstrate that nanocarrier composition and structure modulate biological outcomes, underscoring the importance of rational nanocarrier design to overcome current therapeutic challenges.

Cancer remains a complex and formidable disease that necessitates the development of diverse therapeutic strategies, including the investigation of natural products as complementary agents. Rosmarinic acid (RA), a phenolic compound, has demonstrated promising anticancer activity across various malignancies. Combining RA with conventional chemotherapeutic agents may represent a novel therapeutic approach. In the present study, the efficacy of these combinations was evaluated in vitro through the assessment of cell viability, apoptosis, autophagy, and proliferation, and in vivo by examining their effects on tumor growth in an Ehrlich Ascites Carcinoma (EAC) model. Among the tested combinations, RA and Paclitaxel (PTX) exhibited enhanced cytotoxicity and synergistic activity compared with individual treatments, whereas other combinations demonstrated limited efficacy. Morphological and moleculer analyses indicated induction of apoptosis, evidenced by increased expression of FAS, FADD, and cleaved caspases detected by Western blotting. Moreover, the RA+PTX (Rosmarinic acid + Paclitaxel) combination was associated with impaired autophagic flux, as reflected by elevated LC3 and p62 levels. Although the combined treatment reduced tumor volume in vivo, its antitumor efficacy was comparable to that of RA monotherapy. Collectively, these findings indicate that while the RA+PTX combination enhanced cytotoxicity activity against triple-negative breast cancer in vitro, its therapeutic advantage in vivo requires further investigation.

Conventional chemotherapy is significantly hampered by the inherent hydrophobicity of chemotherapeutic agents, limited tumor-specific targeting, and inadequate intratumoral accumulation, all of which undermine its clinical efficacy. Nonselective distribution of cytotoxic agents leads to suboptimal drug concentrations within tumor tissues, causing systemic toxicity in healthy organs. Tumor microenvironment-responsive nanoplatforms offer a promising strategy for enhancing specificity and efficacy. This study demonstrates the successful development of a nanodrug delivery system, CASS@PTX nanoparticles, where CASS is a cinnamaldehyde-based, disulfide-containing polymer engineered with dual-stimulus responsiveness to glutathione (GSH) depletion and reactive oxygen species (ROS) amplification. This system disrupts intracellular redox homeostasis in tumor cells, triggering the release of encapsulated paclitaxel (PTX) while enhancing chemotherapeutic efficacy through redox-dependent sensitization. GSH consumption and ROS overproduction create a prooxidative microenvironment that enhances PTX-induced apoptosis. Preclinical validation using in vitro cytotoxicity assays and in vivo tumor models demonstrates potent synergistic anti-tumor effects with minimal systemic toxicity. This cascading ROS self-generation strategy represents a promising approach for overcoming multidrug resistance and improving the therapeutic outcomes of cancer chemotherapy.

Combinational therapy has become a pivotal strategy in oncology due to its potential to overcome drug resistance and enhance therapeutic efficacy. Herein, we synthesized a hypoxia-responsive paclitaxel (PTX) prodrug (PA), which can assemble with dimeric indocyanine green (DICG) into PADI NPs in the absence of any adjuvants. PADI NPs possess enhanced colloidal stability and prolonged blood circulation, thus realizing preferential accumulation at the tumor site. In response to a hypoxic tumor microenvironment, PADI NPs undergo a reduction and self-elimination reaction to generate a PTX monomer and synchronously release DICG. Upon irradiation, the generated reactive oxygen species and hyperthermia of DICG not only cooperate with PTX-instructed chemotherapy to synergistically induce immunogenic cell death but also activate the cGAS-STING pathway, ultimately initiating a potent antitumor immune response. The in vivo experiments validated the combination of PTX chemotherapy and DICG phototherapy elicited robust antitumor immunity, realizing a better tumor treatment compared to commercial Abraxane. This hypoxia-responsive nanoplatform exemplifies a promising strategy for enhancing treatment precision and efficacy against tumors.

Spinal cord injury (SCI) is a debilitating disorder characterized by intricate pathological processes that result in severe motor and sensory deficits. Existing therapeutic approaches remain insufficient to achieve comprehensive functional restoration, indicating the necessity of alternative treatment strategies. In this study, an advanced nanoparticle-based drug delivery system was established using extracellular vesicles (EVs) modified with a matrix metalloproteinase (MMP)-responsive peptide, ACPP, to achieve the targeted delivery of paclitaxel (PTX). The ACPP-EVs@PTX formulation integrates the drug loading capacity of EVs, the lesion-targeting capability conferred by ACPP, and the neuroprotective properties of PTX. Enhanced accumulation of PTX at the SCI lesion site was achieved, accompanied by a reduction in the off-target distribution. Both in vitro and in vivo experiments demonstrated marked therapeutic efficacy of ACPP-EVs@PTX through modulation of the SCI microenvironment, including stimulation of angiogenesis, attenuation of inflammatory responses, alleviation of oxidative stress, and promotion of axonal regeneration. In addition, the activation of PINK1-Parkin-mediated mitophagy was observed, leading to improved mitochondrial function and enhanced neuronal repair. Behavioral evaluations further confirmed significant recovery of neurological function, supporting the translational potential of this multitarget, synergistic therapeutic strategy. Collectively, this work establishes an integrated therapeutic strategy for spinal cord repair and supports its translational potential.

Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells.

Self-assembled multicomponent prodrugs with GSH/ROS site-responsiveness enable spatiotemporally controlled release for treating resistant NSCLC.

Molecular profiling of chemotherapy-resistant breast cancer reveals DNA methylation remodeling associated with the acquisition of paclitaxel resistance.

Discovery of valine thiazole-containing derivatives as potent reversers of P-glycoprotein-mediated multidrug resistance.

Synergistic targeting and stimuli-responsive drug delivery from a dual-network injectable hydrogel for enhanced breast cancer treatment.

Drug resistance remains a major challenge to durable responses in ovarian cancer, the fifth leading cause of cancer-related death among women. In this study, we developed long-term resistant (lt-res, several months) pre-clinical models of two drugs inducing mitotic arrest in TP53-mutated cells: adavosertib (ADA), an investigational WEE1 inhibitor targeting the DNA damage response and currently evaluated in clinical trials, and paclitaxel (PTX), a widely used chemotherapeutic agent in cancer care targeting microtubules. Through integrated multi-omics functional profiling, we identify a shared PI3K/AKT-regulated signaling node that governs drug adaptation across all lt-res models. This node modulates the activity of DNA-damage responses and genotoxic stress to toggle between two adaptive states: activated PI3K/AKT driving a proliferative "fast-bypass" program with sustained cell cycle progression and mitotic evasion, or reduced PI3K/AKT signaling initiating a "slow-repair" state characterized by DNA damage checkpoint engagement, replication slowdown, and increased drug efflux. Notably, upregulation of receptor tyrosine kinases, such as ROR1, was observed in both ADA and PTX lt-res models with activated PI3K/AKT signaling. Targeting ROR1 with zilovertamab-vedotin, a monoclonal antibody-drug conjugate, resulted in enhanced cytotoxicity, demonstrating a new approach against recurrent drug-resistant ovarian cancer.

The enhancement of efficacy via the optimization of cancer drug ratios in lipid–polymer hybrid nanocapsules (LPHNs), including doxorubicin (DOX) and paclitaxel (PTX), at diverse ratios, represents a viable approach for optimizing cancer therapy results. This study examined four specific (DOX: PTX) ratios, 20:80 (C1), 40:60 (C2), 60:40 (C3), and 80:20 (C4), to determine the best formulation and develop a dual-loaded fluorescent DOX-PTX nanocapsule with controlled release features for targeting breast cancer cells. This nanocapsule (NC), functionalized with folic acid (FA) and fluorescein isothiocyanate (FITC), exhibited accurate targeting abilities and in vitro visibility, indicating its use in individualized cancer treatment. The structural and physicochemical properties were evaluated via DLS, FTIR, XRD, PL spectroscopy, FESEM, and TEM. The cytotoxicity assay determined the average IC50 values for the MCF-7 cell line at 24 and 48 h, along with the cytotoxicity data presented in four sets, which were compared with those of the free drug against the MCF-7 cancer cell line. The encapsulation and release properties confirmed consistent drug loading and extended drug delivery. Moreover, the advancement of controlled release holds significant promise for enhancing its effectiveness. Single-cell gel electrophoresis (SCGE) demonstrated the pronounced genotoxic effects of LPHNc, which was corroborated by cellular imaging, indicating effective absorption and distribution. The optimized drug concentration induced prominent DNA damage, G2/M phase arrest, and a notable sub-G1 population, confirming apoptosis via cell cycle analysis. These findings highlight the efficacy of LPHNc in inducing genotoxicity, disrupting proliferation, and causing cell death with a steady slope.

Berberine (BER) is an antioxidant, anti-inflammatory, and antitumor agent, while paclitaxel (PTX) is a widely used synthetic chemotherapeutic agent for breast cancer. Several reports have suggested the use of a PTX and BER combination for the effective treatment of breast cancer, and many pharmaceutical scientists are working to develop a novel drug delivery system incorporating this combination. However, the literature lacks a reliable simultaneous estimation method for this combination. Therefore, in the present study, we aimed to develop a robust reversed-phase high-performance liquid chromatography method for the simultaneous estimation of PTX and BER in free drug form in liposomal formulation. The method employed a C18 column (250 × 4.6 mm, 5 µm) with acetonitrile and water (70:30, v/v) as the mobile phase at a flow rate of 0.8 mL/min and detection at 250 nm. Retention times were 2.84 and 5.62 min for PTX and BER, respectively. Theoretical plates >2000 were demonstrated, and peak tailing of <2 in validation as per ICH Q2(R2) was observed. In the 10-50 ppm range, linearity was found with R2 values of 0.9979 (PTX) and 0.9975 (BER). Furthermore, the method achieved within acceptable limits precision (<2% relative standard deviation) and accuracy (90%-110%). Robustness assessments checked method reliability in small variations. In addition, using the method effectively, entrapment efficiencies of 85.27 ± 1.74% and 78.62 ± 2.38% were obtained for PTX and BER in liposomal formulations. Moreover, in vitro release studies revealed 98.83 ± 2.94% (PTX) and 96.56 ± 1.92% (BER) release over 24 h. The validated method was precise, accurate, and reliable, making it suitable for application in drug formulation analysis.

Abstract Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype with limited therapeutic options and poor prognosis. Monocarboxylate transporter 4 (MCT4) is a key lactate efflux transporter involved in cancer metabolism. However, the mechanistic role of MCT4 in TNBC progression and its potential as a therapeutic target remain unclear. Methods: MCT4 expression was analyzed in TNBC patient tissues and correlated with clinical outcomes. MDA-MB-231 cells were subjected to hypoxia treatment and paclitaxel (PTX) exposure. MCT4 was knocked down using siRNA. Cell proliferation, invasion, migration, and PTX sensitivity were assessed. In vivo xenograft experiments were performed to evaluate tumor growth and drug response. RNA-sequencing and KEGG pathway analysis were conducted. Lactate secretion and glucose uptake were measured. Western blot analysis examined MAPK pathway proteins and histone modifications. CUT&amp;Tag sequencing analyzed histone H3K9 lactylation changes and associated gene transcription. Results: MCT4 was significantly overexpressed in TNBC tissues and high expression correlated with poor patient prognosis. Both hypoxia and PTX treatment upregulated MCT4 expression in MDA-MB-231 cells. MCT4 knockdown markedly inhibited cell proliferation, invasion, and migration while enhancing PTX sensitivity. In vivo xenograft studies confirmed that MCT4 knockdown significantly retarded tumor growth and increased PTX sensitivity. RNA-sequencing revealed that MCT4 knockdown dramatically downregulated MAPK signaling pathway. Metabolically, MCT4 knockdown reduced both lactate secretion and glucose uptake. Western blot analysis confirmed that MCT4 knockdown decreased MAPK pathway-related proteins. Under hypoxic conditions, RNA-sequencing showed MAPK pathway activation, which was accompanied by increased histone lactylation levels and H3K9 lactylation. MCT4 knockdown reversed these histone modifications. CUT&amp;Tag analysis revealed that hypoxia-induced H3K9 lactylation promoted transcription of MAPK pathway genes. Notably, MCT4 was not identified among the genes with increased H3K9 lactylation-mediated transcription, suggesting that MCT4 functions as an upstream regulator of histone lactylation rather than a downstream target, establishing a direct mechanistic link between lactate metabolism and gene regulation. Conclusions: This study demonstrates that MCT4 promotes TNBC progression through a novel lactate-histone lactylation-MAPK axis. MCT4 facilitates lactate production and efflux, which drives histone H3K9 lactylation and subsequent activation of MAPK signaling genes, ultimately enhancing cancer cell aggressiveness and chemoresistance. Our findings are validated both in vitro and in vivo, providing strong mechanistic evidence for MCT4 as a therapeutic target in TNBC. Clinical Relevance: MCT4 represents a promising biomarker for TNBC prognosis and a novel therapeutic target. Targeting MCT4-mediated lactate metabolism could enhance chemotherapy efficacy and improve clinical outcomes in TNBC patients. This metabolic-epigenetic crosstalk mechanism opens new avenues for combination therapy strategies. Citation Format: Y. Peng, Q. Luo, S. Liu. Mct4 drives triple-negative breast cancer progression via lactate-induced histone lactylation and mapk pathway activation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-10.