RESUMEN

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide because of its high morbidity and the absence of effective therapies. Even though paclitaxel is a powerful anticancer chemotherapy drug, recent studies have indicated its ineffectiveness against GC cells. Long non-coding RNA (lncRNA) PVT1 has a high expression in GC cells and increases the progression of tumors via inducing drug resistance. In the present study, the effects of the siRNA-mediated lncRNA PVT1 gene silencing along with paclitaxel treatment on the rate of apoptosis, growth, and migration of AGS GC cells were investigated. AGS cells were cultured and then transfected with siRNA PVT1 using electroporation. The MTT test was used to examine the effect of treatments on the viability of cultured cells. Furthermore, the flow cytometry method was used to evaluate the impact of treatments on the cell cycle process and apoptosis induction in GC cells. Finally, the mRNA expression of target genes was assessed using the qRT-PCR method. The results showed that lncRNA PVT1 gene suppression, along with paclitaxel treatment, reduces the viability of cancer cells and significantly increases the apoptosis rate of cancer cells and the number of cells arrested in the G2/M phase compared to the control group. Based on the results of qRT-PCR, combined treatment significantly decreased the expression of MMP3, MMP9, MDR1, MRP1, Bcl-2, k-Ras, and c-Myc genes and increased the expression of the Bax gene compared to the control group. The results of our study showed that lncRNA PVT1 gene targeting, together with paclitaxel treatment, induces apoptosis, inhibits growth, alleviates drug resistance, and reduces the migratory capability of GC cells. Therefore, there is a need for further investigations to evaluate the feasibility and effectiveness of this approach in vivo in animal models.

Asunto(s)

Apoptosis , Resistencia a Antineoplásicos , Silenciador del Gen , Paclitaxel , ARN Largo no Codificante , Neoplasias Gástricas , ARN Largo no Codificante/genética , Paclitaxel/farmacología , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Apoptosis/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , ARN Interferente Pequeño/genética

RESUMEN

Drug treatment of glioblastoma, the most aggressive and widespread form of brain cancer, is complicated due to the difficulty of penetration of chemotherapeutic drugs through the blood-brain barrier (BBB). Moreover, with surgical removal of tumors, in 90 % of cases they reappear near the original focus. To solve this problem, we propose to use hydrogel based on cellulose nanocrystals grafted with poly(N-isopropylacrylamide) (CNC-g-PNIPAM) as a promising material for filling postoperative cavities in the brain with the release of antitumor drugs. The CNC-g-PNIPAM is formed by "grafting to" method for precise control of molecular weight and grafting density. This colloidal system is liquid under injection conditions (at r. t.) and turns into a gel at human body temperature (when filling the postoperative area). It was shown for the first time that due to the rod-shaped of CNC, the gel has a fibrillar structure and, thus, mechanical properties similar to those of brain tissue, including nonlinear mechanics (strain-stiffening and compression softening). The biocompatibility of the hydrogel with primary brain cells is demonstrated. In addition, the release of the antitumor drug paclitaxel from the hydrogel and its antitumor activity is shown. The resulting nanocolloid system provides an innovative alternative approach to filling postoperative cavities and can be used for postoperative treatment due to the programmable release of drugs, as well as for in vitro modeling of tumor interaction with the BBB affecting drug transport in the brain.

Asunto(s)

Resinas Acrílicas , Materiales Biocompatibles , Celulosa , Hidrogeles , Nanopartículas , Celulosa/química , Nanopartículas/química , Resinas Acrílicas/química , Humanos , Animales , Materiales Biocompatibles/química , Hidrogeles/química , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Paclitaxel/química , Paclitaxel/farmacología , Paclitaxel/administración & dosificación , Temperatura , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Liberación de Fármacos , Barrera Hematoencefálica/metabolismo

RESUMEN

Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of histone methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

Asunto(s)

Quitosano , Dextranos , Proteína Potenciadora del Homólogo Zeste 2 , Epigénesis Genética , Melanoma , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Quitosano/química , Quitosano/análogos & derivados , Dextranos/química , Animales , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/inmunología , Ratones , Humanos , Epigénesis Genética/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Hidrogeles/química , Línea Celular Tumoral , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química

RESUMEN

Breast cancer is a malignant tumor that poses a significant threat to women's health and single therapy fails to play a good oncological therapeutic effect. Synergistic treatment with multiple strategies may make up for the deficiencies and has gained widespread attention. In this study, sulfhydryl-modified hyaluronic acid (HA-SH) was covalently crosslinked with polydopamine (PDA) via a Michael addition reaction to develop an injectable hydrogel, in which PDA can be used not only as a matrix but also as a photothermal agent. After HSA and paclitaxel were spontaneously organized into nanoparticles via hydrophobic interaction, hyaluronic acid with low molecular weight was covalently linked to HSA, thus conferring effectively delivery. This photothermal injectable hydrogel incorporates PTX@HSA-HA nanoparticles, thereby initiating a thermochemotherapeutic response to target malignancy. Our results demonstrated that this injectable hydrogel possesses consistent drug delivery capability in a murine breast cancer model, collaborating with photothermal therapy to effectively suppress tumor growth, represented by low expression of Ki-67 and increasing apoptosis. Photothermal therapy (PTT) can effectively stimulate immune response by increasing IL-6 and TNF-α. Notably, the treatment did not elicit any indications of toxicity. This injectable hydrogel holds significant promise as a multifaceted therapeutic agent that integrates photothermal and chemotherapeutic modalities.

Asunto(s)

Neoplasias de la Mama , Ácido Hialurónico , Hidrogeles , Paclitaxel , Terapia Fototérmica , Animales , Ácido Hialurónico/química , Hidrogeles/química , Hidrogeles/farmacología , Femenino , Neoplasias de la Mama/terapia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ratones , Terapia Fototérmica/métodos , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/administración & dosificación , Humanos , Indoles/química , Indoles/farmacología , Ratones Endogámicos BALB C , Polímeros/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Nanopartículas/química , Portadores de Fármacos/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Fototerapia/métodos

RESUMEN

Cancer chemotherapy increases the risk of thrombosis; however, the mechanisms underlying this thrombosis are not completely understood. Plasminogen activator inhibitor (PAI)-1 is a key molecule in the fibrinolytic system that inhibits tissue plasminogen activator and urokinase, which converts plasminogen into plasmin; therefore, excess PAI-1 increases the risk of thrombosis. In this study, we investigated whether temporary treatment of the human luminal A-type breast cancer cell line MCF-7 with antitumor drugs clinically used for breast cancer therapy promotes PAI-1 production. Treatment of MCF-7 cells with paclitaxel (PTX), a microtubule-stabilizing antitumor drug, at 1 µM for 2 h elevated the PAI-1 concentration of the conditioned medium at 48 h after treatment but not in those treated with tamoxifen and cyclophosphamide. Microtubule assembly inhibitors vinblastine (VBT) and vincristine (VCT) also increased the PAI-1 concentration in the conditioned medium. PAI-1 (SERPINE1) expression was upregulated in MCF-7 cells after PTX, VBT, and VCT treatment; this increase in expression persisted for eight days. In contrast, PAI-1 production in MDA-MB-231 cells treated with PTX, VBT, or VCT did not increase with increasing PAI-1 concentration. This study demonstrated that temporary low-dose treatment with microtubule-associated anticancer drugs increased PAI-1 release from MCF-7 cells but not from MDA-MB-231 cells. These results indicate that chemotherapy against luminal A-type breast cancer using microtubule-associated drugs may cause thrombosis through the inhibition of the fibrinolytic system by PAI-1.

Asunto(s)

Neoplasias de la Mama , Paclitaxel , Inhibidor 1 de Activador Plasminogénico , Vinblastina , Humanos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Paclitaxel/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Vinblastina/farmacología , Células MCF-7 , Femenino , Línea Celular Tumoral , Antineoplásicos Fitogénicos/farmacología , Vincristina/farmacología

RESUMEN

BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.

Asunto(s)

Adipocitos , Exosomas , MicroARNs , Invasividad Neoplásica , Neoplasias Ováricas , Paclitaxel , Femenino , Exosomas/metabolismo , Humanos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Neoplasias Ováricas/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/patología , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Epiplón/patología , Epiplón/metabolismo , Proliferación Celular/efectos de los fármacos , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/metabolismo , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos

RESUMEN

Microtubules (MTs) are widely recognized as targets for cancer therapies. They are directly related to unique mechanical properties, closely dependent on MT architecture and tubulin molecular features. Taxol is known to affect tubulin interactions resulting in the stabilization of the MT lattice, and thus the hierarchical organization stability, mechanics, and function. A deeper understanding of the molecular mechanisms through which taxol modulates intertubulin interactions in the MT lattice, and consequently, its stability and mechanical response is crucial to characterize how MT properties are regulated by environmental factors, such as interacting ligands. In this study, a computational analysis of the effect of taxol on the MT was performed at different scales, combining molecular dynamics simulation, dynamical network analysis, and elastic network modeling. The results show that the taxol-induced conformational differences at the M-loop region increase the stability of the lateral interactions and the amount of surface in contact between laterally coupled tubulins. Moreover, the conformational rearrangements in the taxane binding site result in a different structural communication pattern. Finally, the different conformation of the tubulin heterodimers and the stabilized lateral interactions resulted in a tendency toward higher deformation of the vibrating MT in the presence of taxol. Overall, this work provides additional insights into taxol-induced stabilization and relates the conformational changes at the tubulin level to the MT mechanics. Besides providing useful insights into taxol effect on MT mechanics, a methodological framework that could be used to characterize the effects of other MT stabilizing agents is presented.

Asunto(s)

Microtúbulos , Simulación de Dinámica Molecular , Paclitaxel , Tubulina (Proteína) , Paclitaxel/farmacología , Paclitaxel/química , Microtúbulos/metabolismo , Microtúbulos/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/química , Sitios de Unión , Humanos

RESUMEN

Aiming to improve the retrieval rate of retrievable vena cava filters (RVCF) and extend its dwelling time in vivo, a novel hydrogel coating loaded with 10 mg/mL heparin and 30 mg/mL cyclodextrin/paclitaxel (PTX) inclusion complex (IC) was prepared. The drug-release behavior in the phosphate buffer solution demonstrated both heparin and PTX could be sustainably released over approximately two weeks. Furthermore, it was shown that the hydrogel-coated RVCF (HRVCF) with 10 mg/mL heparin and 30 mg/mL PTX IC effectively extended the blood clotting time to above the detection limit and inhibited EA.hy926 and CCC-SMC-1 cells' proliferation in vitro compared to the commercially available bare RVCF. Both the HRVCF and the bare RVCF were implanted into the vena cava of sheep and retrieved at at 2nd and 4th week after implantation, revealing that the HRVCF had a significantly higher retrieval rate of 67 % than the bare RVCF (0 %) at 4th week. Comprehensive analyses, including histological, immunohistological, and immunofluorescent assessments of the explanted veins demonstrated the HRVCF exhibited anti-hyperplasia and anticoagulation properties in vivo, attributable to the hydrogel coating, thereby improving the retrieval rate in sheep. Consequently, the as-prepared HRVCF shows promising potential for clinical application to enhance the retrieval rates of RVCFs.

Asunto(s)

Ciclodextrinas , Heparina , Hidrogeles , Paclitaxel , Filtros de Vena Cava , Ciclodextrinas/química , Ciclodextrinas/farmacología , Paclitaxel/farmacología , Paclitaxel/química , Heparina/química , Heparina/farmacología , Animales , Hidrogeles/química , Hidrogeles/farmacología , Humanos , Ovinos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Coagulación Sanguínea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Liberación de Fármacos

RESUMEN

Paclitaxel is among the most active chemotherapy drugs for the aggressive triple negative breast cancer (TNBC). Unfortunately, it often induces painful peripheral neuropathy (CIPN), a major debilitating side effect. Here we demonstrate that in naive and breast tumor-bearing immunocompetent mice, a clinically relevant dose of FTY720/Fingolimod that targets sphingosine-1-phosphate receptor 1 (S1PR1), alleviated paclitaxel-induced neuropathic pain. FTY720 also significantly attenuated paclitaxel-stimulated glial fibrillary acidic protein (GFAP), a marker for activated astrocytes, and expression of the astrocyte-secreted synaptogenic protein Sparcl1/Hevin, a key regulator of synapse formation. Notably, the formation of excitatory synapses containing VGluT2 in the spinal cord dorsal horn induced by paclitaxel was also inhibited by FTY720 treatment, supporting the involvement of astrocytes and Sparcl1 in CIPN. Furthermore, in this TNBC mouse model that mimics human breast cancer, FTY720 administration also enhanced the anti-tumor effects of paclitaxel, leading to reduced tumor progression and lung metastasis. Taken together, our findings suggest that targeting the S1P/S1PR1 axis with FTY720 is a multipronged approach that holds promise as a therapeutic strategy for alleviating both CIPN and enhancing the efficacy of chemotherapy in TNBC treatment.

Asunto(s)

Clorhidrato de Fingolimod , Neuralgia , Paclitaxel , Animales , Clorhidrato de Fingolimod/farmacología , Paclitaxel/farmacología , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Neuralgia/patología , Ratones , Femenino , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Línea Celular Tumoral , Receptores de Esfingosina-1-Fosfato/metabolismo , Humanos , Progresión de la Enfermedad , Antineoplásicos Fitogénicos/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética

RESUMEN

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose-response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity.

Asunto(s)

Supervivencia Celular , Células Madre Pluripotentes Inducidas , Células Receptoras Sensoriales , Taxoides , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/citología , Taxoides/farmacología , Células Receptoras Sensoriales/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Docetaxel/farmacología , Síndromes de Neurotoxicidad/etiología , Hidrocarburos Aromáticos con Puentes/farmacología , Diferenciación Celular/efectos de los fármacos , Paclitaxel/farmacología , Paclitaxel/toxicidad , Línea Celular , Células Cultivadas

RESUMEN

BACKGROUND: Bazedoxifene is a third-generation selective estrogen receptor modulator that inhibits the IL6/IL6R/GP130 signaling pathway by inhibiting IL6-induced homodimerization of GP130. Considering that the IL6/IL6R/GP130 signaling pathway is important in tumorigenesis and metastasis, bazedoxifene is thought to have an antitumor effect, which has been proven preliminarily in breast cancer and pancreatic cancer but has not yet been studied in non-small cell lung cancer (NSCLC). This study is aimed at evaluating the antitumor effect of bazedoxifene in NSCLC. METHODS: A549 and H1299 NSCLC cell lines were employed and exposed to various concentrations of bazedoxifene, paclitaxel, gemcitabine, and their combinations for cell viability, colony formation, and wound healing assays to demonstrate the antitumor effect of bazedoxifene with or without paclitaxel or gemcitabine. RESULTS: MTT cell viability, colony formation, and wound healing assays showed that bazedoxifene was capable of inhibiting cell viability, colony formation, and cell migration in a dose-dependent manner. In addition, bazedoxifene was capable of working with paclitaxel or gemcitabine synergistically to inhibit cell viability, colony formation, and cell migration. CONCLUSION: This study demonstrated the potential antitumor effect of bazedoxifene and its ability to improve the treatment efficacy of paclitaxel and gemcitabine.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Movimiento Celular , Supervivencia Celular , Desoxicitidina , Gemcitabina , Indoles , Neoplasias Pulmonares , Paclitaxel , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Paclitaxel/farmacología , Movimiento Celular/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Indoles/farmacología , Indoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico

RESUMEN

We present a modular strategy to synthesize nanoparticle sensors equipped with dithiomaleimide-based, fluorescent molecular reporters capable of discerning minute changes in interparticle chemical environments based on fluorescence lifetime analysis. Three types of nanoparticles were synthesized with the aid of tailor-made molecular reporters, and it was found that protein nanoparticles exhibited greater sensitivity to changes in the core environment than polymer nanogels and block copolymer micelles. Encapsulation of the hydrophobic small-molecule drug paclitaxel (PTX) in self-reporting protein nanoparticles induced characteristic changes in fluorescence lifetime profiles, detected via time-resolved fluorescence spectroscopy. Depending on the mode of drug encapsulation, self-reporting protein nanoparticles revealed pronounced differences in their fluorescence lifetime signatures, which correlated with burst- vs diffusion-controlled release profiles observed in previous reports. Self-reporting nanoparticles, such as the ones developed here, will be critical for unraveling nanoparticle stability and nanoparticle-drug interactions, informing the future development of rationally engineered nanoparticle-based drug carriers.

Asunto(s)

Nanopartículas , Paclitaxel , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacología , Portadores de Fármacos/química , Espectrometría de Fluorescencia , Micelas , Proteínas/química

RESUMEN

Developing novel therapies that outperform the existing chemotherapeutic treatments is required for treatment-resistant ovarian clear cell carcinoma. We investigated the antitumor effect of metformin on ovarian clear cell carcinoma, enhancement of the antitumor effect by its combination with chemotherapy, and its molecular regulatory mechanism. First, we evaluated the viability of ovarian clear cell carcinoma lines using the water-soluble tetrazolium-1 assay and found that metformin suppressed cell viability. Cell viability was significantly suppressed by co-treatment with cisplatin and metformin. In contrast, co-treatment with paclitaxel and metformin showed no significant difference in viability compared with the group without metformin. Western blot analysis showed increased phosphorylation of AMP-activated protein kinase in some cell lines and suppressed phosphorylation of the mammalian target of rapamycin in a particular cell line. Flow cytometry analysis revealed a significant increase in the rate of apoptosis in the metformin-treated group and rate of cell cycle arrest at the G2/M phase in a particular cell line. These results indicated that metformin may be effective against cultured ovarian clear cell carcinoma cells, particularly in combination with cisplatin.

Asunto(s)

Adenocarcinoma de Células Claras , Antineoplásicos , Apoptosis , Supervivencia Celular , Cisplatino , Metformina , Neoplasias Ováricas , Metformina/farmacología , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Femenino , Cisplatino/farmacología , Apoptosis/efectos de los fármacos , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Antineoplásicos/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Paclitaxel/farmacología , Fosforilación/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos

RESUMEN

Prostate cancer presents as a challenging disease, as it is often characterized as an immunologically "cold" tumor, leading to suboptimal outcomes with current immunotherapeutic approaches in clinical settings. Photodynamic therapy (PDT) harnesses reactive oxygen species generated by photosensitizers (PSs) to disrupt the intracellular redox equilibrium. This process induces DNA damage in both the mitochondria and nucleus, activating the process of immunogenic cell death (ICD) and the cGAS-STING pathway. Ultimately, this cascade of events leads to the initiation of antitumor immune responses. Nevertheless, existing PSs face challenges, including suboptimal tumor targeting, aggregation-induced quenching, and insufficient oxygen levels in the tumor regions. To this end, a versatile bionic nanoplatform has been designed for the simultaneous delivery of the aggregation-induced emission PS TPAQ-Py-PF6 and paclitaxel (PTX). The cell membrane camouflage of the nanoplatform leads to its remarkable abilities in tumor targeting and cellular internalization. Upon laser irradiation, the utilization of TPAQ-Py-PF6 in conjunction with PTX showcases a notable and enhanced synergistic antitumor impact. Additionally, the nanoplatform has the capability of initiating the cGAS-STING pathway, leading to the generation of cytokines. The presence of damage-associated molecular patterns induced by ICD collaborates with these aforementioned cytokines lead to the recruitment and facilitation of dendritic cell maturation. Consequently, this elicits a systemic immune response against tumors. In summary, this promising strategy highlights the use of a multifunctional biomimetic nanoplatform, combining chemotherapy, PDT, and immunotherapy to enhance the effectiveness of antitumor treatment.

Asunto(s)

Muerte Celular Inmunogénica , Inmunoterapia , Proteínas de la Membrana , Nucleotidiltransferasas , Fotoquimioterapia , Fármacos Fotosensibilizantes , Neoplasias de la Próstata , Humanos , Nucleotidiltransferasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/patología , Muerte Celular Inmunogénica/efectos de los fármacos , Muerte Celular Inmunogénica/efectos de la radiación , Proteínas de la Membrana/metabolismo , Masculino , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Ratones , Paclitaxel/química , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Porfirinas/química , Porfirinas/farmacología

RESUMEN

Paclitaxel, a potent anti-tumor drug widely recognized for its therapeutic efficacy, has faced limitations in clinical application due to its poor solubility. The use of Cremophor EL (CrEL) as a cosolvent in paclitaxel injections has been associated with hypersensitivity reactions in some patients. To overcome these challenges, we have developed a novel conjugate by linking a neuropilin-1 targeting peptide, RPPR, to paclitaxel, resulting in PTX-RPPR. This innovative approach has significantly enhanced the solubility of paclitaxel, achieving a 3.8 mg/mL concentration, a remarkable 90-fold increase over the native drug. PTX-RPPR has shown potent anti-tumor activity, inhibiting tumor cell proliferation with an IC50 ranging from 0.26 to 1.64 µM and effectively suppressing migration, invasion, and angiogenesis at a concentration of 75 nM. Notably, in a 4T1 mammary carcinoma model, PTX-RPPR administered at a dose of 0.7 µmol/kg exhibited tumor growth inhibition comparable to that of paclitaxel at a higher dose of 3.5 µmol/kg, with superior efficacy in preventing lung metastasis. Furthermore, PTX-RPPR effectively reduced NRP-1 expression in both tumors and lungs post-treatment. In contrast to paclitaxel formulated with CrEL, PTX-RPPR did not induce IL-6 expression, suggesting a safer profile in terms of immunological response. Characterized by a particle size of 200 nm and a zeta potential of +30 mV, the nano-formulation of PTX-RPPR demonstrated remarkable stability over seven days. This study introduced PTX-RPPR as a promising peptide-drug conjugate that addresses the solubility and hypersensitivity issues associated with paclitaxel, offering a safer therapeutic strategy for cancer treatment.

Asunto(s)

Proliferación Celular , Ratones Endogámicos BALB C , Neuropilina-1 , Paclitaxel , Paclitaxel/farmacología , Neuropilina-1/metabolismo , Animales , Femenino , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Antineoplásicos Fitogénicos/farmacología , Péptidos/farmacología , Péptidos/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Movimiento Celular/efectos de los fármacos , Metástasis de la Neoplasia/prevención & control , Solubilidad

RESUMEN

BACKGROUND: Thiostrepton (TST) is a known inhibitor of the transcription factor Forkhead box M1 (FoxM1) and inducer of heat shock response (HSR) and autophagy. TST thus may be one potential candidate of anticancer drugs for combination chemotherapy. METHODS AND RESULTS: Immunofluorescence staining of mitotic spindles and flow cytometry analysis revealed that TST induces mitotic spindle abnormalities, mitotic arrest, and apoptotic cell death in the MDA-MB-231 triple-negative breast cancer cell line. Interestingly, overexpression or depletion of FoxM1 in MDA-MB-231 cells did not affect TST induction of spindle abnormalities; however, TST-induced spindle defects were enhanced by inhibition of HSP70 or autophagy. Moreover, TST exhibited low affinity for tubulin and only slightly inhibited in vitro tubulin polymerization, but it severely impeded tubulin polymerization and destabilized microtubules in arrested mitotic MDA-MB-231 cells. Additionally, TST significantly enhanced Taxol cytotoxicity. TST also caused cytotoxicity and spindle abnormalities in a Taxol-resistant cell line, MDA-MB-231-T4R. CONCLUSIONS: These results suggest that, in addition to inhibiting FoxM1, TST may induce proteotoxicity and autophagy to disrupt cellular tubulin polymerization, and this mechanism might account for its antimitotic effects, enhancement of Taxol anticancer effects, and ability to overcome Taxol resistance in MDA-MB-231 cells. These data further imply that TST may be useful to improve the therapeutic efficacy of Taxol.

Asunto(s)

Autofagia , Proteína Forkhead Box M1 , Paclitaxel , Huso Acromático , Tioestreptona , Tubulina (Proteína) , Humanos , Paclitaxel/farmacología , Tioestreptona/farmacología , Línea Celular Tumoral , Huso Acromático/efectos de los fármacos , Huso Acromático/metabolismo , Proteína Forkhead Box M1/metabolismo , Autofagia/efectos de los fármacos , Tubulina (Proteína)/metabolismo , Apoptosis/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Femenino , Sinergismo Farmacológico , Microtúbulos/metabolismo , Microtúbulos/efectos de los fármacos , Mitosis/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/metabolismo , Células MDA-MB-231

RESUMEN

BACKGROUND: Long-term anti-angiogenesis leads to pruned vasculature, densely deposited extracellular matrix (ECM), and consequently reduced chemotherapy delivery in esophagogastric cancer (EGC). To address this issue, we evaluated the efficacy of adding a hyaluronidase or a NO-donor to the regimen of chemotherapy and anti-angiogenic drugs. METHODS: A patient-derived EGC xenograft model was developed. Grafted mice were randomly assigned to four experimental groups and one control group. The experimental groups received DC101, a murine angiogenesis inhibitor, and nab-paclitaxel (NPTX), with the addition of hyaluronidase (PEGPH20), or NO-donor (nitroglycerine, NTG), or their combination, respectively. We compared tumor growth during 17 days of treatment. We performed immunohistochemistry for ECM components hyaluronan (HA) and collagen, CD31 for endothelial cells, and γH2AX for DNA damage. The positively stained areas were quantified, and vessel diameters were measured using QuPath software. RESULTS: Prolonged DC101 treatment induced deposition of HA (p<0.01) and collagen (p<0.01). HA was effectively degraded by PEGPH20 (p<0.001), but not by NTG as expected. Both PEGPH20 (p<0.05) and NTG (p<0.01) dilated vessels collapsed in response to long-term DC101 treatment. However, only PEGPH20 (rather than NTG) was found to significantly inhibit tumor growth (p<0.05) in combination with NPTX and DC101. CONCLUSIONS: These findings suggest that the mechanical barrier of HA is the major reason responsible for the resistance developed during prolonged anti-angiogenesis in EGC. Incorporating PEGPH20 into the existing treatment regimen is promising to improve outcomes for patients with EGC.

Asunto(s)

Albúminas , Inhibidores de la Angiogénesis , Neoplasias Esofágicas , Hialuronoglucosaminidasa , Neovascularización Patológica , Paclitaxel , Neoplasias Gástricas , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Paclitaxel/farmacología , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Hialuronoglucosaminidasa/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Humanos , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Albúminas/farmacología , Albúminas/administración & dosificación , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Ratones , Ácido Hialurónico/farmacología , Ratones Desnudos , Femenino , Angiogénesis , Anticuerpos Monoclonales

RESUMEN

The effect of chemotherapy for anti-glioblastoma is limited due to insufficient drug delivery across the blood-brain-barrier. Poloxamer 188-coated nanoparticles can enhance the delivery of nanoparticles across the blood-brain-barrier. This study presents the design, preparation, and evaluation of a combination of PLGA nanoparticles (PLGA NPs) loaded with methotrexate (P-MTX NPs) and PLGA nanoparticles loaded with paclitaxel (P-PTX NPs), both of which were surface-modified with poloxamer188. Cranial tumors were induced by implanting C6 cells in a rat model and MRI demonstrated that the tumors were indistinguishable in the two rats with P-MTX NPs + P-PTX NPs treated groups. Brain PET scans exhibited a decreased brain-to-background ratio which could be attributed to the diminished metabolic tumor volume. The expression of Ki-67 as a poor prognosis factor, was significantly lower in P-MTX NPs + P-PTX NPs compared to the control. Furthermore, the biodistribution of PLGA NPs was determined by carbon quantum dots loaded into PLGA NPs (P-CQD NPs), and quantitative analysis of ex-vivo imaging of the dissected organs demonstrated that 17.2 ± 0.6% of the NPs were concentrated in the brain after 48 h. The findings highlight the efficacy of combination nanochemotherapy in glioblastoma treatment, indicating the need for further preclinical studies.

Asunto(s)

Barrera Hematoencefálica , Neoplasias Encefálicas , Glioblastoma , Metotrexato , Nanopartículas , Poloxámero , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Glioblastoma/diagnóstico por imagen , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Nanopartículas/química , Ratas , Poloxámero/química , Metotrexato/química , Metotrexato/administración & dosificación , Metotrexato/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Distribución Tisular , Portadores de Fármacos/química , Masculino , Sistemas de Liberación de Medicamentos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos

RESUMEN

Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.

Asunto(s)

Antimitóticos , Aurora Quinasa A , Proteínas de Ciclo Celular , Proteínas Asociadas a Microtúbulos , Humanos , Animales , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Antimitóticos/farmacología , Antimitóticos/química , Línea Celular Tumoral , Proteínas Asociadas a Microtúbulos/metabolismo , Ratones , Proteínas Nucleares/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Antineoplásicos/química , Relación Estructura-Actividad , Paclitaxel/farmacología , Ratones Desnudos

RESUMEN

Aggregation-induced emission (AIE) materials are attracting great attention in biomedical fields such as sensors, bioimaging, and cancer treatment, et al. due to their strong fluorescence emission in the aggregated state. In this contribution, a series of tetraphenylene-acetonitrile AIE compounds with D-A-D' structures were synthesized by Suzuki coupling reaction and Knoevenagel condensation, and their relationship of chemical structure and fluorescence properties was investigated in detail, among which TPPA compound was selected as the monomer owing to the longest emission wavelength at about 530 nm with low energy band gap ΔE 3.09 eV of neutral TPPA and 1.43 eV of protonated TPPA. Novel amphiphilic AIE PEG-TA copolymers were prepared by RAFT polymerization of TPPA and PEGMA with about 1.44×104 Mw and narrow PDI, and the molar ratio of TPPA in the PEG-TA1 and PEG-TA2 copolymers was about 23.4 % and 29.6 %. The as-prepared PEG-TA copolymers would self-assembled in aqueous solution to form core-shell structures with a diameter of 150-200 nm, and their emission wavelength could reversibly convert from 545 nm to 650 nm with excellent pH sensitivity. The CLSM images showed that the PEG-TA FONs and PTX drugs-loaded PTX-TA FONs could be endocytosed by cells and mainly enriched in the cytoplasm, and CCK-8 results showed that the PEG-TA FONs had excellent biocompatibility but PTX-TA FONs had high inhibition ratio for A549 cells, moreover, the flow cytometry also showed that PTX-TA FONs could result in the apoptosis of A549 cells with some extent anti-tumor effect.

Asunto(s)

Acetonitrilos , Sistemas de Liberación de Medicamentos , Paclitaxel , Humanos , Relación Estructura-Actividad , Paclitaxel/farmacología , Paclitaxel/química , Acetonitrilos/química , Acetonitrilos/farmacología , Células A549 , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/síntesis química , Tamaño de la Partícula , Estilbenos/química , Estilbenos/farmacología , Estilbenos/síntesis química , Liberación de Fármacos