RESUMEN
Deferoxamine, an iron chelator used to treat diseases caused by excess iron, has had a Food and Drug Administration-approved status for many years. A large number of studies have confirmed that deferoxamine can reduce inflammatory response and promote angiogenesis. Blood vessels play a crucial role in sustaining vital life by facilitating the delivery of immune cells, oxygen, and nutrients, as well as eliminating waste products generated during cellular metabolism. Dysfunction in blood vessels may contribute significantly to the development of life-threatening diseases. Anti-angiogenesis therapy and pro-angiogenesis/angiogenesis strategies have been frequently recommended for various diseases. Herein, we describe the mechanism by which deferoxamine promotes angiogenesis and summarize its application in chronic wounds, bone repair, and diseases of the respiratory system. Furthermore, we discuss the drug delivery system of deferoxamine for treating various diseases, providing constructive ideas and inspiration for the development of new treatment strategies.
Asunto(s)
Deferoxamina , Neovascularización Fisiológica , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Humanos , Animales , Neovascularización Fisiológica/efectos de los fármacos , Regeneración/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , AngiogénesisRESUMEN
Inducing cell migration from the edges to the center of a wound, promoting angiogenesis, and controlling bacterial infection are very important for diabetic wound healing. Incorporating growth factors and antibiotics into hydrogels for wound dressing is considered a potential strategy to meet these requirements. However, some present drawbacks greatly slow down their development toward application, such as the short half-life and high price of growth factors, low antibiotic efficiency against drug-resistant bacteria, insufficient ability of hydrogels to promote cell migration, etc. Deferoxamine (DFO) can upregulate the expression of HIF-1α, thus stimulating the secretion of angiogenesis-related endogenous growth factors. Copper sulfide (CuS) nanoparticles possess excellent antibacterial performance combined with photothermal therapy (PTT). Herein, DFO and CuS nanoparticles are incorporated into a biomimetic hydrogel, which mimics the structure and function of the extracellular matrix (ECM), abbreviated as DFO/CuS-ECMgel. This biomimetic hydrogel is expected to be able to promote cell adhesion and migration, be degraded by cell-secreted matrix metalloproteinases (MMPs), and then release DFO and CuS nanoparticles at the wound site to exert their therapeutic effects. As a result, the three crucial requirements for diabetic wound healing, "beneficial for cell adhesion and migration, promoting angiogenesis, effectively killing drug-resistant bacteria," can be achieved simultaneously.
Asunto(s)
Diabetes Mellitus , Nanopartículas , Humanos , Hidrogeles/química , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Cobre/química , Terapia Fototérmica , Biomimética , Nanopartículas/química , Diabetes Mellitus/tratamiento farmacológico , Antibacterianos/químicaRESUMEN
Identifying novel agents for cancer treatment is critical because of obstacles with anticancer drug resistance and lack of drug effectiveness. Intracellular calcium ion (Ca2+), a common second messenger, regulates various cellular pathophysiological processes including cell proliferation, differentiation and apoptosis. Recent studies have shown that the remodeling of Ca2+ signals is associated with cancer occurrence, progression and metastasis. Ca2+ channels, transporter and pumps regulate calcium movement, and alteration of Ca2+ signal component expression/activity is associated with numerous cancer cell activities. Therefore, targeting Ca2+ signals is an attractive research focus in cancer treatment. Phytochemicals, secondary metabolites in plants, exhibit multifaceted effective anticancer activities in various cancers. Although the mechanisms of the anticancer effects of phytochemicals remain unclarified, studies have indicated that many phytochemicals inhibit cancer progression through modulating calcium signals. In this review, we summarize the phytochemicals with demonstrated anticancer effects through their influence on calcium signaling, which may provide new ideas and directions in cancer research.
Asunto(s)
Calcio , Neoplasias , Proliferación Celular , Quimioprevención , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/prevención & control , Fitoquímicos/farmacología , Fitoquímicos/uso terapéuticoRESUMEN
Dibromoacetonitrile (DBAN) and dichloroacetonitrile (DCAN) are haloacetonitriles (HANs) produced as by-products of chloramine disinfection of drinking water and can cause neurotoxicity. The molecular pathways leading to HAN-induced neuronal cell death remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of oxidation reactions. We explored the role of the sequestosome 1 (p62)-Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway in DBAN- and DCAN-induced mouse hippocampal neuronal (HT22) cell injury. DBAN and DCAN reduced cell viability, increased lactate dehydrogenase release rate, and promoted apoptosis. Over the same treatment time, DBAN at lower concentrations caused cell injury, suggesting that DBAN is more cytotoxic than DCAN. DBAN and DCAN triggered oxidative stress by reducing intracellular glutathione and increasing reactive oxygen species concentrations. DBAN and DCAN activated the Nrf2 pathway. Furthermore, Nrf2 inhibitors (all-trans retinoic acid) attenuated DBAN- and DCAN-induced toxicity, whereas Nrf2 activators (tert-Butylhydroquinone) achieved the opposite effect. This indicates that activation of the Nrf2 pathway mediates DBAN- and DCAN-induced cell injury. Notably, the expression of p62, a noncanonical pathway that mediates Nrf2 activation, increased, whereas the expression of Keap1, another regulator of Nrf2, decreased. We noted that high p62 expression activated the Nrf2 pathway, and p62 was regulated through Nrf2, forming a positive feedback loop. N-acetyl-L-cysteine, a mercaptan substance, protected against DBAN- and DCAN-induced toxicity and inhibited the Nrf2 pathway. In summary, Nrf2 pathway inhibition and mercaptan supplementation prevent DBAN- and DCAN-induced HT22 cell injury, accordingly, targeting them is a potential approach to preventing HAN-induced neurotoxicity.
Asunto(s)
Agua Potable , Acetonitrilos , Acetilcisteína/farmacología , Animales , Desinfección , Hipocampo , Proteína 1 Asociada A ECH Tipo Kelch , Ratones , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Compuestos de SulfhidriloRESUMEN
To investigate the effect and potential mechanism of 3,3'-diindolylmethane (DIM) on ferroptosis against gastric cancer, cells proliferation, lipid reactive oxygen species (ROS) and GSH level were measured in the BGC-823 gastric cancer cells after DIM treatment. Western blotting was used to detect the expression of SLC7A11, GPX4, IP3R and BAP1. Results showed that DIM could induce ferroptosis in the BGC-823 gastric cancer cells via upregulating lipid-ROS level and decreasing GSH generation. Besides, DIM also significantly reduced the protein level of SLC7A11 and GPX4, which was an important regulator of ferroptosis. In addition, DIM promoted the protein level of BAP1 and IP3R in a concentration-dependent manner in the BGC-823 gastric cancer cells. The knockdown of BAP1 could reduce IP3R level and DIM-induced ferroptosis of gastric cancer cells. Taken together, these results indicated that DIM could induce ferroptosis to exert anti-cancer effects via BAP1-IP3R axis, suggesting its effective therapeutic potential in gastric cancer.
Asunto(s)
Ferroptosis , Neoplasias Gástricas , Línea Celular Tumoral , Humanos , Indoles , Lípidos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Proteínas Supresoras de Tumor , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/uso terapéuticoRESUMEN
BACKGROUND: The combination of photothermal therapy (PTT) and chemotherapy has proven to be a promising strategy for cancer treatment. Various nanomaterials have shown great potential in combination therapy, including gold, graphene oxide, iron oxide, and other nanoparticles. However, their undefinable toxicity in vivo greatly slowed down their development for clinical applications. OBJECTIVE: The present work aimed to develop a multifunctional nanoparticle for chemo-photothermal therapy composed of acknowledged biocompatible materials. METHODS: A novel biocompatible nanoparticle (HIT-NPs) was self-assembled through the intrinsic interaction between D-α-tocopherol Succinate (TOS), human serum albumin (HSA) and indocyanine green (ICG). Doxorubicin (DOX) was then loaded due to the ion pairing between DOX and TOS. The feasibility of combined chemo-photothermal therapy induced by DOX-loaded HIT-NPs was carefully evaluated. RESULTS: In vitro, HIT-NPs showed no cytotoxicity on human normal liver cells (HL-7702 cells) but obvious killing effects on murine breast cancer cells (4T1 cells). The combined chemo-photothermal therapeutic effect on 4T1 cells was successfully obtained. DOX-loaded HIT-NPs could effectively accumulate in 4T1 subcutaneous tumors after intravenous injection, and the tumor temperature rapidly increased under laser exposure, indicating the feasibility of PTT in vivo. CONCLUSION: The self-assembled HIT-NPs could provide a promising platform for combined chemo- photothermal cancer therapy with full biocompatibility.
Asunto(s)
Neoplasias de la Mama , Hipertermia Inducida , Nanopartículas , Albúminas , Animales , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Doxorrubicina/farmacología , Femenino , Humanos , Ratones , Fototerapia , Terapia Fototérmica , TocoferolesRESUMEN
Hypoxia-inducible factors (HIFs) are one of the primary transcription factors regulating oxygen balance, and their stability is determined by the hydroxylation state of the prolyl hydroxylase domain (PHD) that is sensitive to oxygen. In recent years, studies have shown that HIFs-prolyl hydroxylases (PHDs) oxygen-sensing pathway is involved in the process of cellular ferroptosis. Ferroptosis, a new type of cell death, different from necrosis, apoptosis, necrotizing apoptosis, and pyroptosis, is essentially a programmed death caused by the accumulation of iron-dependent lipid peroxides in cells. This paper focuses on the role and mechanism of the HIFs-PHDs oxygen-sensing pathway in cellular ferroptosis involved in nerve diseases, tumors, lung injury, and chemical nerve damage from three aspects of iron metabolism, lipid metabolism, and glutathione (GSH) synthesis/metabolism. This review will provide a theoretical basis and new ideas for the development of novel drugs targeting the HIFs-PHDs oxygen-sensing pathway and capable of regulating ferroptosis for the treatment of diseases related to ferroptosis such as nervous system diseases and tumors.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Ferroptosis , Prolil Hidroxilasas , Apoptosis , OxígenoRESUMEN
Vascular dysfunction and bacterial infection are key factors for the non-healing of diabetic ulcers. Growth factors and antibiotics seem to effectively target both issues. However, the short half-life and high cost of growth factors and the antibiotics resistance of bacteria greatly limit their further widespread applications. Novel strategies or agents with both angiogenic and antibacterial activities are urgently desirable. Copper peroxide (CuO2) nanodots were reported to be decomposed into Cu2+ and H2O2 under mild acid conditions (pH 5.5). Considering that both decomposed products are acknowledged antibacterial agents (Cu2+, H2O2) and angiogenesis activator (Cu2+), we believe that CuO2 nanodots are suitable for diabetic ulcer treatment because the pathological environment of infected chronic wounds is mildly acidic with pH 5.5-5.6. As expected, in vitro experiments showed that CuO2 nanodots possessed excellent bactericidal properties against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and even methicillin-resistant Staphylococcus aureus (MRSA). CuO2 nanodots induced the high expression of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs), subsequently promoting the cell migration and tube formation for angiogenesis. In particular, CuO2 nanodots exhibited good dispersibility and sprayable behavior in water. In vivo experiments demonstrated that the spayed CuO2 nanodots in the wound area could effectively combat MRSA, reduce inflammation, promote angiogenesis, and consequently accelerate wound healing. Moreover, the sprayed CuO2 nanodots in the wound sites caused negligible system toxicity. This study provides proof-of-principle evidence for applying the sprayed CuO2 nanodots for infected diabetic ulcer treatment.
Asunto(s)
Diabetes Mellitus , Staphylococcus aureus Resistente a Meticilina , Antibacterianos/farmacología , Bacterias , Cobre , Células Endoteliales de la Vena Umbilical Humana , Humanos , Peróxido de Hidrógeno , Peróxidos , Úlcera , Factor A de Crecimiento Endotelial Vascular , Cicatrización de HeridasRESUMEN
3,3'-Diindolylmethane (DIM), a natural phytochemicals isolated from cruciferous vegetables, has been reported to inhibit human gastric cancer cells proliferation and induce cells apoptosis as well as autophagy, but its mechanisms are still unclear. Store-operated calcium entry (SOCE) is a main Ca2+ influx pathway in various of cancers, which is activated by the depletion of endoplasmic reticulum (ER) Ca2+ store. Stromal interaction molecular 1 (STIM1) is the necessary component of SOCE. In this study, we focus on to examine the regulatory mechanism of SOCE on DIM-induced death in gastric cancer. After treating the human BGC-823 and SGC-7901 gastric cancer cells with DIM, cellular proliferation was determined by MTT, apoptosis and autophagy were detected by flow cytometry or Hoechst 33342 staining. The expression levels of related proteins were evaluated by Western blotting. Free cytosolilc Ca2+ level was assessed by fluorescence monitoring under a laser scanning confocal microscope. The data have shown that DIM could significantly inhibit proliferation and induce apoptosis as well as autophagy in two gastric cancer cell lines. After DIM treatment, the STIM1-mediated SOCE was activated by upregulating STIM1 and decreasing ER Ca2+ level. Knockdown STIM1 with siRNA or pharmacological inhibition of SOCE attenuated DIM induced apoptosis and autophagy by inhibiting p-AMPK mediated ER stress pathway. Our data highlighted that the potential of SOCE as a promising target for treating cancers. Developing effective and selective activators targeting STIM1-mediated SOCE pathway will facilitate better therapeutic sensitivity of phytochemicals acting on SOCE in gastric cancer. Moreover, more research should be performed to validate the efficacy of combination chemotherapy of anti-cancer drugs targeting SOCE for clinical application.
Asunto(s)
Apoptosis/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Indoles/farmacología , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas , Molécula de Interacción Estromal 1/metabolismo , Anticarcinógenos/farmacología , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Proteínas Sensoras del Calcio Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Fitoquímicos/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismoRESUMEN
Cancer is a serious threat to human health. Graphene oxide (GO) is a good carrier for cancer treatment due to its large surface area and high drug loading, while it's unstable under physiological conditions with a high tendency to be uptaken by macrophages in the body. This paper constructs a red blood cell (RBC) membrane modified GO nanocarrier system for cancer chemotherapy. After the modification of RBC, the stability and hemolysis performance of GO were greatly improved, which is beneficial to the biological application. Moreover, DOX-loaded RBC-GO still able to maintain good stability with a pH-dependent DOX release profile. RBC-GO can be uptaken by MCF-7 cells and DOX-loaded RBC-GO nanocomposites have strong concentration-dependent cytotoxicity. More importantly, in vivo study showed that RBC-GO can accumulate at the tumor site in a large quantity, and among all the experimental groups, RBC-GO-DOX had the best anti-tumor effect after tail vein injection in mice and the lowest systemic toxicity. Experiments have proved that RBC-GO can be used as a drug carrier to achieve targeted drug delivery.
Asunto(s)
Grafito , Neoplasias , Animales , Doxorrubicina/farmacología , Portadores de Fármacos , Eritrocitos , Humanos , RatonesRESUMEN
Multi-component combination therapy of cancer is currently a hot spot in the field of cancer treatment research. In this study, a WS2 nanosheet was selected as the substrate material and modified with a cell-like membrane biomimetic liposome (WS2-lipid). The lipid-modified WS2 nanomaterials were successfully prepared with good stability and biocompatibility. Its good photothermal characteristics and high drug loading amount were utilized to achieve a comprehensive chemo and photothermal therapeutic effect. The results showed that the lipid coating strongly enhanced the stability of the WS2 nanosheets before and after DOX loading and the WS2-lipid had a good photothermal performance and drug loading amount. According to the cellular results, WS2-lipid was able to be taken up by MCF-7 cells. Both photothermo-therapy and chemotherapy had a concentration dependent cytotoxicity on MCF-7 cells, and the combined application of both methods had an improved cytotoxicity. In addition, in vivo photothermal experiments indicated that lipid modification could promote intratumoral accumulation of the material. Thus, WS2-lipid can be used as a good nano-platform for phototherapy and chemotherapy combination therapy and has good application prospects in cancer therapy.
Asunto(s)
Materiales Biomiméticos/química , Neoplasias de la Mama/terapia , Liposomas/química , Nanoestructuras/química , Fosfolípidos/química , Sulfuros/química , Compuestos de Tungsteno/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Materiales Biocompatibles/química , Terapia Combinada , Doxorrubicina/química , Doxorrubicina/farmacología , Liberación de Fármacos , Yema de Huevo/química , Femenino , Humanos , Hipertermia Inducida , Rayos Infrarrojos , Células MCF-7 , Ratones , Terapia Fototérmica , SolubilidadRESUMEN
AIMS: Diabetes mellitus (DM) is one of the most common metabolic diseases worldwide characterized by insulin resistance and pancreatic ß-cell dysfunction. In the previous study, endoplasmic reticulum (ER) stress could increase the C/EBP homologous protein (CHOP) expression through inhibiting C/EBß transcriptional activity. However, the role of CHOP and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in pancreatic ß-cell dysfunction remains unknown. The aim of the study was to investigate the effect of CHOP and PGC-1α in pancreatic ß-cell dysfunction and the potential mechanisms underlying its actions. METHODS: We established the pancreatic ß-cell dysfunction model to identify the biological features and functions of CHOP. Apoptosis was detected using Western blot analysis and real-time polymerase chain reaction (RT-PCR). RESULTS: Our results showed that high glucose (HG) increases CHOP and inhibits PGC-1α expression and ameliorates apoptosis in pancreatic ß cells. Silenced CHOP elevates the PGC-1α expression and ameliorates HG-induced apoptosis in pancreatic ß cells. Furthermore, upregulation of the PGC-1α alleviates HG-induced apoptosis in pancreatic ß cells. We also expounded that HG-activated phosphorylation of nuclear factor-κB through increasing PGC-1α expression. CONCLUSION: We verified the function and mechanism of CHOP and provide evidence that CHOP and PGC-1α may serve as potential candidates for the clinical treatment of DM.
Asunto(s)
Diabetes Mellitus/metabolismo , Células Secretoras de Insulina/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Transducción de Señal , Factor de Transcripción CHOP/metabolismo , Animales , Apoptosis , Línea Celular , Diabetes Mellitus/fisiopatología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Regulación de la Expresión Génica , Glucosa/metabolismo , Células Secretoras de Insulina/fisiología , Ratones , FN-kappa B/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Nanoparticle-loaded hydrogels - localized drug delivery devices containing a combination of therapeutic nanoparticles and implantable hydrogel - have been recipients of increased focus and interest for cancer treatment. However, it is difficult for the released nanoparticles to penetrate deeply into tumors because of the dense collagen network in the tumor extracellular matrix, which greatly limits their antitumor effect. We hypothesized that the implantation of a hydrogel loaded with both nanoparticles and losartan (Los) might enhance penetration because Los has been proven to effectively reduce collagen levels in various tumors. Herein, we developed a nanoparticle/Los-loaded hydrogel system and evaluated the intratumoral distribution and anticancer effect after peritumoral implantation of nanoparticles. METHODS: Fluorescent polystyrene nanoparticles (FPNPs, size ~100 nm) and Los were simultaneously encapsulated in a polyethylene glycol (PEG) hydrogel to form the FPNP/Los-loaded hydrogel. After peritumoral implantation in 4T1 tumor-bearing mice for 2 weeks, intratumoral distributions of FPNPs and collagen level were determined. Based on the results, liposomal doxorubicin (Doxil, ~100 nm) was subsequently substituted for FPNPs in the hydrogel. The cellular uptake and cytotoxicity of the Doxil/Los-loaded hydrogel were studied, and the in vivo antitumor efficacy after peritumoral implantation was evaluated. RESULTS: Compared with a standard FPNP-loaded hydrogel, the FPNP/Los-loaded hydrogel resulted in enhanced penetration and reduced collagen levels after implantation. Thereafter, the potential of a Doxil/Los-loaded hydrogel for cancer treatment was studied. Doxorubicin was released from the hydrogel and induced effective cytotoxicity against 4T1 cells. The Doxil/Los-loaded hydrogel showed synergistic antitumor effects in 4T1 tumor-bearing mice and was more effective at tumor inhibition than the Doxil-loaded hydrogel. CONCLUSION: This study provides a proof of principle that the implantation of nanoparticles/Los-loaded hydrogel can increase the intratumoral distribution and antitumor efficacy of nanoparticles, owing to collagen depletion by Los. Future studies may build on this strategy for enhanced tumor penetration of nanoparticles.
Asunto(s)
Antineoplásicos/uso terapéutico , Hidrogeles/química , Implantes Experimentales , Losartán/química , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Endocitosis , Fluorescencia , Humanos , Ratones Desnudos , Nanopartículas/ultraestructura , Neoplasias/patología , Tamaño de la Partícula , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , Poliestirenos/químicaRESUMEN
BACKGROUND AND OBJECT: Polyelectrolyte microcapsule is a promising candidate for multifunctional drug delivery system. However, the lack of reports about animal experiments have greatly slowed down their development for drug delivery. We engineered biodegradable chitosan-alginate polyelectrolyte multilayer capsule filled with bovine serum albumin gel (BSA-gel-capsule). Herein, we demonstrated their applicability for local chemotherapy, a means of treating local or regional malignancies by direct administration of anti-tumor agents to tumor sites. METHOD: Doxorubicin (DOX) was loaded in BSA-gel-capsules and DOX-resistant cell line (MCF-7/ADR cells) was employed for antitumor studies in vitro. The cytotoxicity, cellular uptake and distribution of DOX from BSA-gel-capsules were studied. Afterwards, MCF-7/ADR xenografts tumor model was established in nude mice. The in vivo antitumor efficacy of DOX-loaded BSA-gel-capsules by intratumor injection was then evaluated. RESULT: Compared with free DOX, more effective cytotoxicity against MCF-7/ADR cells after treatment with DOX-loaded BSA-gel-capsules was revealed, demonstrating the positive reversal effect on drug-resistance. Thereafter, the more cellular uptake and nucleus distribution of DOX from BSA-gel-capsules in MCF-7/ADR cells provided convincing explanation for the reversal effect. DOX-loaded BSA-gel-capsules displayed remarkably more antitumor efficacy than free DOX in MCF-7/ADR cell-xenografted mice. Finally, the high DOX accumulation and prolonged retention in tumor site after local administration of DOX-loaded BSA-gel-capsules was demonstrated, displaying the unique advantages of BSA-gel-capsules for local chemotherapy. CONCLUSION: These findings indicate that DOX-loaded BSA-gel-capsules should be considered a potential candidate for the treatment of drug-resistant breast cancer. This paper provides a feasibility for the local chemotherapy of polyelectrolyte microcapsules, which will be a big step towards their application as drug delivery vehicles.
Asunto(s)
Alginatos/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Quitosano/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Albúmina Sérica Bovina/metabolismo , Alginatos/química , Animales , Antineoplásicos/química , Neoplasias de la Mama/patología , Cápsulas/química , Cápsulas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quitosano/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Geles/química , Geles/farmacología , Ácido Glucurónico/química , Ácido Glucurónico/farmacología , Ácidos Hexurónicos/química , Ácidos Hexurónicos/farmacología , Humanos , Células MCF-7 , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Albúmina Sérica Bovina/química , Relación Estructura-ActividadRESUMEN
Hexavalent chromium [Cr(VI)] is a common human carcinogen associated with lung cancer and other pulmonary diseases as exposure to excessive Cr(VI) induces malignant transformation in human lung epithelial cells. The mechanism underlying its carcinogenicity is unclear in terms of how it facilitates metastases. Cr(VI) compounds are reported to briefly promote cell migration in a concentration-dependent manner and oncogene liver kinase B1 (LKB1) was reduced in Cr(VI)-transformed cells. Overexpression of LKB1 in Beas-2B-Cr [Cr(VI) malignantly transformed Beas-2B cells] suppressed cell migration and invasion and inactivated FAK, Src, MMP-2, GSK3ß, ß-catenin, and HEF1, which contribute to cell migration and invasion. Silencing LKB1 with siRNA promoted migration and invasion, and activated these downstream proteins. Long-term exposure to Cr(VI) enhanced the migration and invasiveness of Beas-2B cells and reduced the expression of LKB1, while activating these proteins as mentioned above. Data suggest that LKB1 may regulate downstream proteins such as FAK, Src, MMP-2, GSK3ß, ß-catenin, and HEF1, and affect the migration and invasiveness of Beas-2B-Cr cells.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Cromo/toxicidad , Células Epiteliales/efectos de los fármacos , Neoplasias Pulmonares/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Epiteliales/patología , Humanos , Neoplasias Pulmonares/metabolismo , Ratones Desnudos , Invasividad NeoplásicaRESUMEN
Dichloroacetonitrile (DCAN), an emerging nitrogenous disinfection by-product, is more genotoxic and cytotoxic than the currently regulated carbonaceous disinfection by-products such as haloacetic acids. Few mechanistic studies have been conducted on the hepatic and renal toxicities of DCAN. This study examined the clinical biochemical, hematological, histopathological, oxidative, and mitochondrial functional alterations to evaluate the systematic toxicity after subacute oral exposure of 11 or 44 mg/kg/day in rats for 28 days. Body and spleen weights were lower, and organ-to-body weight ratios of the liver and kidney were higher in rats administered 44-mg/kg DCAN than in controls. The activities of serum alanine aminotransferase and alkaline phosphatase, and concentrations of blood serum urea nitrogen and retinol-binding protein were increased in rats administered 44-mg/kg DCAN compared with those of controls, thereby indicating hepatic and renal damage in this group. This was confirmed by histopathological alterations, including hepatic sinus dilation, extensive hemorrhage, vacuolar degeneration in the liver and glomerulus hemorrhage, and renal tubular swelling, in DCAN-exposed rats. Exposure to 44-mg/kg DCAN induced hepatic oxidative damage shown by the significant increase in malonaldehyde levels, a poisonous product of lipid peroxidation. Exposure to 44-mg/kg DCAN significantly increased hepatic glutathione content and mitochondrial bioenergy as noted by the elevation of mitochondrial membrane potential and cytochrome c oxidase activity, which might be attributed to compensatory pathophysiologic responses to DCAN-induced hepatic mitochondrial damage.
Asunto(s)
Acetonitrilos/toxicidad , Desinfectantes/toxicidad , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Administración Oral , Animales , Desinfección , Riñón/patología , Dosificación Letal Mediana , Hígado/patología , Masculino , Malondialdehído/metabolismo , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Diabetes mellitus has potential to alter the toxicity of hazardous chemicals. Dichloroacetonitrile (DCAN) is one of high-risk nitrogenous disinfection by-products. This study evaluated the neurotoxicity of DCAN (11, 44 and 88mg/kg) in normoglycaemic and streptozotocin (STZ)-induced diabetic rats via orally for 28days. STZ diabetes prolonged the median survival time and total lethal time after DCAN (88mg/kg) exposure when compared with that observed in normoglycaemic rats. DCAN altered motor activity and induced anxiety behaviour in normoglycaemic rats; but it did not exaggerate behavioural changes in STZ diabetic rats. DCAN -induced brain oxidative damage by compensatory increase glutathione content and decrease malonaldehyde levels; but it did not induce oxidative damage in diabetic rats. STZ diabetes slowed down the pathological pace of DCAN-induced brain mitochondrial dysfunction by decreasing reactive oxygen species and increasing cytochrome C oxidase activity. In conclusion, the present study indicated that STZ diabetic rats are resistant to DCAN-induced neurotoxicity at the dosage and with the dosage schedule in 28-day subacute toxicity test.
Asunto(s)
Acetonitrilos/toxicidad , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Síndromes de Neurotoxicidad/prevención & control , Acetonitrilos/administración & dosificación , Administración Oral , Animales , Complejo IV de Transporte de Electrones/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Estrés Oxidativo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina , Pruebas de Toxicidad SubagudaRESUMEN
The major obstacles opposed to doxorubicin (Dox) based chemotherapy are the induction of drug resistance, together with non-specific toxicities for healthy cells. In this study, we prepared a peptide-Dox conjugate aimed at offering Dox molecules a tumor-specific functionality and improving the therapeutic effects of Dox against resistant tumor cells. A slightly acidic pH-sensitive peptide (SAPSP) with high selectivity for cancer cells was attached to Dox to obtain SAPSP-Dox prodrug. The structures and properties of this prodrug were characterized, confirming several merits, including desirable pH-sensitive property, good serum stability and favorable release behavior. Cellular uptake studies demonstrated that SAPSP-Dox was preferably accumulated in cancer cells (Dox-sensitive MCF-7 and Dox-resistant MCF-7/ADR), followed by displaying 26-fold less toxic toward noncancerous MCF-10A cells than free Dox do. The conjugated peptides enabled Dox to escape the efflux effect of P-glycoprotein mediated pump via endocytotic pathway, giving rise to remarkable cytotoxicity and apoptotic effect on MCF-7/ADR cells. Moreover, the superior inhibition efficacy of SAPSP-Dox in vivo was more evident in the both drug-sensitive and drug-resistant xenograft tumor animal models, which enabled Dox to primarily accumulated in tumor. The conjugates also demonstrated a longer half-life in plasma and a lower side effect, for example, reduced cardiac toxicity. Evidence of this study suggests that SAPSP-Dox has the potential to be a potent prodrug for treating drug resistant cancers.
Asunto(s)
Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Péptidos/química , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Línea Celular Tumoral , Femenino , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To facilitate targeting drug delivery and combined therapy, we develop titanium dioxide-encapsulated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs). Titanium dioxide (TiO2), which is employed as a sonosensitizer for sonodynamic therapy (SDT), can also be used for the loading of doxorubicin (DOX). The fabricated Fe3O4@TiO2 NPs exhibit pH-dependent loading and release of doxorubicin (DOX) in vitro. After incubation with cancer cells, reactive oxygen species (ROS) are generated efficiently upon the irradiation of ultrasound. In the biodistribution experiments, extremely high in vivo tumor accumulation of Fe3O4@TiO2 NPs and long-time retention effect are observed. Compared with chemotherapy or sonodynamic treatment alone, the combined therapy demonstrated a synergistic effect, resulting in stronger cytotoxicity and higher therapeutic efficacy. Thus, the constructed NPs are endowed with multifunctions which allow them to selectively deliver combinatorial therapeutic payload to tumor with enhanced therapeutic effectiveness and minimal side effects.