RESUMO
Chemodynamic therapy (CDT), an emerging cancer treatment modality, uses multivalent metal elements to convert endogenous hydrogen peroxide (H2O2) to toxic hydroxyl radicals (â¢OH) via a Fenton or Fenton-like reaction, thus eliciting oxidative damage of cancer cells. However, the antitumor potency of CDT is largely limited by the high glutathione (GSH) concentration and low catalytic efficiency in the tumor sites. The combination of CDT with chemotherapy provides a promising strategy to overcome these limitations. In this work, to enhance antitumor potency by tumor-targeted and GSH depletion-amplified chemodynamic-chemo therapy, the hyaluronic acid (HA)/polydopamine (PDA)-decorated Fe2+-doped ZIF-8 nano-scaled metal-organic frameworks (FZ NMs) were fabricated and utilized to load doxorubicin (DOX), a chemotherapy drug, via hydrophobic, π-π stacking and charge interactions. The attained HA/PDA-covered DOX-carrying FZ NMs (HPDFZ NMs) promoted DOX and Fe2+ release in weakly acidic and GSH-rich milieu and exhibited acidity-activated â¢OH generation. Through efficient CD44-mediated endocytosis, the HPDFZ NMs internalized by CT26 cells not only prominently enhanced â¢OH accumulation by consuming GSH via PDA-mediated Michael addition combined with Fe2+/Fe3+ redox couple to cause mitochondria damage and lipid peroxidation, but also achieved intracellular DOX release, thus eliciting apoptosis and ferroptosis. Importantly, the HPDFZ NMs potently inhibited CT26 tumor growth in vivo at a low DOX dose and had good biosafety, thereby showing promising potential in tumor-specific treatment.
RESUMO
The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment. However, the poor photostability and photothermal conversion efficiency (PCE) of organic small-molecule photosensitizers, and the intracellular glutathione (GSH)-mediated singlet oxygen scavenging largely decline the antitumor efficacy of PTT and PDT. Herein, a versatile nanophotosensitizer (NPS) system is developed by ingenious incorporation of indocyanine green (ICG) into the PEGylated chitosan (PEG-CS)-coated polydopamine (PDA) nanoparticles via multiple π-π stacking, hydrophobic and electrostatic interactions. The PEG-CS-covered NPS showed prominent colloidal and photothermal stability as well as high PCE (ca 62.8 %). Meanwhile, the Michael addition between NPS and GSH can consume GSH, thus reducing the GSH-induced singlet oxygen scavenging. After being internalized by CT26 cells, the NPS under near-infrared laser irradiation produced massive singlet oxygen with the aid of thermo-enhanced intracellular GSH depletion to elicit mitochondrial damage and lipid peroxide formation, thus leading to ferroptosis and apoptosis. Importantly, the combined PTT and PDT delivered by NPS effectively inhibited CT26 tumor growth in vivo by light-activated intense hyperthermia and redox homeostasis disturbance. Overall, this work presents a new tactic of boosting antitumor potency of ICG-mediated phototherapy by PEG-CS-covered NPS.
Assuntos
Quitosana , Glutationa , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Terapia Fototérmica , Polietilenoglicóis , Quitosana/química , Fotoquimioterapia/métodos , Animais , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Glutationa/metabolismo , Polietilenoglicóis/química , Camundongos , Nanopartículas/química , Terapia Fototérmica/métodos , Linhagem Celular Tumoral , Verde de Indocianina/química , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oxigênio Singlete/metabolismo , Humanos , Apoptose/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Polímeros/químicaRESUMO
Purpose: Mounting evidence has revealed the anti-cancer activity of various anti-viral drugs. Oseltamivir phosphate (OP), namely Tamiflu®, is routinely used to combat influenza infections. Although evidence has indicated the anti-cancer effects of OP in vitro and in vivo, little information is known about the effect of OP use on cancers in humans. Methods: A nationwide population-based cohort study involving 13,977,101 cases with 284,733 receiving OP was performed to examine the association between OP use and cancers using the National Health Insurance Research Database in Taiwan between 2009 and 2018. Results: The cohort study found that OP users showed a significantly lower incidence of lung cancer, colon cancer, liver, and intrahepatic bile duct cancer, oral cancer, pancreas cancer, esophagus cancer, stomach cancer, and prostate cancer. Additionally, OP users exhibited a lower risk of cancer-related mortality (adjusted HR=0.779; 95% confidence interval [CI] 0.743-0.817; p<0.001) and a reduced risk of developing liver cancer (adjusted HR=0.895; 95% CI 0.824-0.972; p=0.008), esophagus cancer (adjusted HR=0.646; 95% CI 0.522-0.799; p<0.001) and oral cancer (adjusted HR=0.587; 95% CI 0.346-0.995; p=0.048). Notably, OP users had a significant reduction in liver cancer occurrence over a 10-year period follow-up and a lower cancer stage at liver cancer diagnosis. Conclusion: These findings first suggest the beneficial effects and therapeutic potential of OP use for certain cancers, especially liver cancer.
RESUMO
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children with unknown etiology. Impaired learning ability was commonly reported in ADHD patients and has been associated with dopamine uptake in the striatum of an animal model. Another evidence also indicated that micro-RNA (miR)-200b-3p is associated with learning ability in various animal models. However, the association between miR-200b-3p and ADHD-related symptoms remains unclear. Therefore, the current study investigated the role of miR-200b-3p in ADHD-related symptoms such as inattention and striatal inflammatory cytokines. To verify the influence of miR-200b-3p in ADHD-related symptoms, striatal stereotaxic injection of miR-200b-3p antagomir (AT) was performed on spontaneously hypertensive rats (SHR). The antioxidant activity and expressions of miR-200b-3p, slit guidance ligand 2 (Slit2), and inflammatory cytokines in the striatum of SHR were measured using quantitative real-time polymerase chain reaction (RT-qPCR), immunohistochemistry (IHC), immunoblotting, and enzyme-linked immunosorbent assay (ELISA). The spontaneous alternation of SHR was tested using a three-arm Y-shaped maze. The administration of miR-200b-3p AT or taurine significantly decreased striatal tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in SHR, along with increased super-oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and significantly higher spontaneous alternation. In this paper, we show that miR-200b-3p AT and taurine alleviates ADHD-related symptoms in SHR. These findings provide insights into ADHD's molecular basis and suggest miR-200b-3p as a potential therapeutic target. Concurrently, this study also suggests broad implications for treating neurodevelopmental disorders affecting learning activity such as ADHD.
RESUMO
To effectively treat aggressive breast cancer by tumor-activated targetable photothermal chemotherapy, in this work, folate (FA)-modified hybrid polymeric nanoassemblies (HPNs) with a poly(ethylene glycol) (PEG)-detachable capability are developed as vehicles for tumor-targeted co-delivery of IR780, a lipophilic photothermal reagent, and zoledronic acid (ZA), a hydrophilic chemotherapy drug. Through hydrophobic interaction-induced co-assembly, IR780 molecules and ZA/poly(ethylenimine) (PEI) complexes were co-encapsulated into a poly(lactic-co-glycolic acid) (PLGA)-rich core stabilized by the amphiphilic FA-modified D-α-tocopheryl poly(ethylene glycol) succinate (FA-TPGS) and acidity-sensitive PEG-benzoic imine-octadecane (C18) (PEG-b-C18) conjugates. The developed FA-ZA/IR780@HPNs with high ZA and IR780 payloads not only showed excellent colloidal stability in a serum-containing milieu, but also promoted IR780-based photostability and photothermal conversion efficiency. Furthermore, for FA-ZA/IR780@HPNs under simulated physiological conditions, the premature leakage of IR780 and ZA molecules was remarkably declined. In a mimetic acidic tumor microenvironment, the uptake of FA-ZA/IR780@HPNs by FA receptor-overexpressed 4T1 breast cancer cells was remarkably promoted by PEG detachment combined with FA receptor-mediated endocytosis, thus effectively hindering migration of cancer cells and augmenting the anticancer efficacy of photothermal chemotherapy. Notably, the in vivo studies demonstrated that the FA-ZA/IR780@HPNs largely deposited at 4T1 tumor sites and profoundly suppressed tumor growth and metastasis without severe systemic toxicity upon near infrared (NIR)-triggered IR780-mediated hyperthermia integrated with ZA chemotherapy. This work presents a practical strategy to treat aggressive breast tumors with tumor-triggered targetable photothermal chemotherapy using FA-ZA/IR780@HPNs.
Assuntos
Neoplasias da Mama , Síndrome Neurológica de Alta Pressão , Nanopartículas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Ácido Zoledrônico , Ácido Fólico/química , Síndrome Neurológica de Alta Pressão/tratamento farmacológico , Indóis/química , Fototerapia , Polímeros , Polietilenoglicóis/química , Linhagem Celular Tumoral , Nanopartículas/uso terapêutico , Nanopartículas/química , Microambiente TumoralRESUMO
Human parvovirus B19 (B19V) is a single-stranded non-enveloped DNA virus of the family Parvoviridae that has been associated with various autoimmune disorders. Systemic sclerosis (SSc) is an autoimmune connective tissue disorder with high mortality and has been linked to B19V infection. However, the precise mechanism underlying the B19V contribution to the development of SSc remains uncertain. This study investigated the impacts of the functional B19V-VP1 unique region (VP1u) in macrophages and bleomycin (BLE)-induced SSc mice. Cell experimental data showed that significantly decreased viability and migration of both B19V-VP1u-treated U937 and THP-1 macrophages are detected in the presence of celastrol. Significantly increased MMP9 activity and elevated NF-kB, MMP9, IL-6, TNF-α, and IL-1ß expressions were detected in both B19V-VP1u-treated U937 and THP-1 macrophages. Conversely, celastrol revealed an inhibitory effect on these molecules. Notably, celastrol intervened in this pathogenic process by suppressing the sPLA2 activity of B19V-VP1u and subsequently reducing the inflammatory response. Notably, the administration of B19V-VP1u exacerbated BLE-induced skin fibrosis in mice, with augmented expressions of TGF-ß, IL-6, IL-17A, IL-18, and TNF-α, ultimately leading to α-SMA and collagen I deposits in the dermal regions of BLE-induced SSc mice. Altogether, this study sheds light on parvovirus B19 VP1u linked to scleroderma and aggravated dermal fibrosis.
Assuntos
Infecções por Parvoviridae , Parvovirus B19 Humano , Escleroderma Sistêmico , Animais , Humanos , Camundongos , Proteínas do Capsídeo/genética , Fibrose , Interleucina-6/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infecções por Parvoviridae/complicações , Parvovirus B19 Humano/genética , Escleroderma Sistêmico/induzido quimicamente , Fator de Necrose Tumoral alfa/metabolismo , Proteínas ViraisRESUMO
Human parvovirus B19 (B19V) has been strongly associated with a variety of inflammatory disorders, such as rheumatoid arthritis (RA), inflammatory bowel disease and systemic lupus erythematosus. Nonstructural protein 1 (NS1) of B19V has been demonstrated to play essential roles in the pathological processes of B19V infection due to its regulatory properties on inflammatory cytokines. Celastrol, a quinone methide isolated from Tripterygium wilfordii, has displayed substantial potential in treating inflammatory diseases, such as psoriasis and RA. However, little is known about the effects of celastrol on B19V NS1induced inflammation. Therefore, cell viability assay, migration assay, phagocytosis analysis, zymography assay, ELISA and immunoblotting were conducted to verify the influences of celastrol on macrophages. The present study reported the attenuating effects of celastrol on B19V NS1induced inflammatory responses in macrophages derived from human acute monocytic leukemia cell lines, U937 and THP1. Although the migration was not significantly decreased by celastrol in both U937 and THP1 macrophages, significantly decreased viability, migration and phagocytosis were detected in both B19V NS1activated U937 and THP1 macrophages in the presence of celastrol. Additionally, celastrol significantly decreased MMP9 activity and the levels of inflammatory cytokines, including IL6, TNFα and IL1ß, in B19V NS1activated U937 and THP1 cells. Notably, significantly decreased levels of NLR family pyrin domaincontaining 3, apoptosisassociated specklike, caspase1 and IL18 proteins were observed in both B19V NS1activated U937 and THP1 cells in the presence of celastrol, indicating the involvement of the inflammasome pathway. To the best of our knowledge, the present study is the first to report on the attenuating effects of celastrol on B19V NS1induced inflammatory responses in macrophages, suggesting a therapeutic role for celastrol in B19V NS1related inflammatory diseases.
Assuntos
Artrite Reumatoide , Parvovirus B19 Humano , Humanos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Macrófagos , CitocinasRESUMO
Liver cancer is one of the most lethal malignant cancers worldwide. However, the therapeutic options for advanced liver cancers are limited and reveal scant efficacy. The current study investigated the effects of nivolumab (Niv) and escitalopram oxalate (Esc) in combination on proliferation of liver cancer cells both in vitro and in vivo. Significantly decreased viability of HepG2 cells that were treated with Esc or Niv was observed in a dose-dependent manner at 24 h, 48 h, and 72 h. Administration of Esc (50 µM) + Niv (20 µM), Esc (75 µM) + Niv (5 µM), and Esc (75 µM) + Niv (20 µM) over 24 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Additionally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) over 48 h exhibited synergistic effects, inhibiting the survival of HepG2 cells. Finally, treatment with Esc (50 µM) + Niv (1 µM), Esc (50 µM) + Niv (20 µM), and Esc (75 µM) + Niv (20 µM) for 72 h exhibited synergistic effects, inhibiting HepG2 survival. Com-pared with controls, HepG2 cells treated with Esc (50 µM) + Niv (20 µM) exhibited significantly increased sub-G1 portion and annexin-V signals. In a xenograft animal study, Niv (6.66 mg/kg) + Esc (2.5 mg/kg) significantly suppressed the growth of xenograft HepG2 tumors in nude mice. This study reports for the first time the synergistic effects of combined administration of Niv and Esc for inhibiting HepG2 cell proliferation, which may provide an alternative option for liver cancer treatment.
Assuntos
Escitalopram , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Nivolumabe/farmacologia , Camundongos Nus , Apoptose , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
Chemodynamic therapy (CDT) has emerged as a promising strategy for tumor treatment. Nevertheless, the low Fenton catalytic efficiency and the high concentration of glutathione (GSH) in cancer cells largely decline antitumor efficacy of CDT. To self-augment antitumor effect of the CDT by combining with photothermal therapy (PTT), the unique photothermal nanozymes that doubly depleted GSH, and generated massive hydroxyl radicals (·OH) in the hyperthermia/acidity-activated manner were developed. Through the coordination of Fe3+ ions with PEGylated chitosan (PEG-CS)-modified polydopamine (PDA) nanoparticles, the attained Fe3+@PEG-CS/PDA nanozymes showed outstanding colloidal stability, photothermal conversion efficiency and acidity-triggered Fe3+ release. By GSH-mediated valence states transition of Fe3+ ions and Michael reaction between GSH and quinone-rich PDA, the nanozymes sufficiently executed dual depletion of GSH with the elevated temperature.Under mimic tumor acidity and near-infrared (NIR) irradiation condition, the endocytosed nanozymes effectively converted intracellular H2O2 into toxic ·OH upon amplified Fenton reaction, thereby potently killing 4T1 cancer cells and RAW 264.7 cells. Importantly, the nanozymes prominently suppressed 4T1 tumor growth in vivo and metastasis of cancer cells by CDT/PTT combination therapy without significant systemic toxicity. Our study provides novel visions in design of therapeutic nanozymes with great clinical translational prospect for tumor treatment.
Assuntos
Quitosana , Nanopartículas , Neoplasias , Humanos , Radical Hidroxila , Peróxido de Hidrogênio , Terapia Combinada , Glutationa , Terapia Fototérmica , Linhagem Celular Tumoral , Neoplasias/terapiaRESUMO
Chemotherapy-related cognitive impairment has been reported in patients with breast cancer and received growing attention due to increased survival rate. However, cognitive outcome according to pathological tumor features, especially human epidermal growth factor receptor (HER2) status, has not been clearly elucidated. Despite its potential link with cognitive status through neuroinflammatory response, existing research is sparse and limited to cross-sectional studies. In this observational cohort study, 52 breast cancer patients received a series of neuropsychological examinations before and after chemotherapy. Patients' performances were compared with normative data, and analyzed with Reliable Change Indices and mixed-model analysis of covariance. Results showed that there was a higher percentage of HER2+ patients than HER2- patients who showed defective attention and processing speed before chemotherapy, and that there were more patients with HER2+ status showing cognitive decline on tests of attention and executive functions following chemotherapy. Group-wise analyses confirmed the foregoing pattern and further revealed that patients with HER2+ status also tended to deteriorate more in verbal memory after chemotherapy. These findings indicate that HER2 overexpression may serve as prognostic factors that help explain the heterogeneous cognitive outcome in breast cancer survivors. Further studies are needed to replicate this finding and delineate the underlying mechanisms.
RESUMO
To effectively promote antitumor potency of doxorubicin (DOX), a regularly used chemotherapy drug, the tumor acidity-responsive polymeric nanomicelles from self-assembly of the as-synthesized amphiphilic benzoic imine-containing PEGylated chitosan-g-poly(lactic-co-glycolic acid) (PLGA) conjugates were developed as vehicles of DOX. The attained PEGylated chitosan-g-PLGA nanomicelles with high PEGylation degree (H-PEG-CSPNs) were characterized to exhibit a "onion-like" core-shell-corona structure consisting of a hydrophobic PLGA core covered by benzoic imine-rich chitosan shell and outer hydrophilic PEG corona. The DOX-carrying H-PEG-CSPNs (DOX@H-PEG-CSPNs) displayed robust colloidal stability under large-volume dilution condition and in a serum-containing aqueous solution of physiological salt concentration. Importantly, the DOX@H-PEG-CSPNs in weak acidic milieu undergoing the hydrolysis of benzoic imine bonds and increased protonation of chitosan shell showed dePEGylation and surface charge conversion. Also, the considerable swelling of protonated chitosan shell within DOX@H-PEG-CSPNs accelerated drug release. Notably, the cellular internalization of DOX@H-PEG-CSPNs by TRAMP-C1 prostate cancer cells under mimic acidic tumor microenvironment was efficiently boosted upon acidity-triggered detachment of PEG corona and exposure of positively-charged chitosan shell, thus augmenting DOX-mediated anticancer effect. Compared to free DOX molecules, the DOX@H-PEG-CSPNs appreciably suppressed TRAMP-C1 tumor growth in vivo, thereby showing great promise in improving DOX chemotherapy.
Assuntos
Quitosana , Nanopartículas , Neoplasias , Humanos , Quitosana/uso terapêutico , Cebolas , Polietilenoglicóis/química , Micelas , Doxorrubicina/química , Polímeros/química , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Concentração de Íons de Hidrogênio , Nanopartículas/química , Microambiente TumoralRESUMO
Owing to its high recurrence rate, gastric cancer (GC) is the leading cause of tumor-related deaths worldwide. Besides surgical treatment, chemotherapy is the most commonly used treatment against GC. However, the adverse events associated with chemotherapy use limit its effectiveness in GC treatment. In this study, we investigated the effects of using combinations of low-dose 5-fluorouracil (5-FU; 0.001 and 0.01 mM) with different concentrations of escitalopram oxalate (0.01, 0.02, 0.06, and 0.2 mM) to evaluate whether the assessed combination would have synergistic effects on SNU-1 cell survival. 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.06 mM) administered over 24 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Moreover, 5-FU (0.001 mM) + escitalopram oxalate (0.02 or 0.06 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.02, 0.06, or 0.2 mM) administered over 48 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Compared with controls, SNU-1 cells treated with 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) exhibited significantly increased levels of annexin V staining, reactive oxygen species, cleaved poly (ADP-ribose) polymerase, and caspase-3 proteins. Furthermore, 5-FU (12 mg/kg) + escitalopram oxalate (12.5 mg/kg) significantly attenuated xenograft SNU-1 cell proliferation in nude mice. Our study is the first to report the synergistic effects of the combinational use of low-dose 5-FU and escitalopram oxalate on inhibiting SNU-1 cell proliferation. These findings may be indicative of an alternative option for GC treatment.
Assuntos
Fluoruracila , Neoplasias Gástricas , Animais , Camundongos , Humanos , Fluoruracila/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Escitalopram , Camundongos Nus , Apoptose , Proliferação de Células , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer with poor prognosis. Although recent research has indicated that selective serotonin reuptake inhibitors (SSRIs), including escitalopram, have anticancer effects, little is known about the effects of escitalopram on HCC. METHODS: Both in vitro and in vivo studies were conducted to verify the potentials of escitalopram on HCC treatment. To explore whether the effects of escitalopram are clinically consistent with laboratory findings, a nationwide population-based cohort study was also adopted to examine the association between escitalopram and HCC risk. RESULTS: As compared with THLE-3 cells, escitalopram significantly inhibited the proliferation of HepG2 and Huh-7 cells. Specifically, escitalopram significantly induced autophagy in HepG2 and Huh-7 cells by increasing the LC3-II/LC3-I ratio and the expression of ATG-3, ATG-5, ATG-7, and Beclin-1 proteins. Moreover, escitalopram significantly inhibited the growth of xenografted Huh-7 cells in SCID mice that were treated with 12.5 mg/kg escitalopram. Accordingly, the risk of HCC was negatively correlated with escitalopram use. CONCLUSIONS: These findings provided evidence supporting the therapeutic potential of escitalopram for HCC. Both laboratory and nationwide population-based cohort evidence demonstrated the attenuated effects of escitalopram on HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Autofagia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Escitalopram , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos SCIDRESUMO
Zoledronic acid (ZA), a third-generation bisphosphonate, has been extensively used to treat osteoporosis and cancer bone metastasis and demonstrated to suppress proliferation of varied cancer cells and selectively kill tumor-associated microphages (TAMs). However, the clinical applications of ZA in extraskeletal tumor treatment are largely restricted due to its rapid renal clearance and binding to bones. In this study, to promote intracellular delivery of ZA for amplified antitumor efficacy, tumor acidity-responsive polymeric nanoparticles with high ZA payload (ca. 12.3 wt%) and low premature ZA leakage were designed. As a pivotal material for surface coating, the acidity-sensitive and amphiphilic methoxy poly(ethylene glycol) (mPEG)-benzoic imine-octadecane (C18) (mPEG-b-C18) was synthesized by conjugation of mPEG-CHO with 1-octadecylamine upon Schiff base reaction. Through tailor-made co-assembly of the hydrophobic poly(lactic-co-glycolic acid) (PLGA), amphiphilic tocopheryl polyethylene glycol succinate (TPGS) and mPEG-b-C18 to encapsulate ionic complexes composed of ZA molecules and branched poly(ethylenimine) (PEI) segments, the attained therapeutic polymeric nanoparticles, characterized to have a hydrophobic PLGA/ZA/PEI-constituted core covered with mPEG-b-C18 and TPGS, were able to not only detach mPEG shielding upon acidity-triggered hydrolysis of benzoic imine bonds but also expose surface positive charges of protonated PEI segments. The in vitro cellular uptake and cytotoxicity studies demonstrated that the internalization of acidity-sensitive ZA-encapsulated nanoparticles by TRAMP-C1 mouse prostate cancer cells and murine macrophages RAW 264.7 was considerably promoted upon acidity-elicited PEG detachment and surface charge conversion, thus remarkably boosting intracellular ZA delivery and anticancer potency. Compared to PEG non-detachable ZA-loaded nanoparticles with poor tumor deposition and antitumor effect, the PEG-detachable ZA-carrying nanoparticles markedly accumulated in TRAMP-C1 solid tumors in vivo and inhibited tumor growth, thereby increasing the survival rate of the treated mice. The collective data suggest the great promise of tumor acidity-sensitive ZA-carrying hybrid nanoparticles in the treatment of extraskeletal solid tumors.
Assuntos
Nanopartículas , Neoplasias , Polietilenoglicóis/química , Animais , Iminas , Masculino , Camundongos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , Polímeros/química , Ácido Zoledrônico/farmacologia , Ácido Zoledrônico/uso terapêuticoRESUMO
To achieve effective intracellular anticancer drug release for boosted antitumor efficacy, the acidity-responsive nanovehicles for doxorubicin (DOX) delivery were fabricated by tailor-made co-assembly of amphiphilic PEGylated chitosan20k and hydrophobic poly(lactic-co-glycolic acid) (PLGA) segments at pH 8.5. The attained DOX-loaded PEGylated chitosan20k/PLGA nanoparticles (DOX-PC20kPNs) were characterized to have a spherical shape composed of drug-encapsulated chitosan20k/PLGA-constituted solid core surrounded by hydrophilic PEG shells. Compared to non-pH-sensitive DOX-loaded PLGA nanoparticles (DOX-PNs), the DOX-PC20kPNs displayed outstanding colloidal stability under serum-containing condition and tended to swell in weak acidic milieu upon increased protonation of chitosan20k within hybrid cores, thus accelerating drug release. The in vitro cellular uptake and cytotoxicity studies revealed that the DOX-PC20kPNs after being endocytosed by prostate TRAMP-C1 cancer cells rapidly liberated drug, thus promoting drug accumulation in nuclei to enhance anticancer potency. Moreover, the hydrated PEG shells of DOX-PC20kPNs remarkably reduced their uptake by macrophage-like RAW264.7 cells. Importantly, in vivo animal findings showed that the DOX-PC20kPNs exhibited the capability of inhibiting TRAMP-C1 tumor growth superior to free hydrophobic DOX molecules and DOX-PNs, demonstrating the great potential in cancer chemotherapy.
Assuntos
Antineoplásicos , Quitosana , Nanopartículas , Neoplasias , Animais , Antineoplásicos/farmacologia , Quitosana/química , Doxorrubicina/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Masculino , Nanopartículas/química , Polietilenoglicóis/químicaRESUMO
Purpose: To examine the effects of risperidone, an atypical antipsychotic agent, on gastric cancer. Methods: A triangulation method comprising bench studies, including cell and animal experiments, and a retrospective cohort study, was subsequently performed. Results: The bench study indicated that risperidone exerted more prominent tumor inhibition effects than other atypical antipsychotics on the proliferation of KATO-III cells, a human gastric cancer cell line. Significant and dose-dependent cell viability was observed in Hs27 cells (control cells) in the presence of risperidone compared with in KATO-III cells. Both in vivo and in vitro results indicated that risperidone significantly inhibited the proliferation of KATO-III cells by inducing ROS and apoptosis, and that it suppressed the growth of xenografted KATO-III tumors in nude mice. In addition, the population-based cohort study found that risperidone users had reduced risks of gastric cancer compared with non-users, with lowered adjusted hazard ratios (HRs) for two induction periods (HR = 0.75; 95% confidence interval [CI] 0.68-0.83 for the one-year induction period, and HR = 0.68; 95% CI 0.61-0.75 for the two-year induction period). Conclusion: The findings are consistent with anticancer effects associated with risperidone, but further research and evaluations are warranted.
RESUMO
Colorectal cancer (CRC) is a leading cause of cancer-related death globally. Although surgery is still the major method for CRC therapy, the adoption of alternative treatments, such as traditional Chinese medicine (TCM), for CRC treatment is increasing. Our previous study has indicated the anti-breast cancer activity of T33 (a TCM formula). Interestingly, a major ingredient in T33, Baishao (Paeoniae Radix Alba), was reported to have antiproliferative effects on CRC cells. Therefore, this study further validated the influences of T33 on HT-29 and Caco2 cells both in vitro and in vivo. Viability and migration assays were performed to analyze the influences of T33 on proliferation and migratory activity of HT-29 and Caco2 cells. Immunofluorescence (IF) staining and immunoblotting were performed to confirm T33-induced autophagy in HT-29 and Caco2 cells. Xenograft HT-29 tumors were generated to test the effects of T33 in vivo. Significantly reduced survival and migratory activity were observed in both HT-29 and Caco2 cells treated with T33 along with apparently increased LC3-II protein. Significantly decreased p62/SQSTM1 protein, increased LC3-II/LC3-I ratio, and elevated amounts of Atg7, Atg5, and Beclin-1 proteins were detected in both HT-29 and Caco2 cells treated with T33. Moreover, the volume of xenograft HT-29 tumors was significantly lower in mice receiving 200 or 600 mg/kg T33 than in control-treated mice. These findings indicate that T33 exerts anti-CRC activity by inducing autophagy and suggest the potential of T33 for CRC treatment.
Assuntos
Neoplasias Colorretais , Medicina Tradicional Chinesa , Animais , Apoptose , Autofagia , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/metabolismo , Humanos , CamundongosRESUMO
Liver cancer is a leading cause of cancerrelated mortality globally. Since hepatitis virus infections have been strongly associated with the incidence of liver cancer, studies concerning the effects of antiviral drugs on liver cancer have attracted great attention in recent years. The present study investigated the effects of two antihepatitis virus drugs, lamivudine and ribavirin, and one antiinfluenza virus drug, oseltamivir, on liver cancer cells to assess alternative methods for treating liver cancer. MTT assays, wound healing assays, Τranswell assays, flow cytometry, immunoblotting, ELISA, immunofluorescence staining and a xenograft animal model were adopted to verify the effects of lamivudine, ribavirin and oseltamivir on liver cancer cells. Treatment with ribavirin and oseltamivir for 24 and 48 h significantly decreased the viability of both Huh-7 and HepG2 cells compared with that of THLE3 cells in a dosedependent manner. The subsequent investigations focused on oseltamivir, considering the more serious clinical adverse effects of ribavirin than those of oseltamivir. Significantly decreased migration and invasion were observed in both Huh-7 and HepG2 cells that were treated with oseltamivir for 24 and 48 h. In addition, oseltamivir significantly increased autophagy in Huh7 cells, as revealed by the significantly higher ratios of LC3II/LC3I, increased expression of Beclin1, and decreased expression of p62, whereas no significant increases in the expression of apoptosisrelated proteins, including Apaf1, cleaved caspase3, and cleaved PARP1, were detected. Notably, apoptosis and autophagy were significantly increased in HepG2 cells in the presence of oseltamivir, as revealed by the significant increases in the expression of Apaf1, cleaved caspase3, and cleaved PARP1, the higher ratios of LC3II/LC3I, the increased expression of Beclin1, and the decreased expression of p62. Additionally, significant inhibitory effects of oseltamivir on xenografted Huh7 cells in athymic nude mice were observed. The present study, for the first time to the best of our knowledge, reported the differential effects of oseltamivir on inducing liver cancer cell death both in vitro and in vivo and may provide an alternative approach for treating liver cancer.
Assuntos
Antivirais/farmacologia , Autofagia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Oseltamivir/farmacologia , Animais , Apoptose , Carcinoma Hepatocelular/patologia , Proliferação de Células , Feminino , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Invasividade Neoplásica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: We aimed to investigate the associations of breast cancer (BC) and cancer-related chemotherapies with cytokine levels, and cognitive function. METHODS: We evaluated subjective and objective cognitive function in BC patients before chemotherapy and 3~9 months after the completion of chemotherapy. Healthy volunteers without cancer were also compared as control group. Interleukins (IL) 2, 4, 5, 6, 10, 12p70, 13, 17A, 1ß, IFNγ, and TNFα were measured. Associations of cancer status, chemotherapy and cytokine levels with subjective and objective cognitive impairments were analyzed using a regression model, adjusting for covariates, including IQ and psychological distress. RESULTS: After adjustment, poorer performance in semantic verbal fluency was found in the post-chemotherapy subgroup compared to controls (p = 0.011, η2 = 0.070); whereas pre-chemotherapy patients scored higher in subjective cognitive perception. Higher IL-13 was associated with lower semantic verbal fluency in the post-chemotherapy subgroup. Higher IL-10 was associated with better perceived cognitive abilities in the pre-chemotherapy and control groups; while IL-5 and IL-13 were associated with lower perceived cognitive abilities in pre-chemotherapy and control groups. Our findings from mediation analysis further suggest that verbal fluency might be affected by cancer status, although mediated by anxiety. CONCLUSIONS: Our findings suggest that verbal fluency might be affected by cancer status, although mediated by anxiety. Different cytokines and their interactions may have different roles of neuroinflammation or neuroprotection that need further research.
RESUMO
INTRODUCTION: Glioblastoma multiforme (GBM) is the most aggressive glioma, and its diffuse nature makes resection of it difficult. Moreover, even with the administration of postoperative radiotherapy and chemotherapy, prolonged remission is often not achieved. Hence, innovative or alternative treatments for GBM are urgently required. Traditional Chinese herbs and their functional components have long been used in the treatment of various cancers, including GBM. The current study investigated the antitumor activity of Wedelia chinensis and its major functional components, luteolin and apigenin, on GBM. MATERIALS AND METHODS: MTT assay, Transwell migration assay, and flow cytometry analysis were adopted to assess the cell viability, invasive capability, and cell cycle. Immunofluorescence staining and Western blotting were used to detect the expressions of apoptotic and autophagy-related signaling molecules. RESULTS: The W. chinensis extract (WCE) significantly inhibited the proliferation and invasive ability of both GBM8401 and U-87MG cells in a dose-dependent manner. Moreover, differential effects of WCE on GBM8401 and U-87MG cells were observed: WCE induced apoptosis in GBM8401 cells and autophagy in U-87MG cells. Notably, WCE had significant effects in reducing the cell survival and invasive capability of both GBM8401 and U-87MG cells than the combination of luteolin and apigenin. CONCLUSIONS: Taken together, these findings indicate the potential of using WCE and the combination of luteolin and apigenin for GBM treatment. However, further investigations are warranted before considering recommending the clinical use of WCE or the combination of luteolin and apigenin as the standard for GBM treatment.