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1.
ACS Nano ; 18(11): 8083-8098, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38456744

ABSTRACT

Active polymetallic atomic clusters can initiate heterogeneous catalytic reactions in the tumor microenvironment, and the products tend to cause manifold damage to cell metabolic functions. Herein, bimetallic PtPd atomic clusters (BAC) are constructed by the stripping of Pt and Pd nanoparticles on nitrogen-doped carbon and follow-up surface PEGylation, aiming at efficacious antineoplastic therapy through heterogeneous catalytic processes. After endocytosed by tumor cells, BAC with catalase-mimic activity can facilitate the decomposition of endogenous H2O2 into O2. The local oxygenation not only alleviates hypoxia to reduce the invasion ability of cancer cells but also enhances the yield of •O2- from O2 catalyzed by BAC. Meanwhile, BAC also exhibit peroxidase-mimic activity for •OH production from H2O2. The enrichment of reactive oxygen species (ROS), including the radicals of •OH and •O2-, causes significant oxidative cellular damage and triggers severe apoptosis. In another aspect, intrinsic glutathione (GSH) peroxidase-like activity of BAC can indirectly upregulate the level of lipid peroxides and promote ferroptosis. Such deleterious redox dyshomeostasis caused by ROS accumulation and GSH consumption also results in immunogenic cell death to stimulate antitumor immunity for metastasis suppression. Collectively, this paradigm is expected to inspire more facile designs of polymetallic atomic clusters in disease therapy.


Subject(s)
Antineoplastic Agents , Ferroptosis , Neoplasms , Humans , Hydrogen Peroxide , Reactive Oxygen Species , Apoptosis , Peroxidases , Antineoplastic Agents/pharmacology , Catalysis , Glutathione , Cell Line, Tumor , Neoplasms/drug therapy , Tumor Microenvironment
2.
Biomaterials ; 305: 122446, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38150772

ABSTRACT

Traditional Fe-based Fenton reaction for inducing oxidative stress is restricted by random charge transfer without oriental delivery, and the resultant generation of reactive oxygen species (ROS) is always too simplistic to realize a satisfactory therapeutic outcome. Herein, FeNv/CN nanosheets rich in nitrogen vacancies are developed for high-performance redox dyshomeostasis therapy after surface conjugation with polyethylene glycol (PEG) and cyclic Arg-Gly-Asp (cRGD). Surface defects in FeNv/CN serve as electron traps to drive the directional transfer of the excited electrons to Fe atom sites under ultrasound (US) actuation, and the highly elevated electron density promote the catalytic conversion of H2O2 into ·OH. Meanwhile, energy band edges of FeNv/CN favor the production of 1O2 upon interfacial redox chemistry, which is enhanced by the optimal separation/recombination dynamics of electron/hole pairs. Moreover, intrinsic peroxidase-like activity of FeNv/CN contributes to the depletion of reductant glutathione (GSH). Under the anchoring effect of cRGD, PEGylated FeNv/CN can be efficiently enriched in the tumorous region, which is ultrasonically activated for concurrent ROS accumulation and GSH consumption in cytosolic region. The deleterious redox dyshomeostasis not only eradicates primary tumor but also suppresses distant metastasis via antitumor immunity elicitation. Collectively, this study could inspire more facile designs of chalybeates for medical applications.


Subject(s)
Hydrogen Peroxide , Hyperaldosteronism , Neoplasms , Nitriles , Humans , Reactive Oxygen Species , Oxidation-Reduction , Ultrasonography , Glutathione , Cell Line, Tumor
3.
Small ; : e2307404, 2023 Dec 06.
Article in English | MEDLINE | ID: mdl-38054772

ABSTRACT

Mitochondria are core regulators of tumor cell homeostasis, and their damage has become an arresting therapeutic modality against cancer. Despite the development of many mitochondrial-targeted pharmaceutical agents, the exploration of more powerful and multifunctional medications is still underway. Herein, oxygen vacancy-rich BiO2-x wrapped with CaCO3 (named BiO2-x @CaCO3 /PEG, BCP) is developed for full-fledged attack on mitochondrial function. After endocytosis of BCP by tumor cells, the CaCO3 shell can be decomposed in the acidic lysosomal compartment, leading to immediate Ca2+ release and CO2 production in the cytoplasm. Near-infrared irradiation enhances the adsorption of CO2 onto BiO2-x defects, which enables highly efficient photocatalysis of CO2 -to-CO. Meanwhile, such BiO2-x nanosheets possess catalase-, peroxidase- and oxidase-like catalytic activities under acidic pH conditions, allowing hypoxia relief and the accumulation of diverse reactive oxygen species (ROS) in the tumor microenvironment. Ca2+ overload-induced ion dyshomeostasis, CO-mediated respiratory chain poisoning, ROS-triggered oxidative stress aggravation, and cytosolic hyperoxia can cause severe mitochondrial disorders, which further lead to type I cell death in carcinoma. Not only does BCP cause irreversible apoptosis, but immunogenic cell death is simultaneously triggered to activate antitumor immunity for metastasis inhibition. Collectively, this platform promises high benefits in malignant tumor therapy and may expand the medical applications of bismuth-based nanoagents.

4.
Small ; 19(21): e2300244, 2023 05.
Article in English | MEDLINE | ID: mdl-36843276

ABSTRACT

Energy band structure of inorganic nano-sonosensitizers is usually optimized by surface decoration with noble metals or metal oxide semiconductors, aiming to enhance interfacial charge transfer, augment spin-flip and promote radical generation. To avoid potential biohazards of metallic elements, herein, metal-free graphitic carbon nitride quantum dots (g-C3 N4 QDs) are anchored onto hollow mesoporous TiO2 nanostructure to formulate TiO2 @g-C3 N4 heterojunction. The direct Z-scheme charge transfer significantly improves the separation/recombination dynamics of electron/hole (e- /h+ ) pairs upon ultrasound (US) stimulation, which promotes the yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH). The conjugated g-C3 N4 QDs with peroxidase-mimic activity further react with the elevated endogenous H2 O2 and aggravate oxidative stress. After loading prodrug romidepsin (RMD) in TiO2 @g-C3 N4 , stimulus-responsive drug delivery can be realized by US irradiation. The disulfide bridge of the released RMD tends to be reduced by glutathione (GSH) into a monocyclic dithiol, which arrests cell cycle in G2/M phase and evokes apoptosis through enhanced histone acetylation. Importantly, reactive oxygen species accumulation accompanied by GSH depletion is devoted to deleterious redox dyshomeostasis, leading to augmented systemic oncotherapy by eliciting antitumor immunity. Collectively, this paradigm provides useful insights in optimizing the performance of TiO2 -based nano-sonosensitizers for tackling critical diseases.


Subject(s)
Oxides , Oxidation-Reduction , Ultrasonography , Acetylation
5.
Small ; 18(38): e2203080, 2022 09.
Article in English | MEDLINE | ID: mdl-35989099

ABSTRACT

The therapeutic exploration of nano-zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano-sonosensitizer of ZrO2- x @Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen-deficient ZrO2- x . Compared to 3.09 eV of nano-ZrO2- x , the bandgap of ZrO2- x @Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e- /h+ separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase-mimic activity can promote 1 O2  generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), US-stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals (• R). US-triggered reactive oxygen species generation and hyperthermia-induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic-thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof-of-concept paradigm expands the medical use of nano-zirconia and provides useful insights for its therapeutic perspectives.


Subject(s)
Neoplasms , Ultrasonic Therapy , Animals , Catalase/metabolism , Cell Line, Tumor , Immune Checkpoint Inhibitors , Neoplasms/therapy , Oxidative Stress , Oxygen , Platinum , Propane , Reactive Oxygen Species/metabolism , Singlet Oxygen , Thermodynamics , Tumor Microenvironment
6.
ACS Nano ; 16(8): 12118-12133, 2022 08 23.
Article in English | MEDLINE | ID: mdl-35904186

ABSTRACT

To date, the construction of heterogeneous interfaces between sonosensitizers and other semiconductors or noble metals has aroused increasing attention, owing to an enhanced interface charge transfer, augmented spin-flip, and attenuated activation energy of oxygen. Here, a smart therapeutic nanoplatform is constructed by surface immobilization of glucose oxidase (GOx) onto a TiO2@Pt Schottky junction. The sonodynamic therapy (SDT) and starvation therapy (ST) mediated by TiO2@Pt/GOx (TPG) promote systemic tumor suppression upon hypoxia alleviation in tumor microenvironment. The band gap of TiO2@Pt is outstandingly decreased to 2.9 eV, in contrast to that of pristine TiO2. The energy structure optimization enables a more rapid generation of singlet oxygen (1O2) and hydroxyl radicals (•OH) by TiO2@Pt under ultrasound irradiation, resulting from an enhanced separation of hole-electron pair for redox utilization. The tumorous reactive oxygen species (ROS) accumulation and GOx-mediated glucose depletion facilitate oxidative damage and energy exhaustion of cancer cells, both of which can be tremendously amplified by Pt-catalyzed oxygen self-supply. Importantly, the combinatorial therapy triggers intense immunogenetic cell death, which favors a follow-up suppression of distant tumor and metastasis by evoking antitumor immunity. Collectively, this proof-of-concept paradigm provides an insightful strategy for highly efficient SDT/ST, which possesses good clinical potential for tackling cancer.


Subject(s)
Neoplasms , Ultrasonic Therapy , Humans , Platinum , Tumor Microenvironment , Glucose , Neoplasms/drug therapy , Neoplasms/pathology , Reactive Oxygen Species/metabolism , Glucose Oxidase/pharmacology , Glucose Oxidase/metabolism , Oxygen , Cell Line, Tumor
7.
Nanoscale Res Lett ; 13(1): 380, 2018 Nov 27.
Article in English | MEDLINE | ID: mdl-30483904

ABSTRACT

Enhanced MRI (magnetic resonance imaging) plays a vital role in the early detection of tumor but with low specificity. Molecular imaging of angiogenesis could efficiently deliver contrast agents to the tumor site by specific targeted carriers. We designed and synthesized dual-targeted paramagnetic liposomes functionalized with two angiogenesis-targeting ligands, the αVß3 integrin-specific RGD (Arg-Gly-Asp) and the neuropilin-1 (NRP-1) receptor-specific ATWLPPR (Ala-Thr-Trp-Leu-Pro-Pro-Arg) (A7R). These liposomes were proved to be in the nanoparticle range and demonstrated to effectively encapsulate paramagnetic MRI contrast agents Gd-DTPA (gadolinium-diethylenetriamine pentaacetic acid). T1 relaxivity of various liposome formulations was lower than pure Gd-DTPA but with no statistically significant difference. In vitro cellular uptake and competitive inhibition assay showed the higher binding affinity of dual-targeted liposomes to HUVECs (human umbilical vein endothelial cells) and A549 cells compared with pure Gd-DTPA, non-targeted, and single-targeted liposomes, which was proved to be mediated by the binding of RGD/ανß3-integrin and A7R/NRP1. For MR imaging of mice bearing A549 cells in vivo, dual-targeted liposomes reached the highest SER (signal enhancement rate) value with a significant difference at all experimental time points. It was about threefold increase compared to pure Gd-DTPA and non-targeted liposomes and was 1.5-fold of single-targeted liposomes at 2 h post injection. The SER was lowered gradually and decreased only by 40% of the peak value in 6 h. Dual-targeted liposomes were likely to exert a synergistic effect and the specificity of delivering Gd-DTPA to the tumor site. Therefore, dual-ανß3-integrin-NRP1-targeting paramagnetic liposome with a RGD-ATWLPPR heterodimeric peptide might be a potent system for molecular imaging of tumor.

8.
Zhongguo Fei Ai Za Zhi ; 19(12): 864-870, 2016 Dec 20.
Article in Chinese | MEDLINE | ID: mdl-27978873

ABSTRACT

BACKGROUND: Non-small cell lung cancer (NSCLC) presents the highest morbidity and mortality among malignant tumors worldwide. The overall effective rate of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is 30% to 40%, and PFS (progression-free sruvival) is 12 months. However, EGFR-TKI resistance is typical in clinical observations, and this phenomenon significantly affects tumor suppression. To overcome this resistance, a new prognostic factor associated with lung cancer drug resistance should be discovered. This study investigated the relationship between the inhibitor of differentiation 1 (ID1) and non-small cell lung cancer EGFR-TKI resistance in vivo and in vitro to determine any statistical significance and discuss the underlying mechanism. METHODS: Western blot and qRT-PCR were used to quantify the expression of ID1 in lung cancer. IHC was used to detect the expression of ID1 in pathological tissues (lung cancer tissues and adjacent tissues). MTT was used to detect cell proliferation, in which the cells were treated with gefitinib after being transfected by ID1 slow virus vector. Lung cancer cells were inoculated in nude mice until the tumor diameter grew to certain measurement. Gefitinib treatment was started, and the tumor volume was estimated. RESULTS: ID1 was highly expressed in NSCLC (P<0.05). Both ID1 expression and drug resistance of EGFR-TKI in NSCLC were positively correlated (P<0.05). The treatment group with gefitinib showed obviously less expression than the control group. CONCLUSIONS: ID1 is highly expressed in NSCLC. ID1 expression was positively related to drug resistance of EGFR-TKI in NSCLC. Gefitinib can be used to effectively treat NSCLC, and the mechanism may be associated with an increased level of STAT3 phosphorylation.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm , Inhibitor of Differentiation Protein 1/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Inhibitor of Differentiation Protein 1/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude
9.
Oncol Lett ; 11(1): 535-542, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26870244

ABSTRACT

The present study aimed to explore the role of integrin ß1 and the relevant signaling pathways in acquired gefitinib resistance in non-small cell lung cancer (NSCLC). The inhibitory effects of gefitinib, with or without LY294002, on cellular proliferation were evaluated by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were analyzed by flow cytometry, while western blotting was used to evaluate the expression of EGFR, phosphorylated (phospho)-EGFR, protein kinase B (Akt), phospho-Akt, extracellular signal-regulated kinase (Erk) and phospho-Erk. The gene expression profiles of PC9 and PC9/G cells were determined by DNA microarray. Integrin ß1 was knocked down in PC9/G cells by transiently transfected short interfering RNA (siRNA). A scrambled siRNA sequence was used as a control. Apoptosis of transfected cells was determined by Annexin V-phycoerythrin-Cy5/propidium iodide staining. Sequencing products were amplified by nested PCR. The resistant index of PC9/G cells to gefitinib was ~138- to 256-fold higher than that of PC9 cells, and this resistance was accompanied by significant increase in integrin ß1 expression in PC9/G cells. Knockdown of integrin ß1 with short hairpin RNA in PC9/G cells markedly inhibited proliferation and enhanced apoptosis in response to gefitinib, restoring the sensitivity of PC9/G cells gefitinib. Phosphoinositide 3-kinase (PI3K)/Akt activation was observed in PC9/G cells in the presence of gefitinib and the sensitivity of PC9/G cells to gefitinib was also able to be restored by PI3K/Akt pathway inhibitor LY294002. Finally, knockdown of integrin ß1 significantly reduced the levels of phospho-Akt. These findings suggest that integrin ß1 signaling via the PI3K/Akt pathway may be a significant mechanism underlying gefitinib resistance, and may potentially present an alternative therapeutic target for the treatment of NSCLC unresponsive to EGFR inhibitors.

10.
Article in Chinese | MEDLINE | ID: mdl-26653804

ABSTRACT

OBJECTIVE: To investigate the effects of different concentrations of indium chloride (InCl3) on the proliferation of human lung epithelial (Beas-2B) cells and its potential mechanism. METHODS: Beas-2B cells were exposed to different concentrations of InCl3 (0.3, 1.0, 3.0, 10.0, 30.0, 90.0, 270.0, and 810.0 µmol/L) for 24, 48, and 72 h, respectively. The effects of InCl3 on cell proliferation were determined by the CCK-8 assay. The effects of InCl3 on apoptosis were evaluated using annexin V-PI staining followed by flow cytometry. The level of intracellular reactive oxygen species (ROS) in Beas-2B cells after exposure to InCl3 was determined using 2', 7'-dichlorofluorescein diacetate labeling followed by flow cytometry. RESULTS: Compared with the control group, InCl3 at a relatively low concentration (0.3~3.0 µmol/L) significantly promoted cell proliferation (P < 0.05), while InCl3 at a relatively high concentration (30.0~80.0 µmol/L) significantly inhibited cell proliferation after 72 h (P < 0.05). InCl3 at a concentration of 0.3 µmol/L failed to induce apoptosis within 72 h; however, InCl3 at a concentration of 30.0 or 810.0 µmol/L induced substantial early apoptosis after 72 h. Compared with the control group, cells exposed to 0.3 µmol/L InCl3 showed a slight decrease in the level of intracellular ROS within 72 h, while cells exposed to 30.0 or 810.0 µmol/L InCl3 showed a significant increase in the level of intracellular ROS after 72 h (P < 0.05). CONCLUSION: At a low concentration, InCl3 stimulates cell proliferation by reducing intracellular ROS. However, at a high concentration, InCl3 inhibits cell viability by elevating intracellular ROS and inducing apoptosis.


Subject(s)
Cell Proliferation/drug effects , Epithelial Cells/drug effects , Indium/toxicity , Apoptosis/drug effects , Cell Survival/drug effects , Flow Cytometry , Humans , Reactive Oxygen Species
11.
Oncotarget ; 5(17): 7902-16, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-25277203

ABSTRACT

Several randomized trials have demonstrated non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations can achieve favorable clinical outcomes on treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR mutation is considered as a predictive marker for efficacy of EGFR-TKIs in NSCLC. Here we show miR-200c overexpression was correlated with the epithelial phenotype and sensitivity to gefitinib in EGFR wild-type NSCLC cell lines. Up-regulated miR-200c could regain the sensitivity to gefitinib in the EGFR wild-type cell lines and miR-200c could regulate epithelial to mesenchymal transition through PI3K/AKT and MEK/ERK pathways. NSCLC patients at advanced stage (N=150) who received EGFR-TKIs (gefitinib or erlotinib) as second- or third-line therapy from September 2008 to December 2012 were included in the study. In 66 NSCLC patients with wild-type EGFR, high levels of miR-200c expression was associated with higher disease control rate (DCR), longer progression-free survival (PFS) and longer overall survival (OS) compared with low miR-200c expression subgroup. In the subgroup with EGFR mutation, the trend remained the same but not statistically significant. Overall, these findings indicated that miR-200c might be a predictive biomarker for sensitivity to EGFR-TKIs in advanced NSCLC patients with wild-type EGFR.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/genetics , MicroRNAs/genetics , Aged , Antineoplastic Agents/pharmacology , Blotting, Western , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , ErbB Receptors/genetics , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Protein Kinase Inhibitors/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation
12.
Pulm Pharmacol Ther ; 28(1): 41-48, 2014 Jun.
Article in English | MEDLINE | ID: mdl-23707949

ABSTRACT

BACKGROUND: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) presents great challenges in the treatment of non-small cell lung cancer (NSCLC) patients, while the mechanisms are still not well understood. The ß-catenin signaling pathway has been found to be associated with chemoresistance and can activate the EGFR and its downstream pathways. This study aimed to investigate the role of ß-catenin in acquired resistance to EGFR-TKIs in NSCLC cell lines. METHODS: The expression and transcriptional activity of ß-catenin were measured in both the NSCLC cell line PC9 and its sub-line PC9/AB(2) which has acquired resistance to gefitinib. Knockdown and overexpression of ß-catenin in the PC9/AB(2) and PC9 cells were performed. The cell survival rate and the activation of the EGFR and its downstream pathways were detected in the two cell lines after transfection. RESULTS: Nuclear translocation of ß-catenin was increased in the PC9/AB(2) cells and the baseline expression of members of the ß-catenin signaling pathway was also higher in the PC9/AB(2) cells. Knocking down the expression of ß-catenin increased the sensitivity of the PC9/AB(2) cells to gefitinib by blocking the activation of the EGFR downstream pathways, while ß-catenin overexpression improved PC9 cells resistance to gefitinib by enhancing the activation of the EGFR and its downstream signaling. CONCLUSION: ß-catenin plays an important role in acquired resistance to EGFR-TKIs in NSCLC cell lines and may be a potential therapeutic target for NSCLC patients who have failed to respond to targeted therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Quinazolines/pharmacology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , Gefitinib , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Signal Transduction/drug effects , beta Catenin/genetics , beta Catenin/metabolism
13.
Zhonghua Bing Li Xue Za Zhi ; 42(7): 455-9, 2013 Jul.
Article in Chinese | MEDLINE | ID: mdl-24246864

ABSTRACT

OBJECTIVE: To explore the effect of Wnt signaling suppression on proliferation of non small cell lung cancer to gefitinib, and its related mechanisms. METHODS: PC9 and PC9/AB2 cells of both gefitinib sensitive and resistant were treated with different concentrations of gefitinib, and the proliferation index was measured using CCK8 kit. The members of Wnt signaling pathway were detected by Western blot. Dual luciferase reportor gene assay (TOP Flash) was used to document the transcriptional level of ß-catenin. ß-catenin siRNA was transfected into PC9/AB2 cells to suppress the Wnt signaling transcription, followed by treatment with different concentrations of gefitinib. Western blot was then used to detect the expression of EGFR and its downstream signaling after inhibit the expression of ß-catenin. RESULTS: Treating with different concentrations of gefitinib, the resistance of PC9/AB2 cells to gefitinib was significantly increased (P < 0.05). The members of Wnt signaling expressed at higher level in PC9/AB2 cells than in PC9 cells (t = 24.590, P = 0.000). TOP Flash examination showed that the endogenous transcriptional activity of Wnt signaling was higher in PC9/AB2 cell than that in PC9 cell (t = 4.983, P = 0.008). Compared with the negative control group, apoptotic rate and sensitivity to gefitinib significantly increased in interfered group (P < 0.05). The expression of p-ERK1/2 significantly decreased after Wnt signaling suppression, although other proteins showed no significant alterations. CONCLUSION: Suppressing the activity of Wnt signaling can partly reverse the celluar resistance to gefitinib in non small cell lung cancer.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , Lung Neoplasms , Quinazolines/pharmacology , Wnt Signaling Pathway/drug effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Apoptosis , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation , Dose-Response Relationship, Drug , Gefitinib , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation , Quinazolines/administration & dosage , beta Catenin/metabolism
14.
Zhonghua Zhong Liu Za Zhi ; 35(2): 103-8, 2013 Feb.
Article in Chinese | MEDLINE | ID: mdl-23714663

ABSTRACT

OBJECTIVE: To detect the inhibitory effect of a p38MAPK inhibitor SB203580 in combination with gefitinib on lung adenocarcinoma cell line PC-9 cells and A549 cells, and its cellular and molecular mechanisms of action. METHODS: MTT test was used to detect the growth inhibition of PC-9 and A549 cells by SB203580 alone and in combination with gefitinib. Cell apoptosis and cell cycles were determined by flow cytometry. The expressions of p38 and phosphorylated -p38 proteins in the two cell lines were analyzed by immunofluorescence microscopy. The associated protein expression was determined by Western-blot. RESULTS: Compared with the SB203580 group and gefitinib group, the growth inhibition and cell apoptosis of PC-9 cells in the SB203580 + gefitinib group were significantly increased (P < 0.05). The inhibition rate of PC-9 cells of 2 µmol/L SB203580 + 0.01 µmol/L gefitinib group was (46.6 ± 2.4)%, significantly higher than that induced by 0.01 µmol/L gefitinib (12.7 ± 1.5%) (P < 0.05). Immunofluorescence microscopy showed a low expression of phosphorylated-p38 protein in A549 cells and high expression in PC-9 cells. Flow cytometry showed that PC-9 cells in the SB203580 + gefitinib group were (77.35 ± 2.83)% at G0/G1 phase, (3.38 ± 0.84)% at S phase, and (19.56 ± 1.99)% at G2/M phase. Western-blotting showed that compared with the control group, the expression of phosphorylated Akt and phospho-p38 proteins in PC-9 cells of the SB203580 + gefitinib group was almost completely suppressed. CONCLUSIONS: The results indicate that the small molecular inhibitor SB203580 can effectively enhance the inhibitory effect of gefitinib on lung adenocarcinoma PC-9 cells. The enhanced inhibitory effect of SB203580 may be correlated with the blockage of p38MAPK signal transduction pathway.


Subject(s)
Adenocarcinoma/pathology , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Imidazoles/pharmacology , Lung Neoplasms/pathology , Pyridines/pharmacology , Quinazolines/pharmacology , Adenocarcinoma/metabolism , Adenocarcinoma of Lung , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Drug Synergism , Enzyme Inhibitors/pharmacology , Gefitinib , Humans , Lung Neoplasms/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism
15.
Zhonghua Zhong Liu Za Zhi ; 35(11): 808-13, 2013 Nov.
Article in Chinese | MEDLINE | ID: mdl-24447476

ABSTRACT

OBJECTIVE: To construct angiogenesis-specific RGD10-NGR9 dual-targeting superparamagnetic iron oxide nanoparticles, and to evaluate its magnetic resonamce imaging (MRI) features in nude mice and potential diagnostic value in tumor MRI. METHODS: Dual-targeting peptides RGD10-NGR9 were designed and synthesized. Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles were synthesized by chemical co-precipitation method and the surface was modified to be hydrophilic by coating with dextran. The dual-targeting peptides RGD10-NGR9 were conjugated to USPIO. Cell binding affinity and up-taking ability of the dual-targeting USPIO nanoparticles to integrin ανß3-APN positive cells were subsequently tested by Prussian blue staining and phenanthroline colorimetry in vitro. The RGD10-NGR9 conjugated with USPIO was injected intravenously into xenograft mice, which were scanned by MRI at predetermined time points. The MRI and contrast-to-noise ratio (CNR) values were calculated to evaluate the ability of dual-targeting USPIO as a potential contrast agent in nude mice. RESULTS: P-CLN-Dextran-USPIO nanoparticles with stable physical properties were successfully constructed. The average diameter of Fe3O4 nanoparticles was 8-10 nm, that of Dextran-USPIO was about 20 nm and P-CLN-Dextran-USPIO had an average diameter about 30 nm. The in vitro studies showed a better specificity of dual-targeting USPIO nanoparticles on proliferating human umbilical vein endothelia cells (HUVEC). In vivo, RGD10-NGR9-USPIO showed a significantly reduced contrast in signal intensity and 2.83-times increased the CNR in the tumor MRI in xenograft mice. CONCLUSION: This novel synthesized RGD10-NGR9 dual-targeting USPIO is with better specific affinity in vitro and in vivo, and might be used as a molecular contrast agent for tumor angiogenesis MRI.


Subject(s)
Adenocarcinoma/diagnosis , Contrast Media , Dextrans , Lung Neoplasms/diagnosis , Magnetic Resonance Imaging , Magnetite Nanoparticles , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Aminopeptidases/analysis , Animals , Cell Line, Tumor , Cells, Cultured , Contrast Media/chemistry , Dextrans/chemistry , Ferrosoferric Oxide/metabolism , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Integrin alphaVbeta3/analysis , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Magnetite Nanoparticles/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Oligopeptides/chemistry , Particle Size , Signal-To-Noise Ratio
16.
Exp Ther Med ; 4(6): 1010-1016, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23226765

ABSTRACT

One of the target genes of pemetrexed (PEM), thymidylate synthase (TS), has been shown to have a close association with its efficacy. TS gene polymorphisms have been shown to be associated with the efficacy of antifolate treatment in enteron tumors. The purpose of this study was to investigate the clinical significance of TS gene polymorphisms in patients with advanced NSCLC receiving PEM-based treatment. The variable nucleoid tandem repeat in the 5'-UTR region was amplified and detected using fluorescently labeled multiplex short tandem repeat polymerase chain reaction. The polymorphism in the 3'-UTR region of the TS gene was detected using the Taqman probe. Efficacy of PEM was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. None of the genotypes were associated with gender, smoking status and age. Disease control rate (DCR), objective response rate (ORR) and progression-free survival (PFS) were similar between patients harboring 2R and 3R alleles (PFS, p=0.518; DCR, p=0.631; ORR, p=0.541), as well as those with a 6-bp insertion and 6-bp deletion (PFS, p=0.776; DCR, p=0.626; ORR, p=0.330). To study the combined effect of TS polymorphisms, the study population was divided into three groups: 2R&6 del, 2R&6 ins and 3R&6 del. No significant differences were observed among the different groups according to DCR (p=0.517), ORR (p=0.611) and PFS (p=0.938). In conclusion, polymorphisms of the TS gene do not appear to be a prognostic marker for advanced NSCLC patients receiving PEM-based treatment.

17.
Lung Cancer ; 77(2): 427-32, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22534668

ABSTRACT

BACKGROUND AND PURPOSE: Cisplatin is the major agent in the standard first-line chemotherapy for NSCLC. However, only a small portion of patients achieve a tumor response to cisplatin-based chemotherapy and eventually develop acquired resistance. The aim of this study was to identify potential biomarkers that could predict the efficacy of cisplatin. METHODS: Human lung adenocarcinoma cell line A549 was exposed to cisplatin for development of a resistant cell line, A549/DDP, and cisplatin-sensitivity was tested through the MTT assay. The global protein profiles from A549 and A549/DDP were compared using a proteomic approach. Western blot, real-time PCR and immunohistochemistry validated the expression of DDH2 in cell lines and tumor xenografts. Serum levels of DDH2 were measured by ELISA in 105 NSCLC patients treated with cisplatin-based chemotherapy. RESULT: The resistance of A549/DDP to cisplatin was 8.07-fold higher than that of A549 cells. Proteomic approach identified eight differentially (>5-fold) expressed proteins. Among them, secreted protein DDH2 was further investigated and it was found overexpressed through the method of Western blot, real-time PCR in cell lines, consistent with immunohistochemistry validation in xenograft. Clinical research showed that baseline serum DDH2 level in the patients with a progression disease was significantly higher than the patients of response or stable disease (9.036 vs. 3.529 and 3.982 ng/mL, P<0.001) and serum DDH2 levels were significantly increased after cisplatin-based doublet chemotherapy (5.515 vs. 12.935 vs. 18.406 ng/mL P<0.001, respectively). CONCLUSION: DDH2 expression might be a potential predictor and monitor of cisplatin efficacy in advanced NSCLC patients.


Subject(s)
Antineoplastic Agents/pharmacology , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/enzymology , Cisplatin/pharmacology , Hydroxysteroid Dehydrogenases/metabolism , Lung Neoplasms/enzymology , Adult , Aged , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cisplatin/therapeutic use , Cisplatin/toxicity , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Hydroxysteroid Dehydrogenases/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Proteomics , Transcription, Genetic
18.
J Nanosci Nanotechnol ; 11(5): 3800-7, 2011 May.
Article in English | MEDLINE | ID: mdl-21780371

ABSTRACT

To construct tumor-targeted nanometer particles as a negative magnetic resonance imaging (MRI) contrast agent. Ultra-small superparamagnetic iron oxide (USPIO) nanometer particles were prepared by one-step chemical precipitation. The covalent bond between cyclic RGD (cRGD) containing an Arg-Gly-Asp sequence targeting integrin-alphavbeta3, and USPIO was conducted by chemical crosslinking. The physico-chemical property of cRGD-USPIO was detected. Prussian blue staining was applied to detect the specific binding capacity of cRGD-USPIO and USPIO to human pulmonary adenocarcinoma A549 cells and human umbilical vein endothelial cells. Subsequently, A549 xenografts in nude mice were established, and intravenous injections of USPIO and cRGD-USPIO into the vena caudalis were performed. The enhancement of cRGD-USPIO against tumor MRI signal was evaluated. The mean hydrodynamic diameter of cRGD-USPIO was 43.97 +/- 10.10 nm and the size of the ferric oxide core was 5-10 nm. The specific saturation magnetization was 59.94 A x m2 x Kg(-1). The cell conjugation assay results indicated that the positive staining of the cRGD-USPIO group was significantly enhanced. The in vivo MRI diagnosis indicated that the cRGD-USPIO tumor signal was significantly reduced compared to that of the USPIO group (P < 0.01). The targeted superparamagnetic iron oxide nanometer particle can be a novel MRI negative contrast agent for more specific tumor early diagnosis.


Subject(s)
Contrast Media , Ferric Compounds/chemistry , Magnetic Resonance Imaging/methods , Metal Nanoparticles , Neoplasms/diagnosis , Oligopeptides/chemistry , Animals , Cell Line, Tumor , Humans , Mice , Mice, Inbred BALB C , Mice, Nude
19.
Eur J Radiol ; 80(2): 598-606, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21316892

ABSTRACT

Magnetic resonance molecular imaging has emerged as a potential approach for tumor diagnosis in the last few decades. This approach consists of the delivery of MR contrast agents to the tumor by specific targeted carriers. For this purpose, a lipopeptide was constructed by using a cyclic RGD peptide headgroup coupled to palmitic acid anchors via a KGG tripeptide spacer. Targeted paramagnetic liposomes were then prepared by the incorporation of RGD-coupled-lipopeptides into lipid bilayers for specific bounding to tumor. In vitro, study demonstrated that RGD-targeted liposomes exhibited a better binding affinity to targeted cells than non-targeted liposomes. MR imaging of mice bearing A549 tumors with the RGD-targeted paramagnetic liposomes also resulted in a greater signal enhancement of tumor compared to non-targeted liposomes and pure contrast agents groups. In addition, biodistribution study also showed specific tumor targeting of RGD-targeted paramagnetic liposomes in vivo. Therefore, RGD-targeted paramagnetic liposomes prepared in the present study may be a more promising method for early tumor diagnosis.


Subject(s)
Adenocarcinoma/diagnosis , Liposomes/chemical synthesis , Lung Neoplasms/diagnosis , Nuclear Magnetic Resonance, Biomolecular/methods , Oligopeptides/chemistry , Analysis of Variance , Animals , Cell Line, Tumor , Drug Delivery Systems , Gadolinium DTPA/chemistry , Humans , In Vitro Techniques , Mice , Mice, Inbred BALB C , Mice, Nude , Sensitivity and Specificity , Transplantation, Heterologous
20.
Med Oncol ; 28(2): 572-7, 2011 Jun.
Article in English | MEDLINE | ID: mdl-20237869

ABSTRACT

We sought to improve the understanding of oncogene-dependent and independent non-small-cell lung cancer (NSCLC), which could provide insight into mechanism of sensitivity and/or resistance to tyrosine kinase inhibitors or chemotherapeutics. NSCLC cell lines with different EGFR genotypes were used in this study; MTT assay and flow cytometry were applied to study the sensitivities of these cell lines to gefitinib and cisplatin. Western blot was performed to determine the expression levels of BIM and other Bcl-2 family proteins pre- and pro-treatment. Gefitinib provoked apoptosis of caspase activation via the intrinsic pathways and significantly up-regulated expression of BIM protein in drug-sensitive PC-9 cell line, but not resistant PC-9/BB4 cell line. The knockdown of BIM expression by RNA interference virtually eliminated gefitinib-induced cell killing in PC-9 cells in vitro. Cisplatin could induce apoptosis of the cell lines, including H1299, A549, PC-9, and PC-9/BB4 cells, but which was not associated with overexpression of BIM. BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cell line. Down-regulation of BIM and resistance to gefitinib were both seen in the acquired resistant PC-9/BB4 cell line. The induction of BIM may have a role in the treatment of TKI-resistant tumors.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Apoptosis/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/genetics , Membrane Proteins/genetics , Proto-Oncogene Proteins/genetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/metabolism , Bcl-2-Like Protein 11 , Blotting, Western , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Separation , Cisplatin/pharmacology , ErbB Receptors/genetics , Flow Cytometry , Gefitinib , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Membrane Proteins/metabolism , Mutation , Proto-Oncogene Proteins/metabolism , Quinazolines/pharmacology , RNA Interference , RNA, Small Interfering
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