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1.
Cancer Res ; 84(10): 1680-1698, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38501978

ABSTRACT

Immune checkpoint inhibitors (ICI) have transformed cancer treatment. However, only a minority of patients achieve a profound response. Many patients are innately resistant while others acquire resistance to ICIs. Furthermore, hepatotoxicity and suboptimal efficacy have hampered the clinical development of agonists of 4-1BB, a promising immune-stimulating target. To effectively target 4-1BB and treat diseases resistant to ICIs, we engineered ATG-101, a tetravalent "2+2″ PD-L1×4-1BB bispecific antibody. ATG-101 bound PD-L1 and 4-1BB concurrently, with a greater affinity for PD-L1, and potently activated 4-1BB+ T cells when cross-linked with PD-L1-positive cells. ATG-101 activated exhausted T cells upon PD-L1 binding, indicating a possible role in reversing T-cell dysfunction. ATG-101 displayed potent antitumor activity in numerous in vivo tumor models, including those resistant or refractory to ICIs. ATG-101 greatly increased the proliferation of CD8+ T cells, the infiltration of effector memory T cells, and the ratio of CD8+ T/regulatory T cells in the tumor microenvironment (TME), rendering an immunologically "cold" tumor "hot." Comprehensive characterization of the TME after ATG-101 treatment using single-cell RNA sequencing further revealed an altered immune landscape that reflected increased antitumor immunity. ATG-101 was well tolerated and did not induce hepatotoxicity in non-human primates. According to computational semimechanistic pharmacology modeling, 4-1BB/ATG-101/PD-L1 trimer formation and PD-L1 receptor occupancy were both maximized at around 2 mg/kg of ATG-101, providing guidance regarding the optimal biological dose for clinical trials. In summary, by localizing to PD-L1-rich microenvironments and activating 4-1BB+ immune cells in a PD-L1 cross-linking-dependent manner, ATG-101 safely inhibits growth of ICI resistant and refractory tumors. SIGNIFICANCE: The tetravalent PD-L1×4-1BB bispecific antibody ATG-101 activates 4-1BB+ T cells in a PD-L1 cross-linking-dependent manner, minimizing the hepatotoxicity of existing 4-1BB agonists and suppressing growth of ICI-resistant tumors. See related commentary by Ha et al., p. 1546.


Subject(s)
Antibodies, Bispecific , B7-H1 Antigen , Animals , Antibodies, Bispecific/pharmacology , Antibodies, Bispecific/immunology , Humans , Mice , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 9/antagonists & inhibitors , Female , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Xenograft Model Antitumor Assays , Cell Line, Tumor , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/pathology , T-Lymphocytes/immunology , T-Lymphocytes/drug effects , Tumor Microenvironment/immunology , Tumor Microenvironment/drug effects
3.
Huan Jing Ke Xue ; 44(6): 3488-3499, 2023 Jun 08.
Article in Chinese | MEDLINE | ID: mdl-37309965

ABSTRACT

Based on the concentration data of seven heavy metal elements[As, Cd, Cu, Pb, Hg, Ni, and Cr(Ⅵ)] in the surface soil of a typical industrial park in northwest China, the characteristics of heavy metal pollution in the industrial park were analyzed, and the ecological risk and pollution were evaluated using the potential ecological risk index and the index of geo-accumulation. The positive matrix factorization (PMF) model and random forest (RF) model were used for quantitative source analysis, and the emission data of sampling enterprises and empirical data of the source emission component spectrum were combined to identify the characteristic elements and determine the emission source category. The results showed that the heavy metals at all sampling points in the park did not exceed the second-class screening value of construction land in the soil pollution risk control standard for construction land (GB 36600-2018). However, compared with the local soil background values, five elements, excluding As and Cr, were enriched in different degrees, presenting slight pollution and moderate ecological risk (RI=250.04). Cd and Hg were the main risk elements of the park. The results of source analysis showed that the five main sources of pollution were fossil fuel combustion and chemical production sources (33.73%, 9.71%, total source contribution rate of PMF and RF, respectively; the same below), natural sources and waste residue landfill (32.40%, 40.80%), traffic emissions (24.49%, 48.08%), coal burning and non-ferrous metal smelting (5.43%, 0.11%), and electroplating and ore smelting (3.95%, 1.30%). The simulation R2 of the total variable of the two models were above 0.96, indicating that the models could predict heavy metals well. However, considering the actual situation of the number of enterprises in the park and roading density, the main pollution sources of soil heavy metals in the park should be industrial sources, and the simulation results of the PMF model were closer to the actual situation in the park.

4.
Proc Natl Acad Sci U S A ; 119(30): e2206588119, 2022 07 26.
Article in English | MEDLINE | ID: mdl-35867821

ABSTRACT

Oncogenic mutations within the epidermal growth factor receptor (EGFR) are found in 15 to 30% of all non-small-cell lung carcinomas. The term exon 19 deletion (ex19del) is collectively used to refer to more than 20 distinct genomic alterations within exon 19 that comprise the most common EGFR mutation subtype in lung cancer. Despite this heterogeneity, clinical treatment decisions are made irrespective of which EGFR ex19del variant is present within the tumor, and there is a paucity of information regarding how individual ex19del variants influence protein structure and function. Herein, we identified allele-specific functional differences among ex19del variants attributable to recurring sequence and structure motifs. We built all-atom structural models of 60 ex19del variants identified in patients and combined molecular dynamics simulations with biochemical and biophysical experiments to analyze three ex19del mutations (E746_A750, E746_S752 > V, and L747_A750 > P). We demonstrate that sequence variation in ex19del alters oncogenic cell growth, dimerization propensity, enzyme kinetics, and tyrosine kinase inhibitor (TKI) sensitivity. We show that in contrast to E746_A750 and E746_S752 > V, the L747_A750 > P variant forms highly active ligand-independent dimers. Enzyme kinetic analysis and TKI inhibition experiments suggest that E746_S752 > V and L747_A750 > P display reduced TKI sensitivity due to decreased adenosine 5'-triphosphate Km. Through these analyses, we propose an expanded framework for interpreting ex19del variants and considerations for therapeutic intervention.


Subject(s)
Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Exons , Lung Neoplasms , Alleles , Amino Acid Motifs , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Enzyme Activation/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , ErbB Receptors/genetics , Exons/genetics , Humans , Kinetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Neoplasm Recurrence, Local/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Sequence Deletion
5.
J Thorac Oncol ; 16(7): 1211-1223, 2021 07.
Article in English | MEDLINE | ID: mdl-33839362

ABSTRACT

INTRODUCTION: The programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors, atezolizumab and durvalumab, have received regulatory approval for the first-line treatment of patients with extensive-stage SCLC. Nevertheless, when used in combination with platinum-based chemotherapy, these PD-L1 inhibitors only improve overall survival by 2 to 3 months. This may be due to the observation that less than 20% of SCLC tumors express PD-L1 at greater than 1%. Evaluating the composition and abundance of checkpoint molecules in SCLC may identify molecules beyond PD-L1 that are amenable to therapeutic targeting. METHODS: We analyzed RNA-sequencing data from SCLC cell lines (n = 108) and primary tumor specimens (n = 81) for expression of 39 functionally validated inhibitory checkpoint ligands. Furthermore, we generated tissue microarrays containing SCLC cell lines and patient with SCLC specimens to confirm expression of these molecules by immunohistochemistry. We annotated patient outcomes data, including treatment response and overall survival. RESULTS: The checkpoint protein B7-H6 (NCR3LG1) exhibited increased protein expression relative to PD-L1 in cell lines and tumors (p < 0.05). Higher B7-H6 protein expression correlated with longer progression-free survival (p = 0.0368) and increased total immune infiltrates (CD45+) in patients. Furthermore, increased B7-H6 gene expression in SCLC tumors correlated with a decreased activated natural killer cell gene signature, suggesting a complex interplay between B7-H6 expression and immune signature in SCLC. CONCLUSIONS: We investigated 39 inhibitory checkpoint molecules in SCLC and found that B7-H6 is highly expressed and associated with progression-free survival. In addition, 26 of 39 immune checkpoint proteins in SCLC tumors were more abundantly expressed than PD-L1, indicating an urgent need to investigate additional checkpoint targets for therapy in addition to PD-L1.


Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , B7-H1 Antigen , Humans , Immunotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Progression-Free Survival , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics
6.
Nat Commun ; 12(1): 1382, 2021 03 02.
Article in English | MEDLINE | ID: mdl-33654076

ABSTRACT

Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 - 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.


Subject(s)
ErbB Receptors/chemistry , ErbB Receptors/metabolism , Gene Duplication , Molecular Targeted Therapy , Oncogenes , Amino Acid Sequence , Animals , Cell Line , Cell Proliferation , Epitopes/metabolism , ErbB Receptors/genetics , Ligands , Mice , Neoplasms/metabolism , Phosphorylation , Protein Binding , Protein Domains , Protein Multimerization , Structure-Activity Relationship
7.
Cancers (Basel) ; 12(2)2020 Feb 21.
Article in English | MEDLINE | ID: mdl-32098067

ABSTRACT

Although the judicious use of anticancer drugs that target one or more receptor tyrosine kinases constitutes an effective strategy to attenuate tumor growth, drug resistance is commonly encountered in cancer patients. The ATP-binding cassette transporters are one of the major contributors to the development of multidrug resistance as their overexpression significantly decreases the intracellular concentration and thus, the efficacy of certain anticancer drugs. Therefore, the development of treatment strategies that would not be susceptible to efflux or excretion by specific ABC transporters could overcome resistance to treatment. Here, we investigated the anticancer efficacy of saporin, a ribosome-inactivating protein. Since saporin has poor permeability across the cell membrane, it was encapsulated in a lipid-based nanoparticle system (EC16-1) that effectively delivered the formulation (EC16-1/saporin) intracellularly and produced anti-cancer efficacy. EC16-1/saporin, at nanomolar concentrations, significantly inhibited the cellular proliferation of parental and ABCB1- and ABCG2-overexpressing cancer cells. EC16-1/saporin did not significantly alter the subcellular localization of ABCB1 and ABCG2. In addition, EC16-1/saporin induced apoptosis in parental and ABCB1- and ABCG2-overexpressing cancer cells. In a murine model system, EC16-1/saporin significantly inhibited the tumor growth in mice xenografted with parental and ABCB1- and ABCG2-overexpressing cancer cells. Our findings suggest that the EC16-1/saporin combination could potentially be a novel therapeutic treatment in patients with parental or ABCB1- and ABCG2-positive drug-resistant cancers.

8.
Cancers (Basel) ; 12(2)2020 Feb 12.
Article in English | MEDLINE | ID: mdl-32059437

ABSTRACT

MLN4924 (pevonedistat) is a first-in-class NEDD8-activating enzyme (NAE) inhibitor in clinical trials for the treatment of solid tumors and hematologic malignancies. Despite the promising activity of MLN4924 observed in early trials, drug resistance has been noted in some patients. Identifying the underlying cause of treatment failure may help to better stratify patients that are most likely to benefit from this novel agent. Early preclinical studies revealed that the development of NAE mutations promotes resistance to MLN4924. However, these mutations have not been detected in patients that are relapsed/refractory to MLN4924, suggesting that other mechanisms are driving clinical resistance. To better understand the potential mechanisms of MLN4924 resistance, we generated MLN4924-resistant ovarian cancer cells. Interestingly, these cells did not develop mutations in NAE. Transcriptome analyses revealed that one of the most upregulated genes in resistant cells was ABCG2. This result was validated by quantitative real-time PCR and immunoblotting. Importantly, the sensitivity of MLN4924-resistant cells was restored by lentiviral short hairpin RNA (shRNA) targeting ABCG2. Further investigation using ABCG2-overexpressing NCI-H460/MX20 cells determined that these cells are resistant to the anticancer effects of MLN4924 and can be sensitized by co-treatment with the ABCG2 inhibitors YHO-13351 and fumitremorgin C. Finally, HEK293 models with overexpression of wild-type ABCG2 (R482) and variants (R482G and R482T) all demonstrated significant resistance to MLN4924 compared to wild-type cells. Overall, these findings define an important molecular resistance mechanism to MLN4924 and demonstrate that ABCG2 may be a useful clinical biomarker that predicts resistance to MLN4924 treatment.

9.
Biochem Pharmacol ; 175: 113848, 2020 05.
Article in English | MEDLINE | ID: mdl-32044354

ABSTRACT

The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked efflux function of the MDR cancer cell lines. This inhibition is due to the barred ABCG2 and ABCB1 ATPase activities rather than altering the expression or localization of ABCG2 or ABCB1 transporters. The previous studies showed that non-basic chalcones were ABCG2-specific inhibitors; however, we found that non-basic chalcone CYB-2 can be developed as an ABCG2/ABCB1 dual inhibitor to overcome MDR in cancers that co-express both ABCG2 and ABCB1. Moreover, non-basic chalcone CYB-2 has synthetic tractability compared to other chalcone-based derivatives.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Chalcones/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Neoplasm Proteins/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Antineoplastic Agents/chemistry , Cell Line, Tumor , Chalcones/chemistry , Humans , Molecular Docking Simulation , Neoplasm Proteins/genetics
10.
Eur J Med Chem ; 179: 849-862, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31302589

ABSTRACT

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Diketopiperazines/pharmacology , Drug Resistance, Neoplasm/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Neoplasm Proteins/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Diketopiperazines/chemistry , Diketopiperazines/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/metabolism , Humans , Molecular Structure , Neoplasm Proteins/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured
11.
Chem Commun (Camb) ; 55(26): 3833-3836, 2019 Mar 26.
Article in English | MEDLINE | ID: mdl-30869688
12.
Clin Cancer Res ; 25(11): 3341-3351, 2019 06 01.
Article in English | MEDLINE | ID: mdl-30796031

ABSTRACT

PURPOSE: The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with EGFR-mutant lung cancer. Despite the development of highly selective third-generation inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in in vitro screens. Here, we investigate how G724S confers resistance to osimertinib.Experimental Design: We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro drug-response models and patient genomic profiling. RESULTS: Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse. CONCLUSIONS: Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug-resistance mutation" pair to one focused on the "activating mutation-drug-resistance mutation" trio. This has broad implications across clinical oncology.


Subject(s)
Acrylamides/pharmacology , Alleles , Aniline Compounds/pharmacology , Drug Resistance, Neoplasm/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Acrylamides/chemistry , Aniline Compounds/chemistry , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , ErbB Receptors/chemistry , ErbB Receptors/genetics , ErbB Receptors/metabolism , Exons , Gene Expression Profiling , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Models, Molecular , Protein Binding , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
13.
Cancer Lett ; 442: 104-112, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30392788

ABSTRACT

Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/agonists , Antineoplastic Agents/pharmacology , Colonic Neoplasms/drug therapy , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Neoplasm Proteins/agonists , Phenylurea Compounds/pharmacology , Pyridines/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2/chemistry , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Binding Sites , Cell Line, Tumor , Colonic Neoplasms/genetics , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Drug Synergism , Humans , Male , Mice, Nude , Mitoxantrone/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Neoplasm Proteins/chemistry , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Phenylurea Compounds/chemistry , Protein Binding , Protein Conformation , Pyridines/chemistry , Topotecan/pharmacology , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
14.
Opt Commun ; 411: 53-58, 2018 Mar 15.
Article in English | MEDLINE | ID: mdl-30140109

ABSTRACT

We report the patterned synthesis of ZnO nanorod arrays of diameters between 50 nm and 130 nm and various spacings. This was achieved by patterning hole arrays in a polymethyl methacrylate layer with electron beam lithography, followed by chemical synthesis of ZnO nanorods in the patterned holes using the hydrothermal method. The fabrication of ZnO nanorod waveguide arrays is also demonstrated by embedding the nanorods in a silver film using the electroplating process. Optical transmission measurement through the nanorod waveguide arrays is performed and strong resonant transmission of visible light is observed. We have found the resonance shifts to a longer wavelength with increasing nanorod diameter. Furthermore, the resonance wavelength is independent of the nanowaveguide array period, indicating the observed resonant transmission is the effect of a single ZnO nanorod waveguide. These nanorod waveguides may be used in single-molecule imaging and sensing as a result of the nanoscopic profile of the light transmitted through the nanorods and the controlled locations of these nanoscale light sources.

15.
Cancer Lett ; 424: 19-29, 2018 06 28.
Article in English | MEDLINE | ID: mdl-29518481

ABSTRACT

One of the major mediators of multidrug resistance (MDR) in non-small cell lung cancer (NSCLC) is the overexpression of ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we conducted in vitro and in vivo experiments to determine whether PD153035, an inhibitor of EGFR, could reverse ABCG2-mediated MDR in human NSCLC and transfected cells overexpressing ABCG2. The efficacy of SN-38, topotecan, and mitoxantrone (MX) were significantly increased by PD153035, PD153035 significantly reversed ABCG2-mediated MDR by attenuating the efflux activity of this transporter. In addition, PD153035 significantly down-regulated the expression of the ABCG2 transporter protein. Furthermore, a combination of PD153035 and topotecan, exhibited significant synergistic anticancer activity against mice xenografted with human H460/MX20 cells. These results, provided that they can be extrapolated to humans, suggest that the combination of topotecan and PD153035 could be a promising therapeutic strategy to attenuate the resistance to topotecan, as well as other anticancer drugs, mediated by the overexpression of ABCG2.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Lung Neoplasms/drug therapy , Neoplasm Proteins/genetics , Quinazolines/administration & dosage , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Synergism , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Male , Mice , Quinazolines/pharmacology , Topotecan/administration & dosage , Topotecan/pharmacology , Up-Regulation/drug effects , Xenograft Model Antitumor Assays
16.
Cell Physiol Biochem ; 45(4): 1515-1528, 2018.
Article in English | MEDLINE | ID: mdl-29486476

ABSTRACT

BACKGROUND/AIMS: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. METHODS: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. RESULTS: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. CONCLUSION: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Drug Resistance, Neoplasm/drug effects , Imino Furanoses/pharmacology , Neoplasm Proteins/metabolism , Protein Kinase Inhibitors/pharmacology , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzopyrans/chemistry , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , Doxorubicin/pharmacology , HEK293 Cells , Humans , Imino Furanoses/chemistry , Mitoxantrone/pharmacology , Molecular Docking Simulation , Multidrug Resistance-Associated Proteins/metabolism , Mutation , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Paclitaxel/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary
17.
Oncotarget ; 8(55): 93785-93799, 2017 Nov 07.
Article in English | MEDLINE | ID: mdl-29212189

ABSTRACT

Previous reports have shown that some tyrosine kinase inhibitors (TKIs) could inhibit the ATP-binding cassette (ABC) transporters involved in multidrug resistance (MDR). Quizartinib (AC220), a potent class III receptor tyrosine kinase inhibitor (TKI), was synthesized to selectively inhibit FMS-like tyrosine kinase-3 (FLT3), a target in the treatment of acute myeloid leukemia (AML). Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. While non-toxic to cell lines, quizartinib at 3 µM showed significant reversal effect on wild-type and mutant ABCG2 (R482T)-mediated MDR, and only a moderate reversal effect on mutant ABCG2 (R482G)-mediated MDR. Results also showed that quizartinib reversed MDR not by reducing the expression of ABCG2 protein, but by antagonizing the drug efflux function and increasing the intracellular accumulation of substrate anticancer drugs in ABCG2-overexpressing cells. Importantly, quizartinib at 30 mg/kg strongly enhanced the effect of topotecan (3 mg/kg) in ABCG2-overexpressing (H460/MX20) xenografts in athymic nude mice. These results demonstrated that quizartinib potentiates the antineoplastic activity of wild-type and R482T mutant ABCG2 substrates. These findings may be useful in clinical practice for cancer combination therapy with quizartinib.

18.
Acta Pharm Sin B ; 7(5): 564-570, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28924550

ABSTRACT

Arsenic trioxide (ATO) is used as a chemotherapeutic agent for the treatment of acute promyelocytic leukemia. However, increasing drug resistance is reducing its efficacy. Therefore, a better understanding of ATO resistance mechanism is required. In this study, we established an ATO-resistant human epidermoid carcinoma cell line, KB/ATO, from its parental KB-3-1 cells. In addition to ATO, KB/ATO cells also exhibited cross-resistance to other anticancer drugs such as cisplatin, antimony potassium tartrate, and 6-mercaptopurine. The arsenic accumulation in KB/ATO cells was significantly lower than that in KB-3-1 cells. Further analysis indicated that neither application of P-glycoprotein inhibitor, breast cancer resistant protein (BCRP) inhibitor, or multidrug resistance protein 1 (MRP1) inhibitor could eliminate ATO resistance. We found that the expression level of ABCB6 was increased in KB/ATO cells. In conclusion, ABCB6 could be an important factor for ATO resistance in KB/ATO cells. The ABCB6 level may serve as a predictive biomarker for the effectiveness of ATO therapy.

19.
Oncotarget ; 8(18): 29760-29770, 2017 May 02.
Article in English | MEDLINE | ID: mdl-28423656

ABSTRACT

Cancer cells can acquire resistance to a wide variety of diverse and unrelated drugs, this phenomenon is termed multidrug resistance (MDR). Multidrug resistance has been an obstacle to the success of cancer chemotherapy. The present study investigated the reversal effect of Y6, a new compound obtained by chemically modifying the structure of epigallocatechin-3-gallate (EGCG) extracted from green tea. Y6 was proven to be effective in inhibiting cell proliferation and reversing drug resistance in doxorubicin (DOX) resistant human hepatocellular carcinoma cells (BEL-7404/DOX). BEL-7404/DOX cells were treated with either doxorubicin combination regimen (doxorubicin plus Y6 or epigallocatechin-3-gallate or verapamil separately) or doxorubicin alone. The results showed that cell proliferation was inhibited and late cell apoptosis increased in the combination treatment group, especially in the group treated with doxorubicin plus Y6. Further analysis revealed that the expressions of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein decreased at both messenger RNA and protein levels by treatments with combined drugs compared to doxorubicin alone. Our results indicated that Y6, as a drug resistance reversal agent, increased the sensitivity of drug resistant cells to doxorubicin. The mechanisms of actions of Y6 in reversal effect were associated with the decreased expression of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein.


Subject(s)
Antineoplastic Agents/pharmacology , Catechin/analogs & derivatives , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Apoptosis/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Catechin/chemistry , Catechin/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/genetics , Gene Expression , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism
20.
Mol Cancer Ther ; 16(6): 1021-1030, 2017 06.
Article in English | MEDLINE | ID: mdl-28265007

ABSTRACT

Paclitaxel is one of the most widely used antineoplastic drugs in the clinic. Unfortunately, the occurrence of cellular resistance has limited its efficacy and application. The ATP-binding cassette subfamily B member 1 (ABCB1/P-glycoprotein) and subfamily C member 10 (ABCC10/MRP7) are the major membrane protein transporters responsible for the efflux of paclitaxel, constituting one of the most important mechanisms of paclitaxel resistance. Here, we demonstrated that the Bruton tyrosine kinase inhibitor, ibrutinib, significantly enhanced the antitumor activity of paclitaxel by antagonizing the efflux function of ABCB1 and ABCC10 in cells overexpressing these transporters. Furthermore, we demonstrated that the ABCB1 or ABCC10 protein expression was not altered after treatment with ibrutinib for up to 72 hours using Western blot analysis. However, the ATPase activity of ABCB1 was significantly stimulated by treatment with ibrutinib. Molecular docking analysis suggested the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB1. Importantly, ibrutinib could effectively enhance paclitaxel-induced inhibition on the growth of ABCB1- and ABCC10-overexpressing tumors in nude athymic mice. These results demonstrate that the combination of ibrutinib and paclitaxel can effectively antagonize ABCB1- or ABCC10-mediated paclitaxel resistance that could be of great clinical interest. Mol Cancer Ther; 16(6); 1021-30. ©2017 AACR.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression , Multidrug Resistance-Associated Proteins/genetics , Paclitaxel/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Multiple/genetics , Drug Synergism , Humans , Male , Mice , Models, Molecular , Molecular Conformation , Multidrug Resistance-Associated Proteins/chemistry , Multidrug Resistance-Associated Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Paclitaxel/chemistry , Piperidines , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/chemistry , Pyrimidines/chemistry , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
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