ABSTRACT
Fluorescence molecular tomography (FMT) serves as a noninvasive modality for visualizing volumetric fluorescence distribution within biological tissues, thereby proving to be an invaluable imaging tool for preclinical animal studies. The conventional FMT relies upon a point-by-point raster scan strategy, enhancing the dataset for subsequent reconstruction but concurrently elongating the data acquisition process. The resultant diminished temporal resolution has persistently posed a bottleneck, constraining its utility in dynamic imaging studies. We introduce a novel system capable of simultaneous FMT and surface extraction, which is attributed to the implementation of a rapid line scanning approach and dual-camera detection. The system performance was characterized through phantom experiments, while the influence of scanning line density on reconstruction outcomes has been systematically investigated via both simulation and experiments. In a proof-of-concept study, our approach successfully captures a moving fluorescence bolus in three dimensions with an elevated frame rate of approximately 2.5 seconds per frame, employing an optimized scan interval of 5 mm. The notable enhancement in the spatio-temporal resolution of FMT holds the potential to broaden its applications in dynamic imaging tasks, such as surgical navigation.
Subject(s)
Imaging, Three-Dimensional , Phantoms, Imaging , Imaging, Three-Dimensional/methods , Fluorescence , Animals , Optical Imaging/methods , LightABSTRACT
Native functionality directed the C-H activation cascade to enable rapid construction of molecular complexity, featuring step-economy and synthetic efficiency. Herein, by exploiting bifunctional α-alcohol haloalkynes, we developed Ru(II)-catalyzed carboxylic acid, amine, and amide assisted divergent C-H alkynylation and annulation cascade, affording polyfunctional heterocycles. Significantly, a bilateral aryl C-H polycyclization cascade of azobenzenes was achieved using the versatile haloalkynes.
ABSTRACT
Objective. We introduce a robust image reconstruction algorithm named residual-guided Golub-Kahan iterative reconstruction technique (RGIRT) designed for sparse-view computed tomography (CT), which aims at high-fidelity image reconstruction from a limited number of projection views.Approach. RGIRT utilizes an inner-outer dual iteration framework, with a flexible least square QR (FLSQR) algorithm implemented in the inner iteration and a restarted iterative scheme applied in the outer iteration. The inner FLSQR employs a flexible Golub-Kahan bidiagonalization method to reduce the size of the inverse problem, and a weighted generalized cross-validation method to adaptively estimate the regularization hyper-parameter. The inner iteration efficiently yields the intermediate reconstruction result, while the outer iteration minimizes the residual and refines the solution by using the result obtained from the inner iteration.Main results. The reconstruction performance of RGIRT is evaluated and compared to other reference methods (FBPConvNet, SART-TV, and FLSQR) using projection data from both numerical phantoms and real experimental Micro-CT data. The experimental findings, from testing various numbers of projection views and different noise levels, underscore the robustness of RGIRT. Meanwhile, theoretical analysis confirms the convergence of residual for our approach.Significance. We propose a robust iterative reconstruction algorithm for x-ray CT scans with sparse views, thereby shortening scanning time and mitigating excessive ionizing radiation exposure to small animals.
Subject(s)
Algorithms , Image Processing, Computer-Assisted , Phantoms, Imaging , Tomography, X-Ray Computed , Image Processing, Computer-Assisted/methods , Animals , Tomography, X-Ray Computed/methods , MiceABSTRACT
OBJECTIVE: Macroscopic optical tomography is a non-invasive method that can visualize the 3D distribution of intrinsic optical properties or exogenous fluorophores, making it highly attractive for small animal imaging. However, reconstructing the images requires prior knowledge of surface information. To address this, existing systems often use additional hardware components or integrate multimodal information, which is expensive and introduces new issues such as image registration. Our goal is to develop a multifunctional optical tomography system that can extract surface information using a concise hardware design. METHODS: Our proposed system uses a single programmable scanner to implement both surface extraction and optical tomography functions. A unified pinhole model is used to describe both the illumination and detection procedures for capturing 3D point cloud. Line-shaped scanning is adopted to improve both spatial resolution and speed of surface extraction. Finally, we integrate the extracted surface information into the optical tomographic reconstruction to more accurately map the fluorescence distribution. RESULT: Comprehensive phantom experiments with different levels of complexity were designed to evaluate the performance of surface extraction and fluorescence tomography. We also imaged the axillary lymph nodes in living mice after injection of fluorophore, demonstrating the proposed system facilitates more reliable fluorescence tomography. CONCLUSION: We have successfully developed a versatile optical tomography system by leveraging concise hardware design and unified pinhole modeling. Phantom validation demonstrates that our system provides high-precision surface information with a maximum error of 0.1 mm, while the surface-guided FMT reconstruction is more reliable than the blind reconstruction using simplified surface geometry, elevating several quantitative metrics including RMSE, CNR, and Dice. SIGNIFICANCE: Our work explores the feasibility of obtaining additional surface information using existing components of standalone optical tomography. This makes the optical tomographic technique more accurate and more accessible to biomedical researchers.
Subject(s)
Optical Devices , Tomography, Optical , Mice , Animals , Phantoms, ImagingABSTRACT
Although inhibiting EGFR-mediated signaling proved to be effective in treating certain types of cancers, a quickly evolved mechanism that either restores the EGFR signaling or activates an alternative pathway for driving the proliferation and survival of malignant cells limits the efficacy and utility of the approach via suppressing the EGFR functionality. Given the fact that overexpression of EGFR is commonly seen in many cancers, an EGFR-targeting antibody-drug conjugate (ADC) can selectively kill cancer cells independently of blocking EGFR-mediated signaling. Herein, we describe SHR-A1307, a novel anti-EGFR ADC, generated from an anti-EGFR antibody with prolonged half-life, and conjugated with a proprietary toxin payload that has increased index of EGFR targeting-dependent versus EGFR targeting-independent cytotoxicity. SHR-A1307 demonstrated strong and sustained antitumor activities in EGFR-positive tumors harboring different oncogenic mutations on EGFR, KRAS, or PIK3CA. Antitumor efficacy of SHR-A1307 correlated with EGFR expression levels in vitro and in vivo, regardless of the mutation status of EGFR signaling mediators and a resultant resistance to EGFR signaling inhibitors. Cynomolgus monkey toxicology study showed that SHR-A1307 is well tolerated with a wide therapeutic index. SHR-A1307 is a promising therapeutic option for EGFR-expressing cancers, including those resistant or refractory to the EGFR pathway inhibitors.
Subject(s)
Aminobenzoates/immunology , Antibodies, Monoclonal, Humanized/immunology , Antineoplastic Agents, Immunological/immunology , Drug Resistance, Neoplasm/drug effects , Immunoconjugates/pharmacology , Immunoconjugates/therapeutic use , Neoplasms/drug therapy , Oligopeptides/immunology , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Cell Line, Tumor , Drug Delivery Systems/methods , ErbB Receptors/immunology , Female , HEK293 Cells , Humans , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Transfection , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Poly(ADP-ribose) polymerase (PARP) enzymes play an important role in repairing DNA damage and maintaining genomic stability. Olaparib, the first-in-class PARP inhibitor, has shown remarkable clinical benefits in the treatment of BRCA-mutated ovarian or breast cancer. However, the undesirable hematological toxicity and pharmacokinetic properties of olaparib limit its clinical application. Here, we report the first preclinical characterization of fluzoparib (code name: SHR-3162), a novel, potent, and orally available inhibitor of PARP. Fluzoparib potently inhibited PARP1 enzyme activity and induced DNA double-strand breaks, G2 /M arrest, and apoptosis in homologous recombination repair (HR)-deficient cells. Fluzoparib preferentially inhibited the proliferation of HR-deficient cells and sensitized both HR-deficient and HR-proficient cells to cytotoxic drugs. Notably, fluzoparib showed good pharmacokinetic properties, favorable toxicity profile, and superior antitumor activity in HR-deficient xenografts models. Furthermore, fluzoparib in combination with apatinib or with apatinib plus paclitaxel elicited significantly improved antitumor responses without extra toxicity. Based on these findings, studies to evaluate the efficacy and safety of fluzoparib (phase II) and those two combinations (phase I) have been initiated. Taken together, our results implicate fluzoparib as a novel attractive PARP inhibitor.
Subject(s)
Antineoplastic Agents/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Clinical Trials as Topic , DNA Breaks, Double-Stranded/drug effects , DNA Repair/drug effects , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Phthalazines/pharmacology , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Xenograft Model Antitumor Assays/methodsABSTRACT
High-numerical-aperture (NA) anamorphic imaging projection objectives are the industrial choice for extreme ultraviolet lithography under the advanced technology node. The illumination system has to match the elliptical entrance pupil of the high-NA projector. In this paper, an illumination system suitable for a high-NA anamorphic projection objective is designed. The two-mirror relay system of the illumination system is designed by a two-stage process. The first-order initial configuration with spherical surfaces is calculated by a method based on matrix optics. Then after tilting and decentering the two spherical surfaces to eliminate obscuration, the two mirror surfaces are fitted into conic surfaces. To realize many different illumination modes, a facet mirror matching method based on combinatorial optimization is proposed to allocate the mapping relationship between the field and pupil facets under different illumination modes. Simulation results of the system illumination uniformity show the system can achieve high uniformity on the reticle under different illumination modes.
ABSTRACT
OBJECTIVES: Increasing evidence suggests that long non-coding RNAs (lncRNAs) may play a crucial role in many biological processes in a variety of cancers and serve as the basis for many clinical applications including prognostic biomarkers and potential therapeutic targets. The aim of this study is to develop a prognostic lncRNA signature with RNA-seq data in lung adenocarcinomas. METHODS: LncRNA expression profiles and clinical data of lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA) were analyzed. Univariate Cox proportional regression model was used to identify prognostic lncRNAs, and then multivariate Cox proportional regression model was used to develop a prognostic signature. Survivals were compared using log-rank test, and the biological implications of prognostic lncRNAs were analyzed using the KEGG pathway functional enrichment analysis. RESULTS: We identified eight lncRNAs which had prognostic association with p value <0.01 in a TCGA lung adenocarcinoma cohort of 478 patients. Then a novel prognostic signature with the eight lncRNAs was developed using Cox regression model. Signature high-risk cases had worse overall survival (OS, median 85.97 vs. 38.34 months, p < 0.001) and disease-free survival (DFS, median 44.02 vs. 26.58 months, p = 0.007) than low-risk cases. Multivariate Cox regression analysis suggested that the eight-lncRNA signature was independent of clinical and pathological factors. KEGG pathway functional enrichment analysis indicated potential functional roles of the eight prognostic lncRNAs in tumorigenesis. CONCLUSIONS: Our findings suggest that the eight-lncRNA signature might provide an effective independent prognostic model for the prediction of lung adenocarcinoma patients.
Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Lung Neoplasms/genetics , RNA, Long Noncoding/genetics , Adenocarcinoma/mortality , Adenocarcinoma of Lung , Adult , Aged , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Male , Middle Aged , Prognosis , Proportional Hazards Models , RNA, Long Noncoding/analysis , Sensitivity and Specificity , Transcriptome/geneticsABSTRACT
The HuPrime® human gastric neuroendocrine carcinoma derived xenograft model GA0087 was established in this study. GA0087 PDX model showed high gene expression of vascular endothelial growth factors (VEGF)-A and B, and high potential of lung metastasis. Circulating tumor cells (CTCs) with either large or small size, circulating tumor microemboli (CTM) and lung metastatic lesions were detected in GA0087 PDX mice. The number of CTC correlated to the number of metastatic nodules in lung. Both primary tumor growth and metastasis in terms of the number of dynamically monitored CTCs and metastatic nodules were effectively suppressed by Cisplatin. Diverse subtypes of CTCs in the context of sensitivity to Cisplatin were specifically identified by subtraction enrichment (SE) integrated with in situ Phenotyping of cytokeratin 18 (CK18) and Karyotyping of chromosome 8 (in situ PK CTC by CK-iFISH). All the CK18-/diploid and majority of CK18+/diploid CTC subtypes were chemosensitive, whereas a higher percentage of CK18+/multiploid subtype of CTC were Cisplatin-insensitive. Combined histopathological examination of metastatic lesion and in situ PK CTC in a metastatic PDX (mPDX) tumor model are of particular significance, and may provide an unique and robust platform for cancer research as well as pre-clinical evaluation of therapeutic efficacy of new anti-cancer drugs.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm/physiology , Lung Neoplasms/drug therapy , Neoplastic Cells, Circulating/pathology , Stomach Neoplasms/pathology , Aged , Animals , Biomarkers, Tumor/blood , Biomarkers, Tumor/metabolism , Carcinoma, Neuroendocrine/pathology , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Female , Humans , Lung Neoplasms/secondary , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Transplantation, Heterologous , Vascular Endothelial Growth Factor A/biosynthesis , Vascular Endothelial Growth Factor B/biosynthesisABSTRACT
Breast cancer metastasis is one of the major reasons for the high morbidity and mortality of breast cancer patients. In spite of surgical interventions, chemotherapy, radiation therapy and targeted therapy, some patients are considering alternative therapies with herbal/natural products. In the present study, we evaluated a well-characterized extract from the medicinal mushroom Ganoderma lucidum (GLE) for its affects on tumor growth and breast-to-lung cancer metastasis. MDA-MB-231 human breast cancer cells were implanted into the mammary fat pads of nude mice. GLE (100 mg/kg/every other day) was administered to the mice by an oral gavage for 4 weeks, and tumor size was measured using microcalipers. Lung metastases were evaluated by hematoxylin and eosin (H&E) staining. Gene expression in MDA-MB-231 cells was determined by DNA microarray analysis and confirmed by quantitative PCR. Identified genes were silenced by siRNA, and cell migration was determined in Boyden chambers and by wound-healing assay. Although an oral administration of GLE only slightly suppressed the growth of large tumors, the same treatment significantly inhibited the number of breast-to-lung cancer metastases. GLE also downregulated the expression of genes associated with invasive behavior (HRAS, VIL2, S100A4, MCAM, I2PP2A and FN1) in MDA-MB-231 cells. Gene silencing of HRAS, VIL2, S100A4, I2PP2A and FN1 by siRNA suppressed migration of MDA-MB231 cells. Our study suggests that an oral administration of GLE can inhibit breast-to-lung cancer metastases through the downregulation of genes responsible for cell invasiveness. The anti-metastatic benefits of GLE warrant further clinical studies.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/secondary , Cell Movement/drug effects , Gene Expression Regulation, Leukemic/drug effects , Lung Neoplasms/drug therapy , Plant Extracts/pharmacology , Reishi/chemistry , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Gene Expression Profiling , Humans , Lung Neoplasms/pathology , Mammary Neoplasms, Experimental , Mice , Mice, Nude , Xenograft Model Antitumor AssaysABSTRACT
Members of the EAG K(+) channel superfamily (EAG/Kv10.x, ERG/Kv11.x, ELK/Kv12.x subfamilies) are expressed in many cells and tissues. In particular, two prototypes, EAG1/Kv10.1/KCNH1 and ERG1/Kv11.1/KCNH2 contribute to both normal and pathological functions. Proliferation of numerous cancer cells depends on hEAG1, and in some cases, hERG. hERG is best known for contributing to the cardiac action potential, and for numerous channel mutations that underlie 'long-QT syndrome'. Many cells, particularly cancer cells, express Src-family tyrosine kinases and SHP tyrosine phosphatases; and an imbalance in tyrosine phosphorylation can lead to malignancies, autoimmune diseases, and inflammatory disorders. Ion channel contributions to cell functions are governed, to a large degree, by post-translational modulation, especially phosphorylation. However, almost nothing is known about roles of specific tyrosine kinases and phosphatases in regulating K(+) channels in the EAG superfamily. First, we show that tyrosine kinase inhibitor, PP1, and the selective Src inhibitory peptide, Src40-58, reduce the hERG current amplitude, without altering its voltage dependence or kinetics. PP1 similarly reduces the hEAG1 current. Surprisingly, an 'immuno-receptor tyrosine inhibitory motif' (ITIM) is present within the cyclic nucleotide binding domain of all EAG-superfamily members, and is conserved in the human, rat and mouse sequences. When tyrosine phosphorylated, this ITIM directly bound to and activated SHP-1 tyrosine phosphatase (PTP-1C/PTPN6/HCP); the first report that a portion of an ion channel is a binding site and activator of a tyrosine phosphatase. Both hERG and hEAG1 currents were decreased by applying active recombinant SHP-1, and increased by the inhibitory substrate-trapping SHP-1 mutant. Thus, hERG and hEAG1 currents are regulated by activated SHP-1, in a manner opposite to their regulation by Src. Given the widespread distribution of these channels, Src and SHP-1, this work has broad implications in cell signaling that controls survival, proliferation, differentiation, and other ERG1 and EAG1 functions in many cell types.
Subject(s)
Ether-A-Go-Go Potassium Channels/genetics , Gene Expression Regulation , Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics , src-Family Kinases/genetics , Action Potentials/drug effects , Action Potentials/physiology , Amino Acid Sequence , Animals , Conserved Sequence , Cyclic AMP/metabolism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , HEK293 Cells , Humans , Mice , Molecular Sequence Data , Patch-Clamp Techniques , Peptides/pharmacology , Protein Binding , Protein Structure, Tertiary , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Rats , Sequence Homology, Amino Acid , Signal Transduction , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolismABSTRACT
Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSCs) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here we describe a platform that combines three-dimensional cell cultivation with electrical stimulation to mature hPSC-derived cardiac tissues. We used quantitative structural, molecular and electrophysiological analyses to explain the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allows for the generation of three-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation had markedly increased myofibril ultrastructural organization, elevated conduction velocity and improved both electrophysiological and Ca(2+) handling properties compared to nonstimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate.
Subject(s)
Cell Culture Techniques/methods , Induced Pluripotent Stem Cells/cytology , Myocardium/cytology , Myocytes, Cardiac/cytology , Tissue Engineering/methods , Cell Differentiation/physiology , Electric Stimulation , Electrophysiological Phenomena , Humans , Microscopy, Electron, Transmission , Myocardium/ultrastructureABSTRACT
AIM: The objective of this study was to evaluate the combined effect of a known galectin-3 inhibitor, PectaSol-C modified citrus pectin (MCP), and 2 novel integrative polybotanical compounds for breast and prostate health, BreastDefend (BD) and ProstaCaid (PC), on invasive behavior in human breast and prostate cancer cells in vitro, respectively. METHODS: The effect of MCP and BD and of MCP and PC on invasiveness was assessed by cell adhesion, cell migration, and cell invasion assays. Secretion of urokinase plasminogen activator (uPA) was determined by Western blot analysis. RESULTS: Although low concentrations of MCP (0.25-1.0 mg/mL) do not suppress cell adhesion of breast or prostate cancer cells, the combination of MCP with BD or PC synergistically inhibits adhesion of these cells. Dose-dependent inhibition of breast and prostate cancer cell migration by MCP (0.25-1.0 mg/mL) is synergistically enhanced by BD (20 µg/mL) and PC (10 µg/mL), respectively. BD or PC did not further inhibit the invasion of breast and prostate cancer cells by MCP; however, the combination of MCP with BD or PC suppressed secretion of uPA from breast and prostate cancer cells, respectively. CONCLUSION: The combination of MCP with BD and of MCP with PC synergistically inhibits the metastatic phenotypes of human breast and prostate cancer cells, respectively. Further studies confirming these observations in animal models of breast and prostate cancer metastasis are warranted.
Subject(s)
Breast Neoplasms/drug therapy , Cell Movement/drug effects , Pectins/pharmacology , Plant Extracts/pharmacology , Prostatic Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Adhesion/drug effects , Cell Line, Tumor , Citrus , Drug Synergism , Female , Galectin 3/metabolism , Humans , Integrative Medicine/methods , Male , Neoplasm Invasiveness , Prostatic Neoplasms/pathology , Urokinase-Type Plasminogen Activator/metabolismABSTRACT
BACKGROUND: Epidemiological studies suggest that mushroom intake is inversely correlated with gastric, gastrointestinal and breast cancers. We have recently demonstrated anticancer and anti-inflammatory activity of triterpene extract isolated from mushroom Ganoderma lucidum (GLT). The aim of the present study was to evaluate whether GLT prevents colitis-associated carcinogenesis in mice. METHODS/PRINCIPAL FINDINGS: Colon carcinogenesis was induced by the food-borne carcinogen (2-Amino-1-methyl-6-phenylimidazol[4,5-b]pyridine [PhIP]) and inflammation (dextran sodium sulfate [DSS]) in mice. Mice were treated with 0, 100, 300 and 500 mg GLT/kg of body weight 3 times per week for 4 months. Cell proliferation, expression of cyclin D1 and COX-2 and macrophage infiltration was assessed by immunohistochemistry. The effect of GLT on XRE/AhR, PXR and rPXR was evaluated by the reporter gene assays. Expression of metabolizing enzymes CYP1A2, CYP3A1 and CYP3A4 in colon tissue was determined by immunohistochemistry. GLT treatment significantly suppressed focal hyperplasia, aberrant crypt foci (ACF) formation and tumor formation in mice exposed to PhIP/DSS. The anti-proliferative effects of GLT were further confirmed by the decreased staining with Ki-67 in colon tissues. PhIP/DSS-induced colon inflammation was demonstrated by the significant shortening of the large intestine and macrophage infiltrations, whereas GLT treatment prevented the shortening of colon lengths, and reduced infiltration of macrophages in colon tissue. GLT treatment also significantly down-regulated PhIP/DSS-dependent expression of cyclin D1, COX-2, CYP1A2 and CYP3A4 in colon tissue. CONCLUSIONS: Our data suggest that GLT could be considered as an alternative dietary approach for the prevention of colitis-associated cancer.
Subject(s)
Colonic Neoplasms , Inflammation , Plant Extracts/administration & dosage , Reishi , Aminopyridines/toxicity , Animals , Anti-Inflammatory Agents/administration & dosage , Apoptosis/drug effects , Carcinogens/toxicity , Cell Proliferation/drug effects , Cell Transformation, Neoplastic/drug effects , Colitis/complications , Colitis/drug therapy , Colitis/pathology , Colonic Neoplasms/chemically induced , Colonic Neoplasms/diet therapy , Colonic Neoplasms/metabolism , Dextran Sulfate/toxicity , Gastrointestinal Neoplasms/complications , Gastrointestinal Neoplasms/diet therapy , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hyperplasia/chemically induced , Hyperplasia/diet therapy , Hyperplasia/metabolism , Imidazoles/toxicity , Inflammation/chemically induced , Inflammation/diet therapy , Macrophages/drug effects , Mice , Neoplasms, Experimental/chemically induced , Neoplasms, Experimental/diet therapy , Neoplasms, Experimental/metabolism , Plant Extracts/chemistry , Reishi/chemistryABSTRACT
We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast-to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers.
Subject(s)
Breast Neoplasms/pathology , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Plant Extracts/pharmacology , Administration, Oral , Animals , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/pharmacology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Dietary Supplements/adverse effects , Disease Models, Animal , Down-Regulation , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lung Neoplasms/genetics , Mice , Mice, Nude , Plant Extracts/adverse effects , Plants, Medicinal/chemistry , Receptors, CXCR4/genetics , Toxicity Tests , Urokinase-Type Plasminogen Activator/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: We have recently synthesized novel N-alkylated amino acid-derived hydroxamate, 2-[Benzyl-(2-nitro-benzenesulfonyl)-amino]-N-hydroxy-3-methyl-N-propyl-butyramide (NAHA). Here, we evaluate the anticancer activity of NAHA against highly invasive human breast cancer cells MDA-MB-231 in vitro and in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Cell growth was evaluated by MTT and soft agar assays. Protein expression was determined by DNA microarray and Western blot analysis. Metastatic potential was evaluated by cell adhesion, migration, invasion, capillary morphogenesis, and ELISA assays. The anticancer activity in vivo was evaluated in mouse xenograft model. NAHA inhibited proliferation and colony formation of MDA-MB-231 cells together with the down-regulation of expression of Cdk2 and CDC20 proteins. NAHA inhibited cell adhesion, migration, and invasion through the suppression of secretion of uPA. NAHA suppressed secretion of VEGF from MDA-MB-231 cells and inhibited capillary morphogenesis of human aortic endothelial cells (HAECs). Finally, NAHA at 50 mg/kg was not toxic and decreased tumor volume and tumor weight in vivo. This suppression of tumor growth was associated with the inhibition of mitotic figures and induction of apoptosis, and the reduction of CD31 and VEGF positive cells in tumors. CONCLUSION: NAHA could be a novel promising compound for the development of new drugs for the therapy of invasive breast cancers.
Subject(s)
Amides/chemistry , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Hydroxamic Acids/chemistry , Valine/analogs & derivatives , Animals , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Female , Humans , In Vitro Techniques , Mice , Mice, Nude , Models, Chemical , Neoplasm Invasiveness , Neoplasm Transplantation , Oligonucleotide Array Sequence Analysis , Valine/chemistry , Vascular Endothelial Growth Factor A/metabolismABSTRACT
We have recently demonstrated that the dietary supplement ProstaCaid (PC) inhibits growth and invasive behavior of PC-3 human prostate cancer cells in vitro. In the present study, we evaluated toxicity and whether PC suppresses growth of prostate cancer in a xenograft model of human prostate cancer cells implanted in mice. Here, we show that an oral administration of PC (100, 200 and 400 mg/kg) did not affect body weight or activity of liver enzymes (ALT, AST) and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. In addition, PC treatment resulted in the inhibition of tumor volumes (1024.6 ± 378.6 vs. 749.3 ± 234.3, P<0.001) in a xenograft model of prostate cancer with human hormone refractory (independent) PC-3 prostate cancer cells. Moreover, qRT-PCR analysis demonstrated significant upregulation of expression of CDKN1A (p21) and inhibition of expression of IGF2, NR2F2 and PLAU (uPA) genes by an oral administration of PC in prostate cancer xenografts. Our study demonstrates that the concentrations of the dietary supplement ProstaCaid tested did not show signs of toxicity, and its oral application has significant anticancer activity in vivo and can be considered as an alternative treatment for prostate cancer patients.
Subject(s)
Antineoplastic Agents/pharmacology , Dietary Supplements , Plant Extracts/pharmacology , Prostatic Neoplasms/drug therapy , Tumor Burden/drug effects , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , COUP Transcription Factor II/genetics , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Insulin-Like Growth Factor II/genetics , Male , Mice , Mice, Nude , Plant Extracts/administration & dosage , Plant Extracts/toxicity , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Real-Time Polymerase Chain Reaction , Signal Transduction/drug effects , Time Factors , Urokinase-Type Plasminogen Activator/genetics , Xenograft Model Antitumor AssaysABSTRACT
Although previous studies demonstrated anticancer activities of gossypol through the induction of apoptosis, the molecular mechanism(s) responsible for the inhibitory effects of gossypol on the metastatic behavior of cancer cells remain to be elucidated. Here, we show that gossypol inhibits growth of human prostate cancer cells through the modulation of cell cycle regulatory proteins. We also demonstrate that gossypol inhibits invasive behaviors (adhesion, migration, and invasion) and angiogenesis. These effects are mediated by the suppression of AP-1 and NF-κB activity, resulting in the inhibition of secretion of urokinase plasminogen activator and vascular endothelial growth factor, and the down-regulation of expression of chemokine receptor 4 in PC3 cells. In summary, our data suggest that gossypol could have potential therapeutic effect for the treatment of invasive prostate cancer.
Subject(s)
Cell Division/drug effects , Gossypol/pharmacology , NF-kappa B/metabolism , Neoplasm Invasiveness , Neovascularization, Pathologic/prevention & control , Prostatic Neoplasms/pathology , Signal Transduction/drug effects , Transcription Factor AP-1/metabolism , Cell Line, Tumor , Electrophoretic Mobility Shift Assay , G1 Phase , Humans , Immunohistochemistry , Male , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/metabolism , Resting Phase, Cell CycleABSTRACT
The first synthesis of ganodermanontriol, a bioactive lanostane triterpene from the medicinal mushroom Ganoderma lucidum, has been achieved in 15.3% yield over nine steps, along with its three stereoisomeric triols and ganoderol A. The key steps leading to this family of isomers involve the reconstruction of the trisubstituted alkene by stereoselective and chemoselective phosphonate reactions and the formation of the unusual Δ7,9(11)-diene core by the mild acidic opening of a lanosterone-derived epoxide. Ganodermanontriol showed promising activity on the inhibition and proliferation of breast cancer cells. The effect of ganodermanontriol and its isomers on cell proliferation was assayed; IC50 values of 5.8 and 9.7 µM on breast cancer cell lines MCF-7 and MDA-MB-231, respectively, were found for ganodermanontriol.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Lanosterol/analogs & derivatives , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , Female , Humans , Lanosterol/chemical synthesis , Lanosterol/chemistry , Lanosterol/pharmacology , Molecular Structure , Reishi/chemistry , StereoisomerismABSTRACT
Ganoderma lucidum is a medicinal mushroom that has been recognized by Traditional Chinese Medicine (TCM). Although some of the direct anticancer activities are attributed to the presence of triterpenes-ganoderic and lucidenic acids-the activity of other compounds remains elusive. Here we show that ganodermanontriol (GDNT), a Ganoderma alcohol, specifically suppressed proliferation (anchorage-dependent growth) and colony formation (anchorage-independent growth) of highly invasive human breast cancer cells MDA-MB-231. GDNT suppressed expression of the cell cycle regulatory protein CDC20, which is over-expressed in precancerous and breast cancer cells compared to normal mammary epithelial cells. Moreover, we found that CDC20 is over-expressed in tumors when compared to the tissue surrounding the tumor in specimens from breast cancer patients. GDNT also inhibited invasive behavior (cell adhesion, cell migration, and cell invasion) through the suppression of secretion of urokinase-plasminogen activator (uPA) and inhibited expression of uPA receptor. In conclusion, mushroom GDNT is a natural agent that has potential as a therapy for invasive breast cancers.