scholarly journals Novel CD44-Targeting and pH/redox Dual-Stimuli Responsive Core-Shell Nanoparticles Loading Triptolide to Combat Breast Cancer Growth and Lung Metastasis

2021 ◽  
Author(s):  
Jinfeng Shi ◽  
Yali Ren ◽  
Jiaqi Ma ◽  
Xi Luo ◽  
Jiaxin Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Release ◽  
Lung Metastasis ◽  
Cancer Progression ◽  
Drug Loading ◽  
Tumor Therapy ◽  
Systemic Toxicity ◽  
Migration And Invasion ◽  
Drug Release Profile ◽  
Cd44 Targeting

Abstract BackgroundThe toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited its clinical application. Therefore, we fabricated a CD44-targeting and tumor-microenvironment pH/redox sensitive nanosystem, composed by hyaluronic acid-Vitamin E succinate (HA-VE) and Poly (β-Amino Esters) (PBAEss) polymers, to enhance the suppression of breast cancer proliferation and lung metastasis of TPL. ResultsThe generated TPL/NPs had the high drug loading efficiency (94.93 ± 2.1%) and a desirable average size (191 nm). Mediated by PBAEss core, TPL/NPs displayed a pH/redox dual stimuli drug release profile in vitro. Based on HA coating, TPL/NPs exhibited selective tumor-cellular uptake and high tumor-tissue accumulation capacity via targeting CD44. As a consequence, TPL/NPs showed higher cell proliferation suppression, pro-apoptosis and cell cycle arrest activities, and stronger inhibitory effects on cell migration and invasion than free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and block lung metastasis in a 4T1 breast cancer mice model at equivalent or lower TPL dosage compared to free TPL, with the decreased systemic toxicity. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis, suppressed expression of matrix metalloproteinases, which all these contributed to inhibit tumor growth and pulmonary metastasis. ConclusionCollectively, our results demonstrate that TPL/NPs, which integrates tumor active-targeting and pH/redox responsive drug release, pro-apoptosis, and anti-mobility, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.

scholarly journals Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinfeng Shi ◽  
Yali Ren ◽  
Jiaqi Ma ◽  
Xi Luo ◽  
Jiaxin Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hyaluronic Acid ◽  
Drug Release ◽  
Lung Metastasis ◽  
Drug Loading ◽  
Tumor Therapy ◽  
Systemic Toxicity ◽  
Migration And Invasion ◽  
Stimuli Responsive ◽  
Cd44 Targeting

Abstract Background The toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. Thus, we fabricated a CD44-targeting and tumor microenvironment pH/redox-sensitive nanosystem composed of hyaluronic acid-vitamin E succinate and poly (β-amino esters) (PBAEss) polymers to enhance the TPL-mediated suppression of breast cancer proliferation and lung metastasis. Results The generated TPL nanoparticles (NPs) had high drug loading efficiency (94.93% ± 2.1%) and a desirable average size (191 nm). Mediated by the PBAEss core, TPL/NPs displayed a pH/redox-dual-stimuli-responsive drug release profile in vitro. Based on the hyaluronic acid coating, TPL/NPs exhibited selective tumor cellular uptake and high tumor tissue accumulation capacity by targeting CD44. Consequently, TPL/NPs induced higher suppression of cell proliferation, blockage of proapoptotic and cell cycle activities, and strong inhibition of cell migration and invasion than that induced by free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and blocking lung metastasis with decreased systemic toxicity in a 4T1 breast cancer mouse model at an equivalent or lower TPL dosage compared with that of free TPL. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis and suppressed expression of matrix metalloproteinases, which contributed to inhibiting tumor growth and pulmonary metastasis. Conclusion Collectively, our results demonstrate that TPL/NPs, which combine tumor active targeting and pH/redox-responsive drug release with proapoptotic and antimobility effects, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity. Graphic Abstract

scholarly journals Gremlin-1 Promotes Metastasis of Breast Cancer Cells by Activating STAT3-MMP13 Signaling Pathway

2020 ◽  
Vol 21 (23) ◽  
pp. 9227
Author(s):  
Nam Ji Sung ◽  
Na Hui Kim ◽  
Young-Joon Surh ◽  
Sin-Aye Park
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Lung Metastasis ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Cancer Metastasis ◽  
Migration And Invasion ◽  
Breast Cancer Patients ◽  
Gremlin 1

Gremlin-1 (GREM1), one of the bone morphogenetic protein (BMP) antagonists, can directly bind to BMPs. GREM1 is involved in organogenesis, tissue differentiation, and organ fibrosis. Recently, numerous studies have reported the oncogenic role of GREM1 in cancer. However, the role of GREM1 in metastasis of breast cancer cells and its underlying mechanisms remain poorly understood. The role of GREM1 in breast cancer progression was assessed by measuring growth, migration, and invasion of breast cancer cells. An orthotopic breast cancer mouse model was used to investigate the role of GREM1 in lung metastasis of breast cancer cells. GREM1 knockdown suppressed the proliferation of breast cancer cells, while its overexpression increased their growth, migration, and invasion. Cells with Grem1-knockdown showed much lower tumor growth rates and lung metastasis than control cells. GREM1 enhanced the expression of matrix metalloproteinase 13 (MMP13). A positive correlation between GREM1 and MMP13 expression was observed in breast cancer patients. GREM1 activated signal transducer and activator of transcription 3 (STAT3) transcription factor involved in the expression of MMP13. Our study suggests that GREM1 can promote lung metastasis of breast cancer cells through the STAT3-MMP13 pathway. In addition, GREM1 might be a promising therapeutic target for breast cancer metastasis.

scholarly journals Oncogenic UBE3C promotes breast cancer progression by activating Wnt/β-catenin signaling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chen Hang ◽  
Shanojie Zhao ◽  
Tiejun Wang ◽  
Yan Zhang
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Nuclear Accumulation ◽  
Migration And Invasion ◽  
Ubiquitin Protein Ligase ◽  
Novel Target ◽  
First Time ◽  
Breast Tissues

Abstract Background Breast cancer (BrCa) is the most common female malignancy worldwide and has the highest morbidity among all cancers in females. Unfortunately, the mechanisms of BrCa growth and metastasis, which lead to a poor prognosis in BrCa patients, have not been well characterized. Methods Immunohistochemistry (IHC) was performed on a BrCa tissue microarray (TMA) containing 80 samples to evaluate ubiquitin protein ligase E3C (UBE3C) expression. In addition, a series of cellular experiments were conducted to reveal the role of UBE3C in BrCa. Results In this research, we identified UBE3C as an oncogenic factor in BrCa growth and metastasis for the first time. UBE3C expression was upregulated in BrCa tissues compared with adjacent breast tissues. BrCa patients with high nuclear UBE3C expression in tumors showed remarkably worse overall survival (OS) than those with low nuclear expression. Knockdown of UBE3C expression in MCF-7 and MDA-MB-453 BrCa cells inhibited cell proliferation, migration and invasion in vitro, while overexpression of UBE3C in these cells exerted the opposite effects. Moreover, UBE3C promoted β-catenin nuclear accumulation, leading to the activation of the Wnt/β-catenin signaling pathway in BrCa cells. Conclusion Collectively, these results imply that UBE3C plays crucial roles in BrCa development and progression and that UBE3C may be a novel target for the prevention and treatment of BrCa.

scholarly journals LINC00665 promotes breast cancer progression through regulation of the miR-379-5p/LIN28B axis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wei Ji ◽  
Yu-Ling Diao ◽  
Yi-Ran Qiu ◽  
Jie Ge ◽  
Xu-Chen Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Normal Breast ◽  
Breast Cancer Progression ◽  
Migration And Invasion ◽  
Breast Tumorigenesis ◽  
Mesenchymal Transition ◽  
Tumorigenesis And Progression ◽  
Mirna Sponges

AbstractBreast cancer is the most common malignant tumor among women worldwide. Although increasing evidence indicates that long noncoding RNAs (lncRNAs) play critical roles during breast tumorigenesis and progression, the involvement of most lncRNAs in breast cancer remains largely unknown. In the current study, we demonstrated that LINC00665 promotes breast cancer cell proliferation, migration, and invasion. Accumulating evidence indicates that many lncRNAs can function as endogenous miRNA sponges by competitively binding common miRNAs. In this study, we demonstrated that LINC00665 functions as a sponge for miR-379-5p, reducing the ability of miR-379-5p to repress LIN28B. LINC00665 promoted breast cancer progression and induced an epithelial–mesenchymal transition-like phenotype via the upregulation of LIN28B expression. Clinically, LINC00665 expression was increased but miR-379-5p expression was decreased in breast cancer tissues compared with that in normal breast tissues in the TCGA database. Furthermore, the expression of LINC00665 was negatively related with miR-379-5p expression. Collectively, our results reveal the LINC00665–miR-379-5p–LIN28B axis and shed light on breast cancer therapy.

scholarly journals AMPKα1 Regulates Lung and Breast Cancer Progression by Regulating TLR4-Mediated TRAF6-BECN1 Signaling Axis

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3289
Author(s):  
Mi-Jeong Kim ◽  
Yoon Min ◽  
Juhee Son ◽  
Ji Young Kim ◽  
Ji Su Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
A549 Cells ◽  
Migration And Invasion ◽  
Serum Starvation ◽  
Lung Cancers ◽  
Cancer Migration ◽  
Expression Of Genes ◽  
Autophagy Induction ◽  
Signaling Axis

TRAF6-BECN1 signaling axis is critical for autophagy induction and functionally implicated in cancer progression. Here, we report that AMP-activated protein kinase alpha 1 (AMPKα1, PRKAA1) is positively involved in autophagy induction and cancer progression by regulating TRAF6-BECN1 signaling axis. Mechanistically, AMPKα1 interacted with TRAF6 and BECN1. It also enhanced ubiquitination of BECN1 and autophagy induction. AMPKα1-knockout (AMPKα1KO) HEK293T or AMPKα1-knockdown (AMPKα1KD) THP-1 cells showed impaired autophagy induced by serum starvation or TLR4 (Toll-like receptor 4) stimulation. Additionally, AMPKα1KD THP-1 cells showed decreases of autophagy-related and autophagosome-related genes induced by TLR4. AMPKα1KO A549 cells exhibited attenuation of cancer migration and invasion induced by TLR4. Moreover, primary non-small cell lung cancers (NSCLCs, n = 6) with low AMPKαl levels showed markedly decreased expression of genes related to autophagy, cell migration and adhesion/metastasis, inflammation, and TLRs whereas these genes were significantly upregulated in NSCLCs (n = 5) with high AMPKαl levels. Consistently, attenuation of cancer migration and invasion could be observed in AMPKα1KO MDA-MB-231 and AMPKα1KO MCF-7 human breast cancer cells. These results suggest that AMPKα1 plays a pivotal role in cancer progression by regulating the TRAF6-BECN1 signaling axis for autophagy induction.

scholarly journals The Inhibitory Effect of (−)-Epigallocatechin-3-Gallate on Breast Cancer Progression via Reducing SCUBE2 Methylation and DNMT Activity

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2899 ◽  
Author(s):  
Jie Sheng ◽  
Weilin Shi ◽  
Hui Guo ◽  
Wenlin Long ◽  
Yuxin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Inhibitory Effect ◽  
Breast Cancer Progression ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Complement Protein ◽  
Epidermal Growth Factor Domain ◽  
Potential Implication ◽  
Egcg Treatment

Epigenetic modifications are important mechanisms responsible for cancer progression. Accumulating data suggest that (−)-epigallocatechin-3-gallate (EGCG), the most abundant catechin of green tea, may hamper carcinogenesis by targeting epigenetic alterations. We found that signal peptide-CUB (complement protein C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor) domain-containing protein 2 (SCUBE2), a tumor suppressor gene, was hypermethylated in breast tumors. However, it is unknown whether EGCG regulates SCUBE2 methylation, and the mechanisms remain undefined. This study was designed to investigate the effect of EGCG on SCUBE2 methylation in breast cancer cells. We reveal that EGCG possesses a significantly inhibitory effect on cell viability in a dose- and time-dependent manner and presents more effects than other catechins. EGCG treatment resulted in enhancement of the SCUBE2 gene, along with elevated E-cadherin and decreased vimentin expression, leading to significant suppression of cell migration and invasion. The inhibitory effect of EGCG on SCUBE2 knock-down cells was remarkably alleviated. Further study demonstrated that EGCG significantly decreased the SCUBE2 methylation status by reducing DNA methyltransferase (DNMT) expression and activity. In summary, this study reported for the first time that SCUBE2 methylation can be reversed by EGCG treatment, finally resulting in the inhibition of breast cancer progression. These results suggest the epigenetic role of EGCG and its potential implication in breast cancer therapy.

scholarly journals Drug Release from a Spherical Matrix: Theoretical Analysis for a Finite Dissolution Rate Affected by Geometric Shape of Dispersed Drugs

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 582
Author(s):  
Yung-Sheng Lin ◽  
Ruey-Yug Tsay
Keyword(s):  
Drug Release ◽  
Release Rate ◽  
Shape Factor ◽  
Numerical Solutions ◽  
Drug Loading ◽  
Spherical Geometry ◽  
Detailed Comparison ◽  
Release Profile ◽  
Drug Release Profile ◽  
Drug Release Rate

Amending the neglect of finite dissolution in traditional release models, this study proposed a more generalized drug release model considering the simultaneous dissolution and diffusion procedure from a drug-loaded spherical matrix. How the shape factor (n = 0, 1/2, and 2/3 for the planar, cylindrical, and spherical geometry, respectively) of dispersed drug particles affected the release from the matrix was examined for the first time. Numerical solutions of this generalized model were validated by consensus with a short-time analytical solution for planar drugs and by the approach of the diffusion-controlled limits with Higuchi’s model. The drug release rate increases with the ratio of dissolution/diffusion rate (G) and the ratio of solubility/drug loading (K) but decreases with the shape factor of drug particles. A zero-order release profile is identified for planar drugs before starting the surface depletion layer, and also found for cylindrical and spherical dispersed drugs when K and G are small, i.e. the loaded drug is mainly un-dissolved and the drug release rate is dissolution-controlled. It is also shown that for the case of a small G value, the variation of drug release profile, due to the drug particle geometry, becomes prominent. Detailed comparison with the results of the traditional Higuchi’s model indicates that Higuchi’s model can be applied only when G is large because of the assumption of an instantaneous dissolution. For K = 1/101–1/2, the present analysis suggests an error of 33–85% for drug release predicted by Higuchi’s model for G = 100, 14–44% error for G = 101, while a less than 5% error for G ≧ 103.

Polymeric nanotheranostics for real-time non-invasive optical imaging of breast cancer progression and drug release

2014 ◽  
Vol 352 (1) ◽  
pp. 81-89 ◽  
Author(s):  
Shiran Ferber ◽  
Hemda Baabur-Cohen ◽  
Rachel Blau ◽  
Yana Epshtein ◽  
Einat Kisin-Finfer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Release ◽  
Optical Imaging ◽  
Real Time ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Non Invasive

scholarly journals P38 delta MAPK promotes breast cancer progression and lung metastasis by enhancing cell proliferation and cell detachment

Oncogene ◽  
2017 ◽  
Vol 36 (47) ◽  
pp. 6649-6657 ◽  
Author(s):  
M Wada ◽  
D Canals ◽  
M Adada ◽  
N Coant ◽  
M F Salama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Lung Metastasis ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Cell Detachment

Development and Characterization of Binary Solid Lipid Nano Suspension of Atorvastatin: In-Vitro Drug Release and In-Vivo Pharmacokinetic Studies

2019 ◽  
Vol 11 (11) ◽  
pp. 1522-1530
Author(s):  
Mahwish Kamran ◽  
Mir Azam Khan ◽  
Muhammad Shafique ◽  
Maqsood ur Rehman ◽  
Waqar Ahmed ◽  
...  
Keyword(s):  
Drug Release ◽  
Oral Bioavailability ◽  
Drug Loading ◽  
Lipid Lowering ◽  
Diffusion Method ◽  
Pharmacokinetic Studies ◽  
Drug Release Profile ◽  
Sustained Drug Release ◽  
Solid Lipid

Atorvastatin is an extensively used lipid lowering agent. But the vital issue associated with it is low oral bioavailability (12%) owing to poor aqueous solubility. To overcome this tribulation, binary solid lipid nano suspension of Atorvastatin (ATO) was formulated by solvent diffusion method. The combination of stearic acid and oleic acid was utilized as a lipid carrier with Tween-80 (surfactant) along with Polyvinylpyrrolidone (co-surfactant). Optimized nano formulation was prepared by changing the formulation variables. Optimized nano suspension (ATO-4) represented particle size 228.3 ± 2.1 nm and polydispersity index (PDI) 0.225 ± 0.02 with zeta potential (ZP) – 33.6 ± 0.02 mV. Encapsulation efficiency along with drug loading capacity was 88.3 ± 2.5% and 4.9 ± 0.14% respectively. Scanning electron microscopic (SEM) analysis exposed spherical shaped amorphous particles. Differential scanning calorimetry (DSC) as well as X-ray powder diffraction (P-XRD) established reduction in drug's crystalline state. Fourier transform infrared (FTIR) spectroscopy exposed no interaction amongst the drug and formulation contents. In-vitro studies revealed sustained pattern of drug release. Stability studies confirmed refrigerated temperature as most suitable for storage of binary solid lipid nano suspension. Plasma concentration versus time curve ascertained 2.78-fold increase in oral bioavailability of ATO nano suspension compared to the marketed product (Lipitor®). Findings proposed desired improvement in oral bioavailability of ATO nano suspension with sustained drug release profile. Thus, binary solid lipid nano suspension could be utilized as an advanced drug delivery system for oral deliverance of hydrophobic drugs.

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