scholarly journals Attenuating Tumour Angiogenesis: A Preventive Role of Metformin against Breast Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Shan Gao ◽  
Jingcheng Jiang ◽  
Pan Li ◽  
Huijuan Song ◽  
Weiwei Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumour Progression ◽  
Breast Tumour ◽  
Ovarian Tumour ◽  
Tumour Cells ◽  
Tumour Angiogenesis ◽  
Preventive Role ◽  
Mcf 7

Metformin is one of the most widely prescribed antidiabetics for type 2 diabetes. A critical role of metformin against tumorigenesis has recently been implicated, although several studies also reported the lack of anticancer property of the antidiabetics. Given the controversies regarding the potential role of metformin against tumour progression, the effect of metformin against breast, cervical, and ovarian tumour cell lines was examined followed byin vivoassessment of metformin on tumour growth using xenograft breast cancer models. Significant inhibitory impact of metformin was observed in MCF-7, HeLa, and SKOV-3 cells, suggesting an antiproliferative property of metformin against breast, cervical, and ovarian tumour cells, respectively, with the breast tumour cells, MCF-7, being the most responsive.In vivoassessment was subsequently carried out, where mice with breast tumours were treated with metformin (20 mg/kg body weight) or sterile PBS solution for 15 consecutive days. No inhibition of breast tumour progression was detected. However, tumour necrosis was significantly increased in the metformin-treated group, accompanied by decreased capillary formation within the tumours. Thus, despite the lack of short-term benefit of metformin against tumour progression, a preventive role of metformin against breast cancer was implicated, which is at partially attributable to the attenuation of tumour angiogenesis.

The role of circCNIH4 in the adipocyte's effects on metastasis of breast cancer cells.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13086-e13086
Author(s):  
Xiu Chen ◽  
Jinhai Tang
Keyword(s):  
Breast Cancer ◽  
Wound Healing ◽  
Cell Invasion ◽  
Invasion And Migration ◽  
Non Invasive ◽  
In Vivo Experiments ◽  
And Migration ◽  
Mcf 7

e13086 Background: Obesity is associated with the risk of breast cancer(BCa) incidence and development. However, biological changes in obesity BCa individuals are still uncertain. Nowadays, circCNIH4, one of novel non-coding RNAs, was found to be a non-invasive biomarker in cancers. Methods: We verified the cancer-promoting role of obesity in BCa patients by comparing BMI indexes of 33 BCa and 44 benign tumor patients. Then we cocultured viscera adipose cells(HPA-v) and BCa cells(MCF-7/H and MDA-MB-231/H) to confirm the function of adipocytes on metastasis of BCa cells through wound healing, transwell assays. In vivo experiments were also performed. We analyzed the expression level of circCNIH4 in MCF-7/H, MDA-MB-231/H and different subtypes of BCa cells by quantitative polymerase chain reaction. Simultaneously, we identified inhibited effects of circCNIH4 on metastasis of BCa cells by wound healing, transwell assays and verified the location of circCNIH4 by FISH. Luciferase Assay was used to detect harbored miRNA. Rescue experiments were then applied. Results: We found the BMI of BCa patients(24.37±2.51) was much higher than benign patients(22.97±2.91). Metastasis of BCa cells were obviously promoted after in vitro and in vivo experiments. Then we found the expression of circCNIH4 in MCF-7/H and MDA-MB-231/H were down-regulated 0.71 and 0.52 than that in MCF-7 and MDA-MB-231. Also, circCNIH4 was positively correlated with less aggressive types of BCa cells. Overexpression of circCNIH4 in MDA-MB-231 could suppress cell invasion and migration, while silencing of it in MCF-7 promoted cell invasion and migration. The FISH assay demonstrated that circCNIH4 mainly located in the cytoplasm and might function as a “sponge” for miRNA. MiR-135b functioned as a tumor promoter gene from data of 93 BCa patients (HR = 2.27; 1.01 − 5.12), and it could be captured by circCNIH4 via luciferase and rescued assays. Conclusions: In this study, we revealed that BMI or viscera adipocytes could deteriorate prognosis of BCa and circCNIH4 could be a novel biomarker for non-invasive BCa. In details, circCNIH4 mainly suppressed the adipocyte's pro-metastasis effects on BCa by capturing miR-135b.

scholarly journals Human Drug Efflux Transporter ABCC5 Confers Sensitivity and Acquired Resistance to Pemetrexed in Breast Cancer

2020 ◽  
Author(s):  
Jihui Chen ◽  
Zhipeng Wang ◽  
Shouhong Gao ◽  
Kejin Wu ◽  
Fang Bai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Abc Transporters ◽  
Cancer Cell Lines ◽  
Control Group ◽  
Over Expression ◽  
Mcf 7

Abstract AimPemetrexed, a new generation antifolate drug, is approved for the treatment for locally advanced or metastatic breast cancer, but factors affecting the efficacy and resistance of it have yet to be fully explicit. ATP-binding cassette transporters have been reported as prognostic and adverse effects predictors of many xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and may contribute to treatment regimen optimization for breast cancer.MethodsFirstly, the expression of ABC transporters family members was measured in cell lines, thereafter examined the potential role of ABC transporter in conferring resistance to pemetrexed in primary cancer cell lines isolated from 34 breast cancer patients, and then the role of ABCC5 in mediating transport of pemetrexed and apoptosis pathway in MCF-7 cell lines was assessed. Finally, the functions of ABCC5 on therapeutic effect of pemetrexed was evaluated in breast cancer bearing mice.ResultsThe expressions of ABCC2, ABCC4, ABCC5 and ABCG2 were significantly increased in pan-resistance cell lines, and the ABCC5, the most obvious one, was 5.21 times higher than that of the control group. The expression of ABCC5 was inversely correlated with sensitivity (IC50) of pemetrexed (r = 0.741; p<0.010) in breast cancer cell lines from 34 patients. Further, we found expression of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cell line, and the IC50 were 0.06 μg/ml and 0.20 μg/ml in ABCC5 knock-down and over-expression cells, respectively. In vivo study, we found ABCC5 affected sensitivity of pemetrexed in breast cancer bearing mice, and the tumor volume was much larger in ABCC5 over-expression group than that in control group (2.7 folds vs 1.2 folds).ConclusionsOur results indicated ABCC5 was associated with pemetrexed sensitivity and resistance in vitro and in vivo, and may be a biomarker for regimen optimization of pemetrexed in breast cancer treatment.

scholarly journals The antimicrobial peptide Defensin cooperates with Tumour Necrosis Factor to drive tumour cell death in Drosophila

2019 ◽  
Author(s):  
Jean-Philippe Parvy ◽  
Yachuan Yu ◽  
Anna Dostalova ◽  
Shu Kondo ◽  
Alina Kurjan ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumour Necrosis Factor ◽  
Tumour Cell ◽  
Tumour Necrosis ◽  
Tumour Progression ◽  
Tumour Cells ◽  
Tumour Regression ◽  
Necrosis Factor

AbstractAntimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs’ capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

scholarly journals Role of Differentially Expressed Proteins in Acquired Resistance to Cdk4/6 Inhibitor in Breast Cancer

2021 ◽  
Author(s):  
Binayak Kumar ◽  
Peeyush Prasad ◽  
Ragini Singh ◽  
Ram Krishana Sahu ◽  
Ashutosh Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Targets ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Resistant Cell ◽  
Molecular Signature ◽  
Mcf 7 ◽  
Resistant Cells

Abstract CDK4/6 inhibitors (Abemaciclib, Ab and Palbociclib, Pb) stop the G1-phase in cell-cycle being used to cure advanced stage of breast cancer (BC). Acquired resistance is a major challenge in BC therapy. The molecular signature of the therapy resistance for Ab and Pb drugs in BC should be explored. Here, we developed Ab/Pb-resistant cell-models and explored the molecular changes. Drug’s resistance cells were developed in MCF-7 cells by continuous drug treatment and it was confirmed by MTT-assay, PI-staining-microscopy, and real-time-qPCR. Global proteome profiling done by Labelled-free-Proteome-Orbitrap-Fusion-MS-MS technique. Bioinformatics tools used to analyse the proteome data. Ab-resistant and Pb-resistant MCF-7 cells showed increased tolerance for the respective drug. The BCL-2 and MCL-1 survival genes were up-regulated, while the apoptosis genes BAD, BAX, CASP-3 and PARP-1were down-regulated in the resistant cells. Expression of the MDR-1, ABCG2, ESR-1, CDK4, CDK6, and Cyclin-D1 genes were increased in both resistance cells. For proteomics, 237 and 239 proteins were expressed differently in the resistant Ab and Pb cells, respectively. The NUDT5, PEPD, ABAT, ATP1B1, GGCT, and SELENBP1 proteins were down-regulated and the SBSN, HSD17B10, CD9, PDIA3, PSMB4, SLC2A1, and VTN proteins were up-regulated in Ab-resistant cells. The NUDT5, PEPD, and GGCT proteins were down-regulated, while CD47, HIST1H2BN, LMNA, VTN, PSMB5, HBB, PSMA7, FLNB, PRDX4, VDAC1, GOT2, HSPA5, SERPINH1, EIF4A2, FTH, and VIM proteins were up-regulated in Pb-resistant cells. These proteins are a new set of prognostic markers and drug targets for overcoming the respective drug resistance. However, it is necessary to perform an in vivo or clinical assessment.

scholarly journals Human Drug Efflux Transporter ABCC5 Confers Acquired Resistance to Pemetrexed in Breast Cancer

2021 ◽  
Author(s):  
Jihui Chen ◽  
Zhipeng Wang ◽  
Shouhong Gao ◽  
Kejin Wu ◽  
Fang Bai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Abc Transporters ◽  
Control Group ◽  
Apoptosis Pathway ◽  
Over Expression ◽  
Mcf 7

Abstract AimPemetrexed, a new generation antifolate drug, is approved for the treatment for locally advanced or metastatic breast cancer, but factors affecting the efficacy and resistance of it have yet to be fully explicit. ATP-binding cassette (ABC) transporters have been reported as prognostic and adverse effects predictors of many xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and may contribute to treatment regimen optimization for breast cancer.MethodsFirstly, the expression of ABC transporters family members was measured in cell lines, thereafter examined the potential role of ABC transporter in conferring resistance to pemetrexed in primary cancer cell lines isolated from 34 breast cancer patients, and then the role of ABCC5 in mediating transport of pemetrexed and apoptosis pathway in MCF-7 cell line was assessed. Finally, the functions of ABCC5 on therapeutic effect of pemetrexed was evaluated in breast cancer bearing mice.ResultsThe expressions of ABCC2, ABCC4, ABCC5 and ABCG2 were significantly increased in pan-resistance cell line, and the ABCC5, the most obvious one, was 5.21 times higher than that of the control group. The expression of ABCC5 was inversely correlated with sensitivity (IC50) of pemetrexed (r = 0.741; p<0.001) in breast cancer cells from 34 patients. Furthermore, we found that the expression of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cell line, and the IC50 were 0.06 μg/ml and 0.20 μg/ml in ABCC5 knock-down and over-expression cells, respectively. In in vivo study, we found ABCC5 affected the sensitivity of pemetrexed in breast cancer bearing mice, and the tumor volume was much larger in ABCC5 over-expression group than that in control group (2.7 folds vs 1.3 folds).ConclusionsOur results indicated ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and may be a biomarker for regimen optimization of pemetrexed in breast cancer treatment.

scholarly journals Human drug efflux transporter ABCC5 confers acquired resistance to pemetrexed in breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jihui Chen ◽  
Zhipeng Wang ◽  
Shouhong Gao ◽  
Kejin Wu ◽  
Fang Bai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Abc Transporters ◽  
Breast Cancer Cells ◽  
Breast Cancer Treatment ◽  
Control Group ◽  
Mcf 7

Abstract Aim Pemetrexed, a new generation antifolate drug, has been approved for the treatment of locally advanced or metastatic breast cancer. However, factors affecting its efficacy and resistance have not been fully elucidated yet. ATP-binding cassette (ABC) transporters are predictors of prognosis as well as of adverse effects of several xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and can contribute to the optimization of breast cancer treatment regimen. Methods First, we measured the expression levels of ABC transporter family members in cell lines. Subsequently, we assessed the potential role of ABC transporters in conferring resistance to pemetrexed in primary breast cancer cells isolated from 34 breast cancer patients and the role of ABCC5 in mediating pemetrexed transport and apoptotic pathways in MCF-7 cells. Finally, the influence of ABCC5 expression on the therapeutic effect of pemetrexed was evaluated in an in vivo xenograft mouse model of breast cancer. Results The expression levels of ABCC2, ABCC4, ABCC5, and ABCG2 significantly increased in the pan-resistant cell line, and the ABCC5 level in the MCF-7-ADR cell line was 5.21 times higher than that in the control group. ABCC5 expression was inversely correlated with pemetrexed sensitivity (IC50, r = 0.741; p < 0.001) in breast cancer cells derived from 34 patients. Furthermore, we found that the expression level of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cells, with IC50 values of 0.06 and 0.20 μg/mL in ABCC5 knockout and over-expression cells, respectively. In the in vivo study, we observed that ABCC5 affected the sensitivity of pemetrexed in breast tumor-bearing mice, and the tumor volume was much larger in the ABCC5-overexpressing group than in the control group when compared with their own initial volumes (2.7-fold vs. 1.3-fold). Conclusions Our results indicated that ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and it may serve as a target or biomarker for the optimization of pemetrexed regimen in breast cancer treatment.

scholarly journals Inhibition of Breast Tumour Growth with Intravenously Administered PRKCA siRNA- and PTEN Tumour Suppressor Gene-Loaded Carbonate Apatite Nanoparticles

2021 ◽  
Vol 11 (17) ◽  
pp. 8133
Author(s):  
Nabilah Ibnat ◽  
Rowshan Ara Islam ◽  
Ezharul Hoque Chowdhury
Keyword(s):  
Breast Cancer ◽  
Rna Interference ◽  
Mouse Model ◽  
Cell Line ◽  
Tumour Growth ◽  
Breast Tumour ◽  
Tumour Suppressor ◽  
Carbonate Apatite ◽  
Mcf 7

Gene therapy aims to silence an oncogene through RNA interference, or replace an abnormal tumour suppressor via gene augmentation. In this study, we intended RNA interference for PRKCA oncogene and gene augmentation for PTEN tumour suppressor with a view to reduce tumour growth in a mouse model of breast cancer. Inorganic carbonate apatite nanoparticles (CA NPs) were utilized to deliver the synthetic siRNA and the purified gene-carrying plasmid DNA both in vitro and in vivo. Effects of PRKCA siRNA- and PTEN plasmid-loaded NPs on viability of MCF-7, MDA-MB-231 and 4T1 breast cancer cells were assessed by MTT assay. The cell viability data in MCF-7 cell line demonstrated that combined delivery of PRKCA specific siRNA and PTEN plasmid with CA NPs had an additive effect to significantly decrease cellular growth compared to individual treatments. In addition, we observed a similar pattern of cumulative influence for combined treatment in triple negative MDA-MB-231 breast cancer cell line. Upon treatment with PRKCA siRNA+PTEN plasmid-loaded NPs, a remarkable decrease in the phosphorylated form of AKT protein of PI3K/AKT pathway was observed in Western blot, indicative of diminished proliferative signal. Moreover, in vivo study in MCF-7 xenograft breast cancer mouse model demonstrated that the rate of growth and final tumour volume were reduced significantly in the mouse group that received intravenous treatment of PRKCA siRNA+NPs, and PTEN plasmid+NPs. Our findings demonstrated that PRKCA siRNA and PTEN plasmid loaded into CA NPs attenuated breast tumour growth, suggesting their therapeutic potential in the treatment of breast cancer.

scholarly journals The antimicrobial peptide defensin cooperates with tumour necrosis factor to drive tumour cell death in Drosophila

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jean-Philippe Parvy ◽  
Yachuan Yu ◽  
Anna Dostalova ◽  
Shu Kondo ◽  
Alina Kurjan ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumour Necrosis Factor ◽  
Tumour Cell ◽  
Tumour Necrosis ◽  
Tumour Progression ◽  
Tumour Cells ◽  
Tumour Regression ◽  
Necrosis Factor

Antimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs’ capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties

2018 ◽  
Vol 18 (17) ◽  
pp. 1483-1493
Author(s):  
Ricardo Imbroisi Filho ◽  
Daniel T.G. Gonzaga ◽  
Thainá M. Demaria ◽  
João G.B. Leandro ◽  
Dora C.S. Costa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Hepatic Function ◽  
Anticancer Properties ◽  
Mcf 7

Background: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. Experimental: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. Results and Conclusion: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

Co-delivery of Doxorubicin and D-α-Tocopherol Polyethylene Glycol 1000 Succinate by Magnetic Nanoparticles

2018 ◽  
Vol 18 (8) ◽  
pp. 1138-1147 ◽  
Author(s):  
Esra Metin ◽  
Pelin Mutlu ◽  
Ufuk Gündüz
Keyword(s):  
Breast Cancer ◽  
Polyethylene Glycol ◽  
Magnetic Nanoparticles ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Drug Loading ◽  
Gravimetric Analysis ◽  
Polyethylene Glycol 1000 ◽  
Mcf 7

Background: Although conventional chemotherapy is the most common method for cancer treatment, it has several side effects such as neuropathy, alopecia and cardiotoxicity. Since the drugs are given to body systemically, normal cells are also affected, just like cancer cells. However, in recent years, targeted drug delivery has been developed to overcome these drawbacks. Objective: The aim of this study was targeted co-delivery of doxorubicin (Dox) which is an anticancer agent and D-α-Tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS or simply TPGS) to breast cancer cells. For this purpose, Magnetic Nanoparticles (MNPs) were synthesized and coated with Oleic Acid (OA). Coated nanoparticles were encapsulated in Poly Lactic-co-Glycolic Acid (PLGA) and TPGS polymers and loaded with Dox. The Nanoparticles (NPs) were characterized by Fourier Transform Infrared (FTIR) spectroscopy, zetapotential analysis, Dynamic Light Scattering (DLS) analysis, Thermal Gravimetric Analysis (TGA) and Scanning Electron Microscope (SEM) analysis. Results: The results showed that NPs were spherical, superparamagnetic and in the desired range for use in drug targeting. The targetability of NPs was confirmed. Moreover, TPGS and Dox loading was shown by TGA and FTIR analyses. NPs were internalized by cells and the cytotoxic effect of drug loaded NPs on sensitive (MCF-7) and drug-resistant (MCF-7/Dox) cells were examined. It was seen that the presence of TPGS increased cytotoxicity significantly. TPGS also enhanced drug loading efficiency, release rate, cellular internalization. In MCF- 7/Dox cells, the drug resistance seems to be decreased when Dox is loaded onto TPGS containing NPs. Conclusion: This magnetic PLGA nanoparticle system is important for new generation targeted chemotherapy and could be used for breast cancer treatment after in vivo tests.

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