Overexpression of RSK4 reverses doxorubicin resistance in human breast cancer cells via PI3K/AKT signalling pathway

2020 ◽  
Vol 167 (6) ◽  
pp. 603-611
Author(s):  
Yan Mei ◽  
Xiaoming Liao ◽  
Lingyu Zhu ◽  
Huawei Yang
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Migration ◽  
Western Blot ◽  
Tumour Growth ◽  
Metastatic Breast ◽  
Signalling Pathway ◽  
Chemotherapy Drugs ◽  
Mcf 7

Abstract Doxorubicin (DOX) is one of the most effective chemotherapy drugs for the treatment of metastatic breast cancer (BC), but drug resistance becomes an obstacle to treatment. This study aims to investigate the role of Ribosomal S6 protein kinase 4 (RSK4) in regulating BC resistance to DOX. We first used Kaplan–Meier Plotter to identify the prognostic roles of RSK4 in BC. DOX-resistant BC cells (MCF-7/DOX) were constructed and the expression of RSK4 was determined by reverse transcript polymerase chain reaction and western blot. Subsequently, we overexpressed the RSK4 in MCF-7/DOX cells, and measured drug resistance, colony formation, cell migration, invasion ability and cell apoptosis after transfection. In addition, western blot was used to explore the expression of apoptosis-related proteins and BC-resistance protein. Effects of RSK4 on activation of the PI3K/AKT signalling pathway were also tested. Furthermore, tumour xenograft in nude mice was constructed to observe the effect of RSK4 overexpression on tumour growth in vivo. In conclusion, RSK4 was positively correlated with survival rate in BC patients, which is lowly expressed in MCF-7/DOX. Meanwhile, the overexpression of RSK4 may inhibit drug resistance, cell migration, invasion, apoptosis and tumour growth. RSK4 may effectively attenuate DOX resistance in BC by inhibiting the PI3K/AKT signalling pathway.

scholarly journals Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Shravanti Mukherjee ◽  
Santanu Adhikary ◽  
Shrikanth S. Gadad ◽  
Payel Mondal ◽  
Sabyasachi Sen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Tumor Regression ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Good Prognosis ◽  
Sublethal Dose ◽  
Tumorigenic Potential

AbstractThe major challenge in chemotherapy lies in the gain of therapeutic resistance properties of cancer cells. The relatively small fraction of chemo-resistant cancer cells outgrows and are responsible for tumor relapse, with acquired invasiveness and stemness. We demonstrate that zinc-finger MYND type-8 (ZMYND8), a putative chromatin reader, suppresses stemness, drug resistance, and tumor-promoting genes, which are hallmarks of cancer. Reinstating ZMYND8 suppresses chemotherapeutic drug doxorubicin-induced tumorigenic potential (at a sublethal dose) and drug resistance, thereby resetting the transcriptional program of cells to the epithelial state. The ability of ZMYND8 to chemo-sensitize doxorubicin-treated metastatic breast cancer cells by downregulating tumor-associated genes was further confirmed by transcriptome analysis. Interestingly, we observed that ZMYND8 overexpression in doxorubicin-treated cells stimulated those involved in a good prognosis in breast cancer. Consistently, sensitizing the cancer cells with ZMYND8 followed by doxorubicin treatment led to tumor regression in vivo and revert back the phenotypes associated with drug resistance and stemness. Intriguingly, ZMYND8 modulates the bivalent or poised oncogenes through its association with KDM5C and EZH2, thereby chemo-sensitizing the cells to chemotherapy for better disease-free survival. Collectively, our findings indicate that poised chromatin is instrumental for the acquisition of chemo-resistance by cancer cells and propose ZMYND8 as a suitable epigenetic tool that can re-sensitize the chemo-refractory breast carcinoma.

Predictive computer simulations of tumor drug response demonstrate that 3-D hypoxic gradients significantly increase drug resistance

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2071-2071
Author(s):  
V. Cristini ◽  
H. Frieboes ◽  
J. Fruehauf
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Breast Cancer Cells ◽  
Drug Response ◽  
Tumor Response ◽  
Response To Chemotherapy ◽  
Input Variables ◽  
Mcf 7

2071 Background: We created a three-dimensional physiologically based computer (in-silico) model of cancer based on a description of biological events at the cellular scale with input variables determined from patient specific information, such as in-vitro drug response experiments and in-vivo tumor imaging, with the long term goal of individualized treatment selection. The central hypothesis is that such a model that incorporates basic tumor growth kinetics information is capable of representing and predicting tumor response to chemotherapy. Methods: We measured in-vitro tumor growth and drug response for Doxorubicin sensitive and resistant MCF-7 breast cancer cells through trypan blue exclusion counts, tridiated thymidine incorporation, and the XTT assay. We used these results of parameter-based statistics to define input variables to our in-silico model of cancer, and ran computer simulations to measure the drug response predicted by the model. Results: The computer model could accurately predict the in-vitro response of drug sensitive and resistant MCF-7 breast cancer cells. The model also predicted that gradients of oxygen and nutrient in a tumor microenvironment, whether naturally occurring or induced by treatment, and which in previous work we found could increase the invasive capability of tumor cells and destabilize tumor morphology, could also contribute to acquired drug resistance by increasing the population of quiescent cells. Conclusions: We demonstrated that a rigorously, experimentally calibrated computer model of cancer is accurately predictive of in-vitro tumor response to chemotherapeutic drugs, and established that this model offers a means to quantitatively study tumor drug response. We did this through a grounds-up physical representation of tumor biology, not by fitting to experimental data. This validation begins the path to computational modeling and more efficient prediction of in-vivo tumor response to chemotherapy. No significant financial relationships to disclose.

scholarly journals Exosomes from tamoxifen-resistant breast cancer cells transmit drug resistance partly by delivering miR-9-5p

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jianhui Liu ◽  
Shaoliang Zhu ◽  
Wei Tang ◽  
Qinghua Huang ◽  
Yan Mei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Line ◽  
Bioinformatic Analysis ◽  
In Vivo Experiments ◽  
Luciferase Activity Assay ◽  
Tamoxifen Resistant ◽  
Mcf 7

Abstract Background Resistance to drug therapy is a major impediment for successful treatment of patients suffering from breast cancer (BC). Tamoxifen (TAM) is an extensively used therapeutic agent, which substantially reduces the risk of recurrence and associated mortality in BC. This study demonstrated that exosomal transfer of microRNA-9-5p (miR-9-5p) enhanced the resistance of MCF-7 cells to TAM. Methods Initially, BC-related differentially expressed genes (DEGs) and their upstream regulatory miRNAs were identified. The TAM-resistant MCF-7 (MCF-7/TAM) cell line and the non-medicated sensitive MCF-7 cell line were formulated, followed by isolation of the exosomes. Next, the apoptosis rate of exosome-treated MCF-7 cells was determined after co-culture with TAM. The interaction between miR-9-5p and ADIPOQ was identified by a combination of bioinformatic analysis and luciferase activity assay. In order to validate the effect of miR-9-5p and ADIPOQ on TAM resistance in the MCF-7 cells in vitro and in vivo, miR-9-5p was delivered into the exosomes. ADIPOQ and miR-9-5p were identified as the BC-related DEG and upstream regulatory miRNA. Results Exosomes derived from the MCF-7/TAM cells could increase the resistance of MCF-7 cells to TAM. Notably, miR-9-5p altered the sensitivity of BC cells to TAM. In addition, ADIPOQ was negatively regulated by miR-9-5p. Furthermore, MCF-7/TAM cell-derived miR-9-5p inhibited the apoptosis of MCF-7 cells, and promoted the cell resistance to TAM. In vivo experiments in nude mice ascertained that the tumor injected with exosomal miR-9-5p showed improved resistance to TAM. Conclusions Exosomal transfer of miR-9-5p augmented the drug resistance of BC cells to TAM by down-regulating ADIPOQ, suggesting its functionality as a candidate molecular target for the management of BC.

scholarly journals Ad-Apoptin-hTERTp-E1a Regulates Autophagy Through the AMPK-mTOR-eIF4F Signaling Axis to Reduce Drug Resistance of MCF-7/ADR Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Yaru Li ◽  
Yilong Zhu ◽  
Jicheng Han ◽  
Jinbo Fang ◽  
Zhiru Xiu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Cell Death ◽  
Induce Cell Death ◽  
Chemotherapy Drugs ◽  
Signaling Axis ◽  
Mcf 7

Ad-VT (Ad-Apoptin-hTERTp-E1a) is a type of oncolytic adenovirus with dual specific tumor cell death ability. It can effectively induce cell death of breast cancer cells and has better effect when used in combination with chemotherapy drugs. However, it has not been reported whether Ad-VT reduces the resistance of breast cancer cells to chemotherapy drugs. The purpose of this study is to investigate the effect of Ad-VT on drug resistance of Adriamycin-resistant breast cancer cells. For this, the effects of different doses of Ad-VT on the resistance of breast cancer cells to Adriamycin were analyzed using qualitative and quantitative experiments in vitro and in vivo. The Ad-VT can reduce the resistance of MCF-7/ADR to adriamycin, which is caused by the reduction of MRP1 protein level in MCF-7/ADR cells after treatment with Ad-VT, and MRP1 can be interfered with by autophagy inhibitors. Subsequently, the upstream signal of autophagy was analyzed and it was found that Ad-VT reduced the resistance of cells to doxorubicin by reducing the level of mTOR, and then the analysis of the upstream and downstream proteins of mTOR found that Ad-VT increased the sensitivity of MCF-7/ADR cells to adriamycin by activating AMPK-mTOR-eIF4F signaling axis. Ad-VT can not only significantly induce cell death in MCF-7/ADR cells, but also improved their sensitivity to Adriamycin. Therefore, the combination of Ad-VT and chemotherapy drugs may become a new strategy for the treatment of breast cancer in overcoming Adriamycin resistance.

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 Artemisinic acid exhibits antitumor activity in MCF-7 breast cancer cells through the inhibition of angiogenesis, VEGF, m-TOR and AKT signalling pathways

2016 ◽  
Vol 11 (3) ◽  
pp. 691
Author(s):  
Yan Cui ◽  
Hui Ren ◽  
Hao-Chang Li ◽  
Quan-Shi Wang
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Antitumor Activity ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tube Formation ◽  
Signalling Pathways ◽  
Artemisinic Acid ◽  
Mcf 7

<p>The aim of the present study was to evaluate the antitumor and anti-angiogenic effects of artemisinic acid in MCF-7 human breast cancer cells. Various cell signalling pathways (VEGF, m-TOR and AKT signalling pathways) and MTT assay were used. The in vivo antitumor activity of artemisinic acid was evaluated by means of tumor xenograft mouse model. Transwell cell migration assay was used to examine the chemotactic motility of the human umbilical vascular endothelial cells (HUVECs), while as endothelial cell capillary-like tube formation assay was used to evaluate the effect of artemisinic acid on the tube formation in HUVECs. We found that artemisinic acid considerably reduced both the volume and weight of concrete tumors and reduced angiogenesis in a xenograft mouse tumor model in vivo. Further, artemisinic acid suppressed the VEGF-induced cell migration and capillary-like tube formation of HUVECs in a dose-dependent manner. Artemisinic acid was found to suppress the VEGF-induced phosphorylation of VEGFR2 and also the activity of AKT and m-TOR.</p><p><strong>Video Clip:</strong></p><p><a href="https://youtube.com/v/w7jZqcDvMTc">Western blot assay:</a> 4 min 33 sec </p>

Update of a phase II trial of bevacizumab in combination with hormonal therapy to reverse acquired estrogen independence in metastatic breast cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e12027-e12027
Author(s):  
C. Falkson ◽  
J. Rossman ◽  
L. Nabell ◽  
J. Carpenter ◽  
A. Forero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Hormonal Therapy ◽  
Metastatic Breast ◽  
Hormone Resistance ◽  
Breast Cancer Patients ◽  
Grade 3 ◽  
Mcf 7

e12027 Background: Metastatic breast cancer (MBC) remains the second most common cause of cancer death in women in the US. More than 80% of breast cancers are potentially hormone responsive, but resistance eventually precludes cure. Various mechanisms of acquired hormone resistance have been postulated. Our Breast Cancer SPORE showed that increased expression of VEGF caused acquired tamoxifen resistance in MCF-7 xenografts. VEGF over-expressing MCF-7 cells displayed increased tumor growth rates and estrogen independence in vivo, and reversal of VEGF over-expression in vivo returned tumors to estrogen dependent growth. Methods: We hypothesized that adding the anti-VEGF monoclonal antibody, bevacizumab, to hormonal therapy would result in reversal of acquired hormone resistance. This multi-center, open-label, single arm phase II study was designed to evaluate safety and efficacy of this combination. Primary end point was time to progression (TTP), and the secondary endpoints were response rate and toxicity. Eligible patients had MBC and had progressed on hormonal therapy after previously responding for at least 6 months.Results: We previously reported a planned interim analysis. Results of further analysis after completion of accrual will be reported here. All 27 patients were female with median age of 63 years, and all had ER and/or PR positive MBC. Patients were continued on the same hormonal therapy to which they had become refractory, and bevacizumab (15mg/kg IV every 3 weeks) was added. Treatment was stopped early in 3 patients due to a grade 3 leg ulcer, grade 3 hypertension, and grade 3 fatigue, respectively. Overall, the therapy was tolerated well, and no treatment related deaths or thromboembolic events were seen. Stable disease was documented in 18 (66%) patients. There were no complete or partial responses. Updated median TTP will be reported. Conclusions: The combination of bevacizumab plus hormonal therapy is well tolerated in patients with metastatic breast cancer. This combination may prolong the TTP with acceptable toxicity. Further investigation utilizing this combination in metastatic breast cancer are ongoing. [Table: see text]

IN-VITRO AND IN-VIVO STUDIES OF THE POSSIBLE CHEMOPREVENTIVE FUNCTIONS OF SOYBEAN ISOFLAVONE AND FLAVONOIDS ON BREAST CANCER

2019 ◽  
Vol 31 (06) ◽  
pp. 1950045
Author(s):  
Shoei-Loong Lin ◽  
Ming-Tse Lin ◽  
Mei-Yan Chen ◽  
Ting-Kai Leung
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
In Vivo Experiment ◽  
Mcf 7

Objectives: In this study, we assess the possible influence of soybean isoflavone (genistein) and other flavonoids (quercetin and catechin) on breast cancer chemoprevention. We design in-vitro and in-vivo experiments to analyze the effect of genistein, quercetin and catechin on cell proliferation, cell migration, and angiogenesis of breast cancer cells. Methods: In cell proliferation experiment, MCF-7 cells, SKBR-3 cells, and HUVEC cells were treated with genistein and other flavonoids (catechin and/or quercetin) for 48[Formula: see text]h to assess the influence on cell growth of normal and breast cancer cells. In cell motility test, we analyze the effect of isoflavone and flavonoids on migration ability of MCF-7 cells by 16[Formula: see text]h and SKBR-3 cells by 24[Formula: see text]h in two different concentrations (1.25[Formula: see text][Formula: see text]g/ml and 2.5[Formula: see text][Formula: see text]g/ml). In the in-vivo experiment, SKBR-3 cells mixed with PBS and catechin, respectively, were injected subcutaneously into nude mice, then we investigated the effect of catechin on cell growth by observing subcutaneous tumor size changes after 15 days. Results: The results suggest that genistein and quercetin can significantly inhibit proliferation of breast cancer cells, and their inhibitory effects are independent of estrogen receptor. In cell motility tests, all of the three phytochemicals were effective in the inhibition of cell migration on two breast cancer cell lines, except for quercetin on cell migration of SKBR-3 cell line. In the in-vitro experiment, catechin showed stimulatory effect on cell proliferation of HUVEC cell line, which may consider positive effect on angiogenesis, rather than inhibitory effect. However, in the in-vivo experiment, it showed no significant change in tumor size between the groups of with and without catechin treatment. Conclusions: According to our study, the results suggest that isoflavone and flavonoids tend to inhibit cell growth and metastasis of breast cancer cells. Our in-vivo experiment does not reach a significant result, and it may be due to lower catechin concentration. Under in-vivo environment, we should also consider the possible metabolic forms of catechin that cause different result from the in-vitro study.

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.

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