Chitosan-Dextran sulfate coated doxorubicin loaded PLGA-PVA-nanoparticles caused apoptosis in doxorubicin resistance breast cancer cells through induction of DNA damage

Siddharth, Sumit; Nayak, Anmada; Nayak, Deepika; Bindhani, Birendra Kumar; Kundu, Chanakya Nath

doi:10.1038/s41598-017-02134-z

Cited by 43 publications

(22 citation statements)

References 13 publications

(27 reference statements)

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“…DNA damage is a major mechanism by which doxorubicin acts in BC or TNBC ( 28 – 30 ). To test our hypothesis, γH2A staining was used as a direct way to show shifts in DNA damage and drug resistance in BC cells.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

Zhao

Zhang

et al. 2021

Front. Oncol.

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Doxorubicin (DOX) is a cytotoxic drug used for the treatment of breast cancer (BC). However, the rapid emergence of resistance toward doxorubicin threatens its clinical application, thus the need for combination therapy. Here, we interrogate the role of Emodin, a chemical compound with tumor inhibitory properties, in the resistance of BC to Doxorubicin. We first evaluated the efficacy of Emodin in the treatment of BC cells. We then used γH2A to examine doxorubicin-induced DNA damage in BC cells, with or without Emodin. Data from CCK-8, flow cytometry, and tumor xenograft assays showed that Emodin suppresses the growth of BC cells. Further, we demonstrated that Emodin enhances γH2A levels in BC cells. Moreover, bioinformatics analysis and western blot assays indicated that Emodin down-regulates the AKT1 expression, and marginally decreases the levels of DNA damage proteins (XRCC1, PARP1, and RAD51) as well as increased p53 expression in BC cells. Taken together, our data demonstrates that Emodin affects cell proliferation, and DNA damage pathways in BC cells, thus increasing the sensitivity of BC cells to doxorubicin. Besides, we confirmed that Emodin confers sensitization of BC to doxorubicin through AKT1-mediated DNA.

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Section: Resultsmentioning

confidence: 99%

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

Zhao

Zhang

et al. 2021

Front. Oncol.

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“…Doxorubicin (ADR), a derivative of the natural product daunomycin, works by intercalating DNA and inhibiting the religation step of topoisomerase II. It has long been used as a first-line chemotherapeutic drug to treat breast cancer [3-5]. Unfortunately, doxorubicin drug resistance appears in nearly 50% of treated patients [3].…”

Section: Introductionmentioning

confidence: 99%

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Xu¹,

Chen²,

Yang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Poor response to chemotherapy leads to the relapse and metastatic progression of tumors. Reprogrammed glucose metabolism is one of the important hallmarks of cancer that facilitates cancer cell survival, proliferation and chemoresistance. However, the precise fate of glucose metabolism and its role in therapy responsiveness in cancers remains largely unexplored. Methods: The glycolytic phenotype of doxorubicin (ADR)-resistant breast cancer cells and their parental cells was assessed by measuring glucose uptake, lactate release, and extracellular acidification rate (ECAR). Protein expression was detected by Western blotting analysis and mRNA expression was detected using q-PCR. Cell survival ratio was determined by the cell counting kit 8 assay. The role of fibroblast growth factor receptor 4 (FGFR4) in glycolysis, chemoresistance, and the underlying mechanisms were studied by using gene expression microarray and short hairpin RNA-mediated gene knockdown. Results: We found that glycolytic flux are increased in two doxorubicin (ADR)-resistant breast cancer cell lines compared with their parental wild type cells, as demonstrated by increased glucose uptake, lactate release, and extracellular acidification rate (ECAR). By gene expression microarray, we identified FGFR4 as a critical modulator of ADR resistance and enhanced glucose metabolism. Genetic silencing of FGFR4 increased the chemosensitivity and suppressed the enhanced glycolytic flux in ADR-resistant cells. Mechanistically, activation of FGFR4 signaling in ADR-resistant cells led to the phosphorylation of FGF receptor substrate 2 (FRS2) and further activated the downstream MAPK/ERK signaling. Pharmacological inhibition of FGFR4-FRS2-ERK signaling pathway significantly blocked the chemoresistant and glycolytic phenotypes of ADR-resistant cells. Conclusion: Our findings suggest that high levels of FGFR4 can increase glucose metabolism and lead to chemoresistance in breast cancer and reveal the mechanistic basis for targeting FGFR4 as a therapeutic opportunity for chemoresistant tumors.

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“…DOX acts by inhibiting the topoisomerase activity which disrupts the regulation of cell cycle in S-phase and cells are unable to cross the S-G2 transition in cancer cells 48. An excessive DNA damage in S-phase might be one of the major causes of cell death, showing considerable cell arrest at S-phase for DOX-NP/DOX-Ab-NP treatment than that of free-DOX.…”

Section: Discussionmentioning

confidence: 99%

<p>CD-340 functionalized doxorubicin-loaded nanoparticle induces apoptosis and reduces tumor volume along with drug-related cardiotoxicity in mice</p>

Mondal¹,

Mukherjee²,

Das³

et al. 2019

IJN

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Background and objectiveTargeted drug delivery of nanoparticles decorated with site-specific recognition ligands is of considerable interest to minimize cytotoxicity of chemotherapeutics in the normal cells. The study was designed to develop CD-340 antibody-conjugated polylactic-co-glycolic acid (PLGA) nanoparticles loaded with a highly water-soluble potent anticancer drug, doxorubicin (DOX), to specifically deliver entrapped DOX to breast cancer cells.MethodsThe study showed how to incorporate water-soluble drug in a hydrophobic PLGA (85:15) based matrix which otherwise shows poor drug loading due to leaching effect. The optimized formulation was covalently conjugated to anti-human epidermal growth factor receptor-2 (HER2) antibody (CD-340). Surface conjugation of the ligand was assessed by flow cytometry, confocal microscopy, and gel electrophoresis. Selectivity and cytotoxicity of the experimental nanoparticles were tested on human breast cancer cells SKBR-3, MCF-7, and MDA-MB-231. Both CD-340-conjugated and unconjugated nanoparticles were undergone in vitro and in vivo characterization.ResultHigher level of incorporation of DOX (8.5% W/W), which otherwise shows poor drug loading due to leaching effect of the highly water-soluble drug, was seen in this method. In HER2-overexpressing tumor xenograft model, radiolabeled antibody-conjugated nanoparticles showed preferentially more of the formulation accumulation in the tumor area when compared to the treatments with the unconjugated one or with the other control groups of mice. The ligand conjugated nanoparticles showed considerable potential in reduction of tumor growth and cardiac toxicity of DOX in mice, a prominent side-effect of the drug.ConclusionIn conclusion, CD-340-conjugated PLGA nanoparticles containing DOX preferentially delivered encapsulated drug to the breast cancer cells and in breast tumor and reduced the breast tumor cells by apoptosis. Site-specific delivery of the formulation to neoplastic cells did not affect normal cells and showed a drastic reduction of DOX-related cardiotoxicity.

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Chitosan-Dextran sulfate coated doxorubicin loaded PLGA-PVA-nanoparticles caused apoptosis in doxorubicin resistance breast cancer cells through induction of DNA damage

Cited by 43 publications

References 13 publications

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

RETRACTED: Emodin Interferes With AKT1-Mediated DNA Damage and Decreases Resistance of Breast Cancer Cells to Doxorubicin

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

<p>CD-340 functionalized doxorubicin-loaded nanoparticle induces apoptosis and reduces tumor volume along with drug-related cardiotoxicity in mice</p>

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