45 research outputs found
A novel [Mn-2(mu-(C6H5)(2)CHCOO)(2)(bipy)(4)](bipy)(ClO4)(2) complex loaded solid lipid nanoparticles: synthesis, characterization and in vitro cytotoxicity on MCF-7 breast cancer cells
No full textManganese (Mn)-based complexes have been drawing attention due to the fact that they are more effective than other metal complexes. However, the use of Mn(II)-based complexes in medicine remains limited because of certain side effects. The aim of this study was to investigate the cytotoxic and apoptotic effects of a novel Mn(II) complex [Mn-2(mu-(C6H5)(2)CHCOO)(2)(bipy)(4)](bipy)(ClO4)(2) and Mn(II) complex loaded solid lipid nanoparticles (SLNs) on MCF-7 and HUVEC control cells. The average diameter of Mn(II) complex was about 1120 +/- 2.43nm, while the average particle size of Mn(II) complex-SLNs was approximate to 340 +/- 2.27nm. The cytotoxic effects of Mn(II) complex and Mn(II)-SLNs were 86.8 and 66.4%, respectively (p<.05). Additionally, both Mn(II) complex (39.25%) and Mn(II)-SLNs (38.05%) induced apoptosis and increased the arrest of G(0)/G(1) phase. However, Mn(II) complex exerted toxic effects on the HUVEC control cell (63.4%), whereas no toxic effects was observed when treated with Mn(II)-SLNs at 150M. As a consequence, SLNs might be potentially used for metal-based complexes in the treatment of cancer due to reducing size and toxic effects of metal-based complexes
Synthetically Lethal BMN 673 (Talazoparib) Loaded Solid Lipid Nanoparticles for BRCA1 Mutant Triple Negative Breast Cancer
No full textPurposeThe purpose of the study was to produce BMN 673 loaded solid lipid nanoparticles (SLNs) to improve its therapeutic index, to minimize toxicity and to overcome homologous recombination (HR)-mediated resistance.MethodsFirstly, BMN 673-SLNs were characterized using Nano Zeta Sizer. After treatment with different concentrations of BMN 673 and BMN 673-SLNs, cell viability of HCC1937((BRCA1-/-)), HCC1937-R (BMN 673-resistant) TNBC and MCF-10A normal human mammary breast epithelial cell line was analyzed by WST-1 assay. In an attempt to assess the therapeutic synthetic lethality efficacy of SLNs formulation, cell cycle arrest, DNA damage, mRNA expression levels of PARP1, H2AFX, RAD51 and BRCA1 gene were investigated. Then, PARP, ?H2AX, RAD51 and BRCA1 protein expression and nuclear localization were analyzed by western blot and immunofluorescence analysis.ResultsWhen compared with BMN 673, BMN 673-SLNs showed remarkably a decrease in HCC1937 and HCC1937-R cells with less damage to MCF-10A cells. BMN 673-SLNs significantly induced toxicity through double-stranded DNA breaks, G2/M cell cycle arrest and PARP cleavage in TNBC cells. Additionally, BMN 673-resistance was mediated by miR-107, miR-193b and miR-1255b targeting BRCA1 and RAD51 in HCC1937 and HCC1937-R cells. However, BMN 673-SLNs treatment could overcome HR-mediated resistance in TNBC cells.ConclusionsAs a result, our findings suggest that SLNs formulation strongly provides a synthetic lethal therapeutic potential in BRCA1 mutated sensitive and resistant TNBC cells
E-Health and Bioengineering Conference
No full textThe anti-estrogen tamoxifen (Tam) is the most preferred option for patients with estrogen-receptor (ER)-positive breast cancer. However, multi-drug resistance (MDR) is a considerable clinical problem in the successful chemotherapeutic treatment. Members of the ATP-binding cassette (ABC) transporter family proteins play an important role in acquired drug resistance. Many studies have focused primarily on the clinical significance of P-gp (MDR1), BCRP and MRP1 members belong to ABC transporter superfamily on anticancer-drug resistance. Consequently, several strategies have been improved to overcome drug resistance. Nanoparticle drug delivery systems provide an increase in the intracellular concentration of the drugs as well as a reduction in toxicity of free-drug on healthy cells thanks to unique physical and biological properties. Solid lipid nanoparticles (SLNs) have been improved as an alternative colloidal drug delivery systems due to successful incorporation of both hydrophilic and hydrophobic compounds and their related benefits (controlled drug release, high entrapment efficiency and small size etc.) For this purpose, the aim of this study was to discuss the role of Tam-loaded solid lipid nanoparticles (SLNs) to overcome MDR and determine the ability of Tam-SLNs to induce apoptosis
An in vitro model for the development of acquired tamoxifen resistance
No full textThe development of resistance to tamoxifen (Tam) remains a challenging clinical problem for ER+ breast cancer patients. To understand the mechanisms underlying of resistance, previous studies have driven the acquisition of Tam resistance by exposing cells to varying concentration of drug for varying lengths of time. However, a detailed protocol for the establishment of Tam-resistant cells remains to be clarified. In the present study, we aimed to determine and compare the effect of different in vitro protocols on the degree of resistance to 4-hydroxytamoxifen (4-OH Tam) for MCF7 cells. For this purpose, MCF7-Tam resistance (MCF7-TamR) cells were developed by treated with different concentrations (100, 200, 400, 600, 800 and 1000 nM) of 4-OH Tam over 3 months. The relative resistance was measured by WST-1 analysis. Studies characterizing of the 4-OH Tam resistance of MCF7-TamR cells were performed by 17 beta-oestradiol (E2) and Annexin V/PI analysis. In addition, the expression levels of ABCC1, ABCG2 and ABCG1 were detected by RT-PCR, any changes in morphological of each resistance group were observed at the end of each month and compared with parental MCF7 cells. Consequently, exposure time and concentration can affect the degree of resistance to 4-OH Tam; thus, dose and treatment duration should be chosen according to the desired degree of resistance. This work presents a novel procedure for the generation of MCF7-TamR cells, thus enabling the identification and characterization of MCF7-TamR cells
Triple negative breast cancer: new therapeutic approaches and BRCA status
No full textTreatment of triple negative breast cancer (TNBC) is a clinically challenging problem due to intriguing clinical and pathologic features of TNBC and natural or induced resistance to existing therapies. However, a great understanding of features of TNBC particularly associated with BRCA mutations has led to the development of different therapeutic approaches. Besides, identification of TNBC subtypes contribute to investigation of the underlying molecular differences and development of new strategies for the treatment of TNBC patients. In this review, we discussed the definition and characteristic properties of TNBC. We summarized an up-to-date description of the reported clinical trials of novel targeted strategies especially PARP inhibitors (PARPi) due to novel and highly potent for the treatment of TNBC. Additionally, we reviewed published studies which investigated the prevalence and types of BRCA1/2 mutation in breast cancer patients to assess and draw attention of association of BRCA status with TNBC. Consequently, the definition subtype of TNBC has important predictive value for the development of new therapeutic agents in the treatment of TNBC. Additionally, the incidence and types of mutations in BRCA-related pathways may be affected by ethnic origin and contribute to the risk of developing TNBC
Investigation of APC mutations of a patient with FAP and her family members by heterodublex analyses
No full textFamilial adenomatous polyposis coli (FAP) is an autosomal dominant disease characterised by the presence of 100 or more colorectal adenomatous polyps. Mutations in the adenomatous polyposis gene(APC) gene primarily responsible for the development of this disease. In this study, we examined one patient with FAP and 21 family members including one effected person from FAP and 20 nonsemptomatic persons. Our proband case who have a retinal lesions (congenital hypertrophy of the retinal pigment epithelium,called CHRPE) and hundreds adenomatous polyps on all colon and rectum is a 36 years old woman. We isolated DNA from pheripheral blood samples of proband and her family members by proteinaz K incubation and phenol-chloroform extraction. We studied E,D, F,and G segments of exon 15 of APC gene by heterodublex analyses (HDA). For staining, we used non-radioactive silver staining method. We determined mutation in 5 person from this family in segmentF of exon 15 of APC. Two of them were patients with FAP (one is ourproband case) and another three persons were non semptomatic family members. Result of sequencing analysis of these cases, wedetermined T deletion at position 3554 causing a frameshift mutation in APC gene
Association of PALB2 sequence variants with the risk of early-onset breast cancer in patients from Turkey
No full textPotential role of solid lipid nanoparticles in overcoming the acquired tamoxifen resistance of breast cancer
No full textTalazoparib nanoparticles for overcoming multidrug resistance in triple-negative breast cancer
No full textHerein, we investigated efflux pumps-mediated talazoparib-resistance in the treatment of triple-negative breast cancer (TNBC). Furthermore, we produced a novel talazoparib-solid lipid nanoparticles (SLNs) and then explored in vitro therapeutic efficacy of talazoparib-SLNs to overcome talazoparib-resistance in TNBC cells. Talazoparib-SLNs formulation was produced and then characterized. Calcein and Rho-123 were used to analyze the functional activity of drug efflux pumps in these cells. Additionally, RT-PCR, western blot and immunofluorescence analysis were used to detect the messenger RNA, and protein expression level, and cellular localization of the multidrug resistance (MDR1), breast cancer resistance protein (BCRP), and MRP1. We found that talazoparib efflux was mediated by BCRP and MRP1 pumps in TNBC cells. Talazoparib-SLNs could significantly enhance therapeutic efficacy of talazoparib. Furthermore, talazoparib-SLNs were more effective in the suppression of MDR1, BCRP, and MRP1 gene and protein expression levels than talazoparib. Consequently, this study suggests that talazoparib-SLNs formulation represents a promising therapeutic carrier to reverse MDR-mediated resistance in TNBC
Investigation of APC mutations in a Turkish familial adenomatous polyposis family by heterodublex analysis
No full textPURPOSE: Familial adenomatous polyposis is an autosomal dominant disease characterized by the presence of 100 or more colorectal adenomatous polyps. Mutations in the adenomatous polyposis coli gene are primarily responsible for the development of this disease. This study was designed to investigation of adenomatous polyposis coli (APC) gene mutations in members of familial adenomatous polyposis family to identify individuals at risk of the disease. METHODS: We examined one patient with familial adenomatous polyposis and 21 family members including one affected person from familial adenomatous polyposis and 20 nonsymptomatic persons. We studied E, D, F, and G segments of exon 15 of the adenomatous polyposis coli gene by heteroduplex analysis. RESULTS: We used silver staining method for staining. We found a mutation for five persons at segment F of exon 15 of the adenomatous polyposis coli gene. Two of them were affected by colorectal cancer, one of whom was the proband, and the other three were non-symptomatic family members. The pathogenetic mutation was a T deletion at codon 1172, causing a frameshift in the adenomatous polyposis coli gene, as a result of the sequencing analysis of these cases. CONCLUSIONS: Investigation of adenomatous polyposis coli gene mutations is very important for the identification of genetic susceptibility to colorectal cancer and for the definition of tumor developing at an early stage. Furthermore, the identification of this mutation for the first time in a Turkish family will be useful to foster further studies on familial adenomatous polyposis in Turkey
