Browsing by Subject "Panobinostat"

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Open Access
Characterization of chemosensitivity profiles of breast cancer cell lınes, with and without stem cell like features = Kök-hücre özelliği olan ve olmayan meme kanseri hücre hatlarının ilaç hassasiyet profillerinin tanımlanması
(2014) Akbar, Muhammad Waqas
Breast cancer is the second most common cause of death worldwide from cancer due to complications with its diagnosis and resistance to therapy. Recent studies have shown that breast tumors when compared with other solid tumors also contain a subpopulation termed as cancer stem cells (CSCs). CSCs are hard to kill due to their therapy resistant capacities. These unharmed cells then result into relapse of tumor after treatment. Some established breast cancer cell lines also behave in similar fashion to CSCs in overall manner thus termed as CSC like cell lines. This study primarily focuses on characterizing CSC like cell lines from non CSC like cell lines based upon their gene expression and prediction of drugs which can target these groups separately. In this study two databases, Cancer Cell Line Encyclopedia (CCLE) and Cancer Genome Project (CGP), were used which contain gene expression data and drugs cytotoxicity data for most of the established cancer cell lines. Breast cancer cell lines gene expression data was used to predict two gene lists which can separate breast cancer cell lines into CSC like and non CSC like cell lines by in silico analysis. These gene lists were named as Patentable and Non Patentable. Additionally four drugs were predicted which can target CSC like group (Midostaurin and Elesclomol) and non CSC like group (Panobinostat and Lapatinib) separately. Later these findings were validated in vitro. Non Patentable gene list could not be validated due to low concordance with microarray data. On the other hand, Patentable gene list was validated and was found concordant with microarray data. Out of four selected drugs, Panobinostat and Lapatinib showed increased toxicity to non CSC like cell lines while only Midostaurin showed toxicity to CSC like cell lines. To investigate further that cell lines were grown in 3D cell culture conditions, to increase their stem cell like properties (stemness). But only one cell line MDA-MB-157 which was found as CSC like, showed expected behavior. Additionally this cell line increased resistance to Lapatinib and Panobinostat and became more sensitive to Midostaurin. Correlation analysis showed some genes as potential biomarkers for selected drugs. In conclusion, in this study various genes are proposed to differentiate CSC like cell lines from non CSC like cell lines. And Midostaurin can be potential drug to treat CSC like cells while Lapatinib and Panobinostat showed increased activity against non CSC like cell lines.
Open Access
Identification of a novel experimental model to reveal mechanisms leading to epigenetic changes and subsequent activation of cancer testis genes in cancer
(2016-08) Küçükkaraduman, Barış
Epigenetic aberrations are frequently observed in cancer. Tumor-suppressor genes are often repressed with anomalous hypermethylation in cancer, while DNA hypomethylation has been identified in repetitive sequences and promoter regions of cancer testis (CT) genes resulting in genomic instability. Although it has been shown that CT genes are often regulated by dissociation of repressive proteins from promoter-proximal regions and epigenetic mechanisms, including DNA methylation, histone methylation and acetylation, the process leading to epigenetic changes and de-repression of CT genes remains largely unknown. This study aimed to reveal molecular mechanisms which may have role in coordinating CT gene expression. For this purpose, we designed two groups of experiments. The first was based on extending our previous observations related to two genes (ALAS2, CDR1) which showed inverse expression patterns, compared to CT genes in cancer cell lines. The ex vivo analysis of expression patterns of these genes, however, did not support an inverse relation between their expression and that of CT genes. The second approach was based on categorizing cancer cells into CT-high, CT-intermediate and CT-low groups to define differentially expressed non-CT genes that could help explain mechanisms underlying epigenetic changes and subsequent activation of CT genes. Surprisingly, we could not identify any transcripts that differentially expressed between these subgroups. We therefore, hypothesized that non-overlapping and distinct mechanisms could be involved in the upregulation of CT genes in different tumors. As our earlier work suggested a relationship between epithelial to mesenchymal transition (EMT) and CT expression we asked if an EMT based classification could help elucidate these mechanisms. Indeed, differential genes and differentially activated signaling pathways were discovered when cancer cells were first grouped by their EMT status. This helped us identify candidate proteins (BMI1, PCGF2, RB1 and RBL1) and pathways including MAPK/ERK and PTEN/PI3K pathways which can coordinate CT gene expression in cancer. Thirdly, we investigated clinical relevance of high CT gene expression in triple negative breast cancer by attempting to correlate this with drug sensitivity. Drug sensitivity against panobinostat showed correlation with CT gene expression. In summary, this study suggests new approaches to elucidate mechanisms which coordinate epigenetic aberrations in cancer and how these can be utilized for cancer therapy.