Phd Degree / Doktora

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Multi-organ-on-a-chip for cancer drug testing
(Izmir Institute of Technology, 2022) Mohammed, Abdurehman Eshete; Pesen Okvur, Devrim; Erdal Bağrıyanık, Şerife Esra
Cancer is one of the devastating and fatal severe diseases worldwide that kills millions of people every year. Globally cancer is the second leading cause of death after cardiovascular disease and was responsible for 10 million deaths in 2020. Breast cancer is one of the predominant cancers in females and is the cause of more than half a million females death each year. The primary cause of cancer patients' death is cancer metastasis. Triple-negative BREAST cancer (TNBC) is mainly treated by chemotherapy. In the current drug discovery and development processes, the efficacy and toxicity of chemotherapies identify using 2D and animal testing but not simulating the in vivo microenvironment. This research designed multiorgan-on-a-chip with liver and breast cell line compartments, and drug PKPD modeling was done by Monolix software. In this research, a unique multiorgan-on-a-chip (MOC) was designed and fabricated, generated experimental PK and PD data using the new MOC device, and modeled and simulated PK and PD using the experimental data. To conclude, we developed a new multiorgan-on-a-chip (MOC) platform used for PKPD modeling and PKPD simulations that would be helpful in the preclinical research to evaluate the effectiveness and toxicity of drugs. In the future, using calceinAM, a fluorescent cell viability dye, generating PD data for each cell type and determining side effects of doxorubicin in each cell line is essential. Adding more organs to the MOC, such as heart tissue, to study the cytotoxicity of doxorubicin in different organs gives more efficient data for PKPD modeling.
Invetigation of Mechanical Vibration Effects on Breast Cancer Cells
(Izmir Institute of Technology, 2018) Olçum Uzan, Melis; Özçivici, Engin; Erdal Bağrıyanık, Şerife Esra
In this doctoral dissertation, low magnitude mechanical signals (LMMS, <1g in magnitude) were used to test the stress shielding model hypothesized on breast cancer cells. The hypothesis was that the breast cancer cells will be sensitive to mechanical vibrations and will respond to these vibrations. It was similarly used to test the adipogenic differentiation of Lamin A/C knockdown (by siRNA) bone marrow-derived mesenchymal stem cells. It is known that Lamin A/C plays a role in the nucleus and intracellular organization in these cells and affects gene expression by chromatin regulation. The hypothesis was that if these cells are deprived of the organization for the nucleus, they will be sensitive to mechanical vibrations, but that the mechanical vibrations cannot restore the effect of lamin A/C on gene regulation. We investigated the effects of high-frequency low-density mechanical signals (LMMS) on cell proliferation, apoptosis, cell cycle, protein expression, differentiation, cytoskeleton and phenotypic change processes. According to findings, LMMS caused cell cycle arrest in the aggressive type of breast cancer cells and slowed proliferation. Non-aggressive breast cancer has not responded to LMMS. In mammary epithelial cells, LMMS has not shown an effect that triggers proliferation. In the mesenchymal stem cell model, Lamin A/C knockdown accelerated adipogenic differentiation. Although LMMS in these cells decreased the rate of adipogenic differentiation, it was not sufficient to restore the baseline.
The Investigation of Anticancer Properties of (r)-4'-methylklavuzon in Liver Cancer Cells and Liver Cancer Stem Cells
(Izmir Institute of Technology, 2017) Delman, Murat; Çağır, Ali; Erdal, Esra
Hepatocellular carcinoma (HCC) is the fifth most seen cancer type and the third leading cause of death from cancers. HCC is a fatal disease and HCC patients have a 5-year survival rate of 14%. Discovery and identification of mechanisms of action for new therapeutic agents are required for a better treatment of HCC. One of the most important target in cancer treatment is the epigenetic acetylation of histones. Histone deacetylases (HDAC) and sirtuins provide chromatin compaction and transcriptional repression by removing acetyl groups from histone proteins and nonhistone proteins. Re-acetylation of chromatin and re-expression of tumor suppressor genes with the discovery of novel HDAC and/or sirtuin inhibitors are therapeutic targets in cancer research. In this study, (R)-4’-methylklavuzon was found to be cytotoxic in HuH-7 cells with IC50 values of 1.25 μM for HuH-7 parental cells, 2.5 μM for EpCAM+/CD133+ HuH-7 cells and 1.25 μM for EpCAM-/CD133- HuH-7 cells. It was observed that (R)-4’-methylklavuzon causes cell cycle arrest at G1 phase at 1.00 μM concentration in three cell populations, it induces apoptosis at 10 μM concentration at the end of 24 hours incubation. (R)-4’-methylklavuzon does not inhibit Class I/II HDACs in vitro whereas it causes inhibition of endogenous HDACs and/or sirtuins inside the cells sorted by MACS and FACS at 0.10 μM concentration. (R)-4’-methylklavuzon upregulates p21 expression significantly in HuH-7 cell populations to cause G1 arrest. It causes 45% inhibition in p53/MDM2 complex formation when examined with pure p53 and MDM2 proteins. Drug candidate causes 46% SIRT1 inhibition at 100 μM concentration in vitro whereas there was no inhibition of HDAC1 enzyme at the same concentration. SIRT1 protein levels in HuH-7 parental cells were upregulated to 240% within 24 hours of incubation with 3.00 μM of drug candidate. It was found that (R)-4’-methylklavuzon can also inhibit CRM1 protein providing increased retention of tumor suppressor proteins in the nucleus. p53 was overexpressed at 0.10 and 1.00 μM concentrations within 6 and 24 hours in HepG2 cells but slightly overexpressed in HuH-7 parental cells.

Phd Degree / Doktora

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