Date of Award

Spring 2021

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Swapan Ray

Abstract

Glioblastoma is the most malignant and prevalent brain tumor in adults. It can grow and spread quickly causing harm to brain health. The deregulation of epigenetic mechanisms is considered the main agent in the developing of GBM. One of the enzymes involved in epigenetic alternation and cancer development are histone deacetylases enzyme (HDAC) by removal acetyl group from histone and create condensed chromatin that suppresses transcription gene to histone and non-histone proteins involved in tumorigenesis. Histone deacetylase inhibitors (HADCi) are the most common therapeutic methods for many types of cancer treatments. In the present study, we used relative HDAC inhibitor suberoylanilide hydroxamic acid (SAHA ) combined (4-hydroxyphenyl) retinamide (4HPR) and These compounds are used alone or in combination for synergistic actions for inducing apoptosis in rat C6 and human T98G glioblastoma cell lines. The combination contributed to induce apoptosis and cell cycle arrest mediated in death tumor cells in vitro and in vivo by activating the apoptotic protein (Bax, Caspase8, Caspase 3 , p21(waf1/cip1 ) and inhibiting the anti-apoptotic protein (Bcl-2,Bid). Also, the synergism of two drugs significantly contributed to inhibition of HDAC1, which plays an important role in growth of cancer cells. The data also showed that combination significantly stimulated astrocytic differentiation in both cells via down regulating telomerase reverse transcriptase (TERT), DAN-binding protein inhibitor Id2, and c-Myc while upregulating glial fibrillary acidic protein (GFAP). Furthermore, combination of two drugs reduced cell invasion and angiogenesis by down regulating MMP2, MMP9, and VEGF. Also Mocetinostat, also known as MGCD0103 is an isotype-selective histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1−3 used in this study alone with different concentrations to induce apoptosis in glioblastoma and differentiation and inhibits invasion, angiogenesis through modulating in the molecular mechanism for many pathways inside of cells such as suppression of PI3K/AKT pathway and HDAC1, and activation intrinsic and extrinsic pathway involved in apoptosis by upregulating BAX and, downregulating Bcl2. Also, MGCDO103 induced differentiation by activating differentiation marker GFAP and inhibiting differentiation marker (Id2, N-Myc) hence the MGCD0103 is promising anticancer agent that play important role treatment of glioblastoma cells. Furthermore, we investigated from Diosgenin that is a natural steroidal sapogenin extracted from fenugreek and wild yam and it is one of the major bioactive compounds used in the treatment of diabetes, hypercholesterolemia, and inflammation. We examined the effects of different concentrations of diosgenin on proliferation of C6 and T98G glioblastoma cell lines. We noticed that diosgenin had a high inhibitory effect induced differentiation in the cells by increasing expression (GFAP) and decreasing expression such as Id2, c-Myc, TERT, and Notch-1. It also induced apoptosis in C6 and T98G cell lines by increase expression of Bax protein and decrease in Bcl-2 protein. Further, diosgenin suppressed cell migration and invasion by down regulating MMP2 and MMP9 and angiogenesis by down regulating VEGF and FGF2.

Rights

© 2021, Firas Hameed Khathayer

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