Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone

Bibliographic Details
Main Author:	Racoma, Ira Oliva
Language:	English
Published:	The Ohio State University / OhioLINK 2013
Subjects:	Biomedical Research
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=osu1369923513

id	ndltd-OhioLink-oai-etd.ohiolink.edu-osu1369923513
record_format	oai_dc
spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-osu13699235132021-08-03T05:23:42Z Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone Racoma, Ira Oliva Biomedical Research AbstractGlioblastoma is a grade IV glioma and remains the most aggressive and devastating cancer of the central nervous system with a median survival of 15 months. It is the most common malignant brain tumor diagnosed in adults and accounts for 23% of all primary brain tumors. Adding to this statistic is the number of recurring tumors, which occurs in a vast majority of cases. Glioblastomas are resistant to treatment due to the upregulation of survival pathways, decreased expression in pro-apoptotic proteins and overexpression of anti-apoptotic proteins. There has been a growing interest in natural compounds with anti-cancer properties because they are relatively non-toxic to healthy cells and are available in a readily ingested form. The dietary phytochemical thymoquinone (TQ) is the primary bioactive component of Nigella sativa Linn seed (also known as black seed) oil which has been used for centuries in Middle Eastern, Indian and European countries for culinary purposes and to promote good health. We have previously shown that TQ induces apoptosis in HL-60 leukemia cells and MCF-7/DOX doxorubicin-resistant breast cancer cells. The work presented in this thesis describes the mechanism of action TQ in apoptosis-resistant glioblastoma cells. On the molecular level, TQ induced intense DSBs and cell cycle alterations. We found that TQ mediated these effects on DNA and the cell cycle via arylation of target molecules, and not via generation of reactive oxygen species. Additionally, TQ did not exert the same detrimental effects on normal human astrocytes, confirming reports of the selectivity of TQ for cancer cells. Glioblastoma are characterized by their resistance to apoptosis due to upregulation of several survival signaling pathways. In recent years, autophagy has emerged as a bona fide survival pathway for a number of tumors. TQ inhibited autophagy in glioblastoma cells, which was found to be a consequence of permeabilization of the lysosomal membrane. Additionally TQ induced the release of cathepsins into the cytosol which can mediate caspase-independent death in apoptosis-resistant cells. Finally, TQ was tested in vivo by evaluating the survival time of mice with intra-cranial tumors. TQ resulted in a promising increase of survival time in treated mice. Orally administered drug did not result in adverse reactions and appears to be able to reach a neurological tumor site. The significance of this work was to investigate the modulation of a novel tumor survival pathway with a natural compound in the hopes of shedding light on new approaches to the treatment of a recalcitrant tumor. 2013-08-27 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1369923513 http://rave.ohiolink.edu/etdc/view?acc_num=osu1369923513 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Biomedical Research
spellingShingle	Biomedical Research Racoma, Ira Oliva Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone
author	Racoma, Ira Oliva
author_facet	Racoma, Ira Oliva
author_sort	Racoma, Ira Oliva
title	Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone
title_short	Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone
title_full	Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone
title_fullStr	Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone
title_full_unstemmed	Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone
title_sort	targeting glioblastoma survival signaling: a novel mechanism of action of thymoquinone
publisher	The Ohio State University / OhioLINK
publishDate	2013
url	http://rave.ohiolink.edu/etdc/view?acc_num=osu1369923513
work_keys_str_mv	AT racomairaoliva targetingglioblastomasurvivalsignalinganovelmechanismofactionofthymoquinone
_version_	1719419786922819584

Targeting Glioblastoma Survival Signaling: A Novel Mechanism of Action of Thymoquinone

Similar Items