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ANTI-CANCER EFFECTS OF NOVEL GLIDOBACTIN TYPE PROTEASOME
INHIBITORS
by
FNU Ashish Anshu
A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(MOLECULAR MICROBIOLOGY AND IMMUNOLOGY)
May 2011
Copyright 2011 FNU Ashish Anshu
Object Description
| Title | Anti-cancer effects of novel glidobactin type proteasome inhibitors |
| Author | Ashish Anshu, Fnu |
| Author email | anshu@usc.edu; ashish.microbio@gmail.com |
| Degree | Master of Science |
| Document type | Thesis |
| Degree program | Molecular Microbiology & Immunology |
| School | Keck School of Medicine |
| Date defended/completed | 2011-03-25 |
| Date submitted | 2011 |
| Restricted until | Unrestricted |
| Date published | 2011-05-03 |
| Advisor (committee chair) | Schönthal, Axel |
| Advisor (committee member) |
Tahara, Stanley Hofman, Florence M. |
| Abstract | Proteasome inhibitors are widely used today as an important tool for anti-cancer treatment, which has led to a wide search of novel proteasome inhibitors. Proteasome inhibitors tested in this study are analogues of glidobactin, which are a new class of proteasome inhibitors. Similarly, these compounds effectively inhibit the 26S proteasome activity. In this study, we investigated the cytotoxic effect of these compounds on human multiple myeloma (MM), human Waldenstrom macroglobulinemia (BCWM1), and human lymphocytic leukemia cells (REH). Of the four compounds we tested, T-02 and T-04 were most potent ones and their proteasome inhibitory effect directly correlates with their cell cytotoxicity. Induction of mild ER stress provides a survival benefit to cells, however severe ER stress is known to inhibit proliferation of cells leading to apoptosis. Since a number of proteasome inhibitors have been shown to trigger ER stress induced apoptosis, we investigated whether these novel proteasome inhibitors have this anti-cancer efficacy. Our results suggest that it is indeed the case. We further explored whether the combination of these compounds with other known ER stress inducers leads to aggravated ER stress and enhancement of their anti-cancer efficacy. T-02 or T-04 in combination with thapsigargin (a known inhibitor of sarco/endoplasmic reticulum Ca(2+) ATPase) and dimethyl celecoxib (DMC), an analogue of celecoxib demonstrate enhanced cytotoxic effect with more severe ER stress induction and apoptosis mediated cell death. Taken together, our findings suggest these novel compounds are very effective proteasome inhibitors and trigger the ER stress response with enhanced apoptosis mediated cell death. In addition, in combination with other ER inducer(s), cytotoxic effects of these compounds are highly potentiated. |
| Keyword | apoptosis; autophagy; endoplasmic reticulum stress; glidobactin A; hematological malignancy; proteasome |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3860 |
| Rights | Ashish Anshu, Fnu |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-ANSHU-4594 |
| Archival file | uscthesesreloadpub_Volume44/etd-ANSHU-4594.pdf |
Description
| Title | Page 1 |
| Full text | ANTI-CANCER EFFECTS OF NOVEL GLIDOBACTIN TYPE PROTEASOME INHIBITORS by FNU Ashish Anshu A Thesis Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (MOLECULAR MICROBIOLOGY AND IMMUNOLOGY) May 2011 Copyright 2011 FNU Ashish Anshu |
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