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An investigation of curcumin derivatives and their effects in prostate cancer

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TitleInfo
Title
An investigation of curcumin derivatives and their effects in prostate cancer
Name (type = personal)
NamePart (type = family)
Pung
NamePart (type = given)
Douglas
NamePart (type = date)
1988-
DisplayForm
Douglas Pung
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Kong
NamePart (type = given)
Ah-Ng Tony
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Ah-Ng Tony Kong
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Hatefi
NamePart (type = given)
Arash
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Arash Hatefi
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Kagan
NamePart (type = given)
Leonid
DisplayForm
Leonid Kagan
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2017
DateOther (qualifier = exact); (type = degree)
2017-01
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2017
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Prostate Cancer is one of the leading diagnosed cancers and sixth leading cause of cancer deaths worldwide. Prostate cancer has a variety of risk factors including age, diet susceptibility genes and somatic gene defects, all of which can drive prostate carcinogenesis. Phytochemicals have been shown to act as a chemoprevention agent in carcinogenesis, where the chemicals "delay" or inhibit cancer at any step of initiation, promotion, progression or metastasis. The phytochemical curcumin has been shown to possess chemopreventive anti-cancer and anti-inflammation properties, both of which have been indicated in prostate cancer models. The master regulator of anti-oxidative stress, nuclear-factor erythroid 2 related factor (Nrf2) is responsible for many detoxifying and anti-oxidation enzymes. In prostate carcinogenesis, oxidative stress and inflammation are major factors in the development of prostate cancer and nrf2 is necessary to maintain a stable, non-toxic environment. In the present study, curcumin derivative FN1 was used to investigate its potential in restoring Nrf2 activity through modulation of epigenetic enzymes in mouse prostate cancer TRAMPC1 cells. Compounds were first tested on the HepG2-C8 stably transfected ARE-luciferase cell line to determine its Nrf2/ARE induction potential. Real time PCR and western blot were performed to determine levels of expression of Nrf2 related enzymes at protein and mRNA level. Bisulfite genomic sequencing (BGS) and methylated DNA immunoprecipitation (MeDIP) were used to determine methylation status of Nrf2 CpG islands. Anchorage-independent colony-formation analysis was performed to examine the compounds potential as a tumor inhibitor. FN1 revealed to be a significant inhibitor of colony formation. FN1 was found to be a more potent inducer of the Nrf2/ARE pathway than curcumin. Expression of Nrf2 and its downstream targets were increased by FN1. Epigenetic modifying enzymes were also found to be downregulated. Methylation status of Nrf2 through BGS and MeDIP revealed reduced methylation of CpG sites. These results indicate that in TRAMPC1 cells, FN1 can increase level of Nrf2 and its downstream genes by activation of the Nrf2/ARE pathway. In the next study, curcumin derivatives BDMC and DMC were used to investigate potential epigenetic activation of Nrf2 in human prostate cancer cells. LNCaP cells were treated with varying concentrations of the compound to determine cell viability. Real time PCR and western blot were performed to determine levels of expression of Nrf2 related enzymes as well as various epigenetic modifying enzymes, at protein and mRNA level. Bisulfite genomic sequencing (BGS) was used to determine methylation status of the human Nrf2 promoter region CpG islands. mRNA expression of Nrf2 and its downstream genes were induced by both curcumin derivatives. BDMC and DMC treatment resulted in inhibition of DNMT1 and DNMT3B while expression of DNMT3A was increased. Western blot analysis reflected mRNA results with increases of Nrf2 and its downstream targets at the protein level. HDAC proteins expression was inhibited by the curcumin derivatives. Methylation of Nrf2 CpG sites were not reduced by BDMC and DMC treatment. The derivatives of curcumin have shown to activate Nrf2 and its phase II detoxifying genes, by which mechanism, remains unclear and requires further investigation. In summary, the potential of these curcumin derived chemicals to act as a chemoprevention agents in prostate cancer is high. FN1 displayed the ability to restore expression of Nrf2 and its downstream genes via hypomethylation of Nrf2’s promoter CpG sites. BDMC and DMC displayed a potential to activate Nrf2, however, the two compounds were stronger inducers of Nrf2’s downstream genes, HO-1 and NQO-1.
Subject (authority = RUETD)
Topic
Pharmaceutical Science
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_7812
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (ix, 69 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Subject (authority = ETD-LCSH)
Topic
Prostate--Cancer--Treatment
Subject (authority = ETD-LCSH)
Topic
Turmeric--Therapeutic use
Note (type = statement of responsibility)
by Douglas Pung
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T3542R2S
Genre (authority = ExL-Esploro)
ETD graduate
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RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Pung
GivenName
Douglas
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2017-01-02 09:21:38
AssociatedEntity
Name
Douglas Pung
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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