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The Resource Novel Dichloroacetate Prodrugs for Improved Targeting of Breast Cancer Chemotherapeutics, Danielle Nola Thomas

Novel Dichloroacetate Prodrugs for Improved Targeting of Breast Cancer Chemotherapeutics, Danielle Nola Thomas

Creator
Author
Contributor
Summary
It is well documented that most cancer cells utilize aerobic glycolysis or Warburg metabolism instead of mitochondrial oxidative phosphorylation for cell energy production. Dichloroacetate is a synthetic small molecule with proven anticancer effect. As a pyruvate mimic, dichloroacetate is a glycolytic inhibitor that inactivates pyruvate dehydrogenase kinase causing the activation of pyruvate dehydrogenase. This activity enables pyruvate conversion to acetyl-CoA leading to mitochondrial remodeling via the reversal of the Warburg effect and the release of pro-apoptotic mediators into the cytoplasm. The primary aim of this dissertation is to synthesize dichloroacetate prodrugs that improve DCA targeting to different breast cancer subtypes, triple negative and ER+ breast cancers to have enhanced cancer cell death. The general hypothesis and aims of this work are introduced in Chapter 1. A literature review is provided on cancer etiology, breast cancer epidemiology, and the influence of DCA on cancer, specifically breast cancer metabolism in Chapter 2. Chapters 3 and 4 detail the physicochemical analysis of phenoxyethyl dichloroacetamide (PE-DCA) and functionalized glucose-dichloroacetamide (G-DCA), respectively. Physicochemical analysis include: LC/MS, FT-IR, SEM, P-XRD, and 13C and 1H NMR spectroscopy. Chapter 3 focuses specifically on the physicochemical analysis of PE-DCA. PE-DCA was synthesized with a yield of 87.11%, and molecular weight was quantified using LC/MS and corresponded to the expected molecular weight of 247 g/mol. The chemical structure and formula of PE-DCA were confirmed using FTIR and NMR spectroscopy. XRD and SEM analysis indicated that the morphological structure is different suggesting that the structural integrity of native DCA in comparison to that of the native DCA, which could influence cellular uptake of the prodrug. The physicochemical properties of G-DCA are presented in Chapter 4. G-DCA was synthesized in a two-step process with yields >97% for each step. Using LC/MS, the molecular weight was confirmed to be 502.09 g/mol. G-DCA's chemical structure and formula were further confirmed using FTIR and NMR spectroscopy. XRD and SEM analysis illustrate that G-DCA has a contrasting morphology and composition than that of native DCA. The differences in the physicochemical properties of the prodrugs can give insight on their metabolic profile. The cell viability and toxicity activity of MDA-MB 231, MCF-7, and MCF-10A (normal breast epithelial cells) when treated with PE-DCA and G-DCA for 24 h, respectively, are described in Chapters 5 and 6. As compared to native DCA, with CC50 values of 25 mM and 25-30 mM in MDA-MB 231 and MCF-7 cell lines, respectively, CC50 values for PE-DCA (MDA-MB 231=14.72 æM; MCF-7=47.60 æM) and G-DCA (MDA-MB 231=16.22 æM; MCF-7=97.54 æM) were substantially lower, further proving that the prodrugs enhance DCA's targeting to cancer cells to reverse the Warburg effect. The metabolic profiles of the two cancerous cell lines after treatment with G-DCA, PE-DCA, and DCA in different media environments (pyruvate, low glucose and high glucose) are elucidated in Chapter 7. Intracellular ROS and autophagosome production were quantified in the various conditions to explore the relationship between ROS production and the induction of autophagy when exposed to different media environments. Results for both cancer cell lines indicate an increase intracellular ROS production in high glucose media which further exploits the similarities in the metabolic profiles of breast cancer subtypes. Moreover, related to autophagosome production, upon drug treatment in varying concentrations and media conditions, the relationship between ROS and autophagy induced apoptosis was explored. The intracellular DCA uptake in MCF-10A, MCF-7, and MDA-MB 231 cell lines after treatment with DCA, PE-DCA, and G-DCA are quantified in Chapter 8. Results showed that the DCA prodrugs are more cell targeted to cancer cells than normal breast epithelial tissues further proving that because of DCA conjugation, DCA's target specificity is more refined. This dissertation gives a comprehensive analysis of the metabolic and physicochemical characteristics of the novel DCA prodrugs and their influence on breast cancer proliferation and cell death
Language
eng
Work
Publication
Extent
1 online resource (147 pages)
Note
  • "A dissertation in Pharmaceutical Sciences and Molecular Biology and Biochemistry."
  • Advisor: Russell Melchert
  • Vita
Contents
  • Introduction
  • Literature review
  • Synthesis and physicochemical analysis of phenoxyethyl dichloroacetamide (PE-DCA) prodrug
  • Physicochemical analysis of glucose dichloroacetamide (G-DCA) prodrug
  • Biological analysis of breast cancer cell response to phenoxyethyl dichloroacetamide (PE-DCA) prodrug
  • Biological analysis of breast cancer cell response to Glucose dichloroacetamide (G-DCA) prodrug
  • Quantifying metabolic response in breast cancer cells after DCA prodrug treatment
  • Quantifying intracellar uptake of dichloroacetate via LC-MS/MS
  • Summary & future perspectives
  • Appendix. Abbreviations
Instance
Label
Novel Dichloroacetate Prodrugs for Improved Targeting of Breast Cancer Chemotherapeutics
Title
Novel Dichloroacetate Prodrugs for Improved Targeting of Breast Cancer Chemotherapeutics
Statement of responsibility
Danielle Nola Thomas
Creator
Contributor
Author
Degree supervisor
Subject
Genre
Language
eng
Summary
It is well documented that most cancer cells utilize aerobic glycolysis or Warburg metabolism instead of mitochondrial oxidative phosphorylation for cell energy production. Dichloroacetate is a synthetic small molecule with proven anticancer effect. As a pyruvate mimic, dichloroacetate is a glycolytic inhibitor that inactivates pyruvate dehydrogenase kinase causing the activation of pyruvate dehydrogenase. This activity enables pyruvate conversion to acetyl-CoA leading to mitochondrial remodeling via the reversal of the Warburg effect and the release of pro-apoptotic mediators into the cytoplasm. The primary aim of this dissertation is to synthesize dichloroacetate prodrugs that improve DCA targeting to different breast cancer subtypes, triple negative and ER+ breast cancers to have enhanced cancer cell death. The general hypothesis and aims of this work are introduced in Chapter 1. A literature review is provided on cancer etiology, breast cancer epidemiology, and the influence of DCA on cancer, specifically breast cancer metabolism in Chapter 2. Chapters 3 and 4 detail the physicochemical analysis of phenoxyethyl dichloroacetamide (PE-DCA) and functionalized glucose-dichloroacetamide (G-DCA), respectively. Physicochemical analysis include: LC/MS, FT-IR, SEM, P-XRD, and 13C and 1H NMR spectroscopy. Chapter 3 focuses specifically on the physicochemical analysis of PE-DCA. PE-DCA was synthesized with a yield of 87.11%, and molecular weight was quantified using LC/MS and corresponded to the expected molecular weight of 247 g/mol. The chemical structure and formula of PE-DCA were confirmed using FTIR and NMR spectroscopy. XRD and SEM analysis indicated that the morphological structure is different suggesting that the structural integrity of native DCA in comparison to that of the native DCA, which could influence cellular uptake of the prodrug. The physicochemical properties of G-DCA are presented in Chapter 4. G-DCA was synthesized in a two-step process with yields >97% for each step. Using LC/MS, the molecular weight was confirmed to be 502.09 g/mol. G-DCA's chemical structure and formula were further confirmed using FTIR and NMR spectroscopy. XRD and SEM analysis illustrate that G-DCA has a contrasting morphology and composition than that of native DCA. The differences in the physicochemical properties of the prodrugs can give insight on their metabolic profile. The cell viability and toxicity activity of MDA-MB 231, MCF-7, and MCF-10A (normal breast epithelial cells) when treated with PE-DCA and G-DCA for 24 h, respectively, are described in Chapters 5 and 6. As compared to native DCA, with CC50 values of 25 mM and 25-30 mM in MDA-MB 231 and MCF-7 cell lines, respectively, CC50 values for PE-DCA (MDA-MB 231=14.72 æM; MCF-7=47.60 æM) and G-DCA (MDA-MB 231=16.22 æM; MCF-7=97.54 æM) were substantially lower, further proving that the prodrugs enhance DCA's targeting to cancer cells to reverse the Warburg effect. The metabolic profiles of the two cancerous cell lines after treatment with G-DCA, PE-DCA, and DCA in different media environments (pyruvate, low glucose and high glucose) are elucidated in Chapter 7. Intracellular ROS and autophagosome production were quantified in the various conditions to explore the relationship between ROS production and the induction of autophagy when exposed to different media environments. Results for both cancer cell lines indicate an increase intracellular ROS production in high glucose media which further exploits the similarities in the metabolic profiles of breast cancer subtypes. Moreover, related to autophagosome production, upon drug treatment in varying concentrations and media conditions, the relationship between ROS and autophagy induced apoptosis was explored. The intracellular DCA uptake in MCF-10A, MCF-7, and MDA-MB 231 cell lines after treatment with DCA, PE-DCA, and G-DCA are quantified in Chapter 8. Results showed that the DCA prodrugs are more cell targeted to cancer cells than normal breast epithelial tissues further proving that because of DCA conjugation, DCA's target specificity is more refined. This dissertation gives a comprehensive analysis of the metabolic and physicochemical characteristics of the novel DCA prodrugs and their influence on breast cancer proliferation and cell death
Cataloging source
UMK
http://library.link/vocab/creatorDate
1988-
http://library.link/vocab/creatorName
Thomas, Danielle Nola
Degree
Ph.D.
Dissertation note
(School of Pharmacy and School of Biological Sciences).
Dissertation year
2019.
Granting institution
University of Missouri-Kansas City,
Illustrations
illustrations
Index
no index present
Literary form
non fiction
Nature of contents
  • dictionaries
  • bibliography
  • theses
http://library.link/vocab/relatedWorkOrContributorName
Melchert, Russell B.
http://library.link/vocab/subjectName
  • Breast
  • Prodrugs
  • Drug targeting
Label
Novel Dichloroacetate Prodrugs for Improved Targeting of Breast Cancer Chemotherapeutics, Danielle Nola Thomas
Instantiates
Publication
Copyright
Note
  • "A dissertation in Pharmaceutical Sciences and Molecular Biology and Biochemistry."
  • Advisor: Russell Melchert
  • Vita
Antecedent source
not applicable
Bibliography note
Includes bibliographical references (pages 137-146)
Carrier category
online resource
Carrier category code
  • cr
Carrier MARC source
rdacarrier
Color
black and white
Content category
text
Content type code
  • txt
Content type MARC source
rdacontent
Contents
Introduction -- Literature review -- Synthesis and physicochemical analysis of phenoxyethyl dichloroacetamide (PE-DCA) prodrug -- Physicochemical analysis of glucose dichloroacetamide (G-DCA) prodrug -- Biological analysis of breast cancer cell response to phenoxyethyl dichloroacetamide (PE-DCA) prodrug -- Biological analysis of breast cancer cell response to Glucose dichloroacetamide (G-DCA) prodrug -- Quantifying metabolic response in breast cancer cells after DCA prodrug treatment -- Quantifying intracellar uptake of dichloroacetate via LC-MS/MS -- Summary & future perspectives -- Appendix. Abbreviations
Control code
1120125582
Dimensions
unknown
Extent
1 online resource (147 pages)
File format
one file format
Form of item
online
Level of compression
mixed
Media category
computer
Media MARC source
rdamedia
Media type code
  • c
Other physical details
illustrations.
Quality assurance targets
not applicable
Specific material designation
remote
System control number
(OCoLC)1120125582
System details
  • The full text of the dissertation is available as an Adobe Acrobat .pdf file; Adobe Acrobat Reader required to view the file
  • Mode of access: World Wide Web
Label
Novel Dichloroacetate Prodrugs for Improved Targeting of Breast Cancer Chemotherapeutics, Danielle Nola Thomas
Publication
Copyright
Note
  • "A dissertation in Pharmaceutical Sciences and Molecular Biology and Biochemistry."
  • Advisor: Russell Melchert
  • Vita
Antecedent source
not applicable
Bibliography note
Includes bibliographical references (pages 137-146)
Carrier category
online resource
Carrier category code
  • cr
Carrier MARC source
rdacarrier
Color
black and white
Content category
text
Content type code
  • txt
Content type MARC source
rdacontent
Contents
Introduction -- Literature review -- Synthesis and physicochemical analysis of phenoxyethyl dichloroacetamide (PE-DCA) prodrug -- Physicochemical analysis of glucose dichloroacetamide (G-DCA) prodrug -- Biological analysis of breast cancer cell response to phenoxyethyl dichloroacetamide (PE-DCA) prodrug -- Biological analysis of breast cancer cell response to Glucose dichloroacetamide (G-DCA) prodrug -- Quantifying metabolic response in breast cancer cells after DCA prodrug treatment -- Quantifying intracellar uptake of dichloroacetate via LC-MS/MS -- Summary & future perspectives -- Appendix. Abbreviations
Control code
1120125582
Dimensions
unknown
Extent
1 online resource (147 pages)
File format
one file format
Form of item
online
Level of compression
mixed
Media category
computer
Media MARC source
rdamedia
Media type code
  • c
Other physical details
illustrations.
Quality assurance targets
not applicable
Specific material designation
remote
System control number
(OCoLC)1120125582
System details
  • The full text of the dissertation is available as an Adobe Acrobat .pdf file; Adobe Acrobat Reader required to view the file
  • Mode of access: World Wide Web

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