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Therapeutic Dual-Targeting Of Cytosolic And Mitochondrial One-Carbon Metabolism, Aamod Sanjeev Dekhne
Therapeutic Dual-Targeting Of Cytosolic And Mitochondrial One-Carbon Metabolism, Aamod Sanjeev Dekhne
Wayne State University Dissertations
One-carbon metabolism (1CM) is compartmentalized in the mitochondria and cytosol and generates a host of metabolites critical to tumor propagation. Although drug-targeting of cytosolic 1CM remains a clinically-relevant mainstay, development of clinically-useful agents targeting mitochondrial 1CM remains elusive. Of particular pharmacological interest is the mitochondrial 1CM enzyme, serine hydroxymethyltransferase2 (SHMT2). SHMT2 expression correlates with the oncogenic phenotype in lung, colon, breast, glioma, and liver cancer and, overall, is the fifth-most differentially expressed metabolic enzyme in cancer cell versus normal tissue. Despite the unequivocal oncogenic importance and therapeutic potential of SHMT2, there are no clinically relevant (i.e. active in vivo) inhibitors …
Timing And Duration Of Folate Restriction Differentially Impacts Colon Carcinogenesis., Ali M. Fardous
Timing And Duration Of Folate Restriction Differentially Impacts Colon Carcinogenesis., Ali M. Fardous
Wayne State University Dissertations
Colorectal cancer (CRC) constitutes a major burden on the healthcare system as the second most commonly diagnosed cancer in the developed world. Dietary folate is considered an important modulator of colorectal cancer. Folate restriction has been implicated in increasing CRC incidence by disrupting nucleotide synthesis, Impacting DNA methylation and inducing genetic instability. Our research shows that the timing and duration of dietary folate restriction can differentially impact Colorectal cancer initiation. Acclimating mice to folate restriction for 8 weeks results in a reduced number of preneoplastic lesions compared to mice placed of folate restriction for 1 week prior to initiating the …
The Relationship Between Excessive Folic Acid Intake And Genome Instability In Human Lymphocytes, Khadijah Ibrahim Alnabbat
The Relationship Between Excessive Folic Acid Intake And Genome Instability In Human Lymphocytes, Khadijah Ibrahim Alnabbat
Wayne State University Dissertations
Since its synthesis in 1945, Folic acid (FA) is widely used as a supplement/additive to our food due to its stability and high bioavailability. FA is proposed to alleviate anemia and reduce neural tube defects (NTD). As a provitamin, FA is activated through a two-step reaction catalyzed by dihydrofolate reductase (DHFR) in the folate metabolism pathway. FA activation rate is found to be slow in humans. After the implementation of mandatory food fortification program of grain and grain products with folic acid in the USA in 1998, many concerns have been raised about the unintended deleterious consequence of exposing the …
Structural Characterization And Therapeutic Utility Of The Proton-Coupled Folate Transporter, Michael Roy Wilson
Structural Characterization And Therapeutic Utility Of The Proton-Coupled Folate Transporter, Michael Roy Wilson
Wayne State University Dissertations
Folate is a B9 vitamin essential to DNA synthesis. The proton-coupled folate transporter (PCFT) is a newly discovered proton/folate symporter with an acidic pH optimum and broad expression across a variety of solid tumor types, with limited expression in normal tissues. Several antifolate molecules have been developed as cancer therapeutics, although these classical antifolates display numerous off-target effects due to transport by the ubiquitous reduced folate carrier (RFC). In this dissertation, we determine the roles of multiple PCFT structure/function domains, and develop PCFT-specific antifolates to target solid tumors. We utilize substituted cysteine accessibility methods (SCAM) to identify a novel reentrant …
The Impact Of Folate Deficiency On The Base Excision Repair Pathway: Analysis Of Enzyme Coordination In Response To Dna Damage And Imbalanced Repair, Amanda Pilling
Wayne State University Dissertations
The condition of folate deficiency has been implicated in carcinogenesis, with the strongest evidence formulated in colon cancer. The role of folate in DNA repair, DNA synthesis and methylation reactions renders this nutrient an valuable target for studying the onset and progression of cancer. Using molecular techniques to determine gene and protein expression, enzyme activity and methylation status elucidates the mechanism of DNA repair and damage in folic acid deficient animals in response to carcinogen. The findings presented in this study indicate failure to remove and repair damage in the condition of folate deficiency and suggest that the accumulation of …