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Free Content Multiple Cytoproliferative Effects of Elevated Pyrimidines are DNA-Synthesis-Independent and Include p53 Repression: DNA-Synthesis-Independent Proliferative Mechanisms of Elevated Pyrimidines

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Several types of cytoproliferative diseases, including cancers and autoimmune diseases, are associated with elevated cellular levels of pyrimidine nucleotides. This review assembles literature evidence supporting a thesis that elevated pyrimidine levels drive cytoproliferation largely through DNA-synthesis-independent mechanisms, which circumstance, it is proposed, inherently limits clinical efficacy of DNA-synthesis-targeting cytostatic drugs. Five hypothetical mechanisms, with supporting literature evidence, are presented: (1) Pyrimidine nucleotides released from ion channels auto/paracrinally and persistently activate the EGFR, PKC and ERK signaling pathway, upregulating cytokines and Cdk2; (2) One effect of ERK activation is reversal of allosteric control of de novo pyrimidine biosynthesis; thus pyrimidines' auto/paracrine ERK activation may reflect positive autoregulation; (3) Elevated intracellular pyrimidine nucleotides preferentially upregulate tumorigenic genes; (4) Elevated pyrimidines promote aberrant glycosylation of transcription factors; and (5) These diverse pyrimidine effects contribute, by different paths yet collectively, to repression of p53 or of its function. Also reviewed are alternate pyrimidine biosynthesis pathways relevant to disease. Based on these hypotheses, a clinical strategy for cytoproliferative disease is proposed that co-targets three cellular processes seen as "linchpins" of pyrimidines' auto/paracrine effects, including targeting alternate pyrimidine biosynthesis pathways.

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Keywords: AUTOIMMUNE DISEASE; CANCER; CDK; CTP; CYCLIN DEPENDENT KINASE; CYTOKINES; DNA SYNTHESIS; EGFR; ERYTHEMATOSUS; LUPUS; MULTIPLE SCLEROSIS; P2Y; P53; PYRIMIDINE BIOSYNTHESIS; PYRIMIDINES; RHEUMATOID ARTHRITIS; UDP; UTP; VRAC

Document Type: Review Article

Publication date: 2014-03-01

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  • Journal of Pharmaceutical Sciences and Pharmacology is being launched to address the disconnect among different research areas related to pharmaceutical sciences and pharmacology. The extreme specialization has resulted in compartmentalization and complete segregation of disciplines related to pharmaceutical sciences. Relating a new development in drug delivery has become difficult to be noticed by the researchers in other related disciplines like the pharmacologists and/or clinicians. The aim of this journal is to publish high quality original research work and broad reviews in all related disciplines relevant to drugs under the same umbrella. Our expectation is that it will help the researchers, scholars and scientists to put their and others' work in the bigger context resulting in enhanced interdisciplinary and integrated research effort. The journal is intended to cover all disciplines and challenges in science, technology and engineering that contribute to the development of new improved drug molecules and their uses including pharmaceutical aspects.
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