Preclinical Development of a Nontoxic Oral Formulation of Monoethanolamine, a Lipid Precursor, for Prostate Cancer Treatment.

Autor:	Saxena R; Department of Biology, Georgia State University, Atlanta, Georgia., Yang C; Department of Biology, Georgia State University, Atlanta, Georgia., Rao M; Department of Biology, Georgia State University, Atlanta, Georgia., Turaga RC; Department of Biology, Georgia State University, Atlanta, Georgia., Garlapati C; Department of Biology, Georgia State University, Atlanta, Georgia., Gundala SR; Department of Biology, Georgia State University, Atlanta, Georgia., Myers K; Department of Biology, Georgia State University, Atlanta, Georgia., Ghareeb A; Department of Biology, Georgia State University, Atlanta, Georgia., Bhattarai S; Department of Biology, Georgia State University, Atlanta, Georgia., Kamalinia G; Department of Biology, Georgia State University, Atlanta, Georgia., Bristi S; Department of Biology, Georgia State University, Atlanta, Georgia., Su D; Department of Chemistry, Georgia State University, Atlanta, Georgia., Gadda G; Department of Chemistry, Georgia State University, Atlanta, Georgia., Rida PCG; Department of Biology, Georgia State University, Atlanta, Georgia., Cantuaria GH; Department of Gynecologic Oncology, Northside Hospital Cancer Institute, Atlanta, Georgia., Aneja R; Department of Biology, Georgia State University, Atlanta, Georgia. raneja@gsu.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Jul 15; Vol. 23 (14), pp. 3781-3793. Date of Electronic Publication: 2017 Feb 06.
DOI:	10.1158/1078-0432.CCR-16-1716
Abstrakt:	Purpose: Most currently available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly dividing normal cells resulting in toxic side-effects. This nonspecificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel nontoxic orally deliverable anticancer formulation of monoethanolamine (Etn) for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design: We first evaluated gastrointestinal tract stability, drug-drug interaction liability, pharmacokinetic, and toxicokinetic properties of Etn to evaluate its suitability as a nontoxic orally deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results: Our data demonstrate that Etn exhibits excellent bioavailability, gastrointestinal tract stability, and no drug-drug interaction liability. Remarkably, orally fed Etn inhibited tumor growth in four weeks by approximately 67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions: Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose nontoxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. Clin Cancer Res; 23(14); 3781-93. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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