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Published on: September 3, 2013
Preclinical Development of a Nontoxic Oral Formulation of Monoethanolamine, a Lipid Precursor, for Prostate Cancer
Roopali Saxena1, Chunhua Yang1, Mukkavilli Rao1
1Department of Biology, Georgia State University, Atlanta, Georgia.
Abstract:
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.
Insights
Monoethanolamine (Etn) is a novel, orally delivered anticancer agent that targets prostate cancer by inhibiting phosphatidylethanolamine (PE) lipid biosynthesis. This formulation demonstrates significant tumor growth inhibition with no apparent toxicity, supporting its clinical development.
Area of Science:
- Oncology
- Lipid Metabolism
- Drug Development
Background:
- Current chemotherapies lack specificity, causing toxic side-effects by targeting rapidly dividing cells.
- Novel therapeutic strategies are needed to target cancer-specific pathways, such as lipid biosynthesis.
- Targeting lipid metabolism in cancer remains an underexplored therapeutic avenue.
Purpose of the Study:
- To develop a novel, nontoxic, orally deliverable anticancer formulation for prostate cancer.
- To investigate monoethanolamine (Etn) as a therapeutic agent targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis.
- To assess the suitability of Etn as a safe and effective oral anticancer drug.
Main Methods:
- Evaluated gastrointestinal stability, drug-drug interaction, pharmacokinetic, and toxicokinetic properties of Etn.
- Conducted in vitro and in vivo experiments to determine efficacy and mechanism of action.
- Utilized human prostate cancer PC-3 xenografts in mice for in vivo studies.
Main Results:
- Etn demonstrated excellent oral bioavailability, gastrointestinal stability, and no drug-drug interaction liability.
- Oral Etn administration inhibited prostate cancer xenograft tumor growth by approximately 67% in four weeks.
- Etn selectively targets cancer cells by exploiting choline kinase overexpression, leading to metabolic stress and cell death via HIF-1α downregulation.
Conclusions:
- Etn exhibits superior anticancer activity and nontoxicity, meeting FDA-approved standards.
- This study provides the first evidence for Etn's potential as an effective prostate cancer therapeutic.
- The findings strongly support the clinical development of Etn for prostate cancer management.
