Preclinical Development of a Nontoxic Oral Formulation of Monoethanolamine, a Lipid Precursor, for Prostate Cancer Treatment.
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 performedin vitroandin vivoexperiments 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.
Department of Biology, Georgia State University, Atlanta, Georgia.
Roopali
R
Saxena
Department of Biology, Georgia State University, Atlanta, Georgia.
Chunhua
C
Yang
Department of Biology, Georgia State University, Atlanta, Georgia.
Mukkavilli
M
Rao
Department of Biology, Georgia State University, Atlanta, Georgia.
Ravi Chakra
RC
Turaga
Department of Biology, Georgia State University, Atlanta, Georgia.
Chakravarthy
C
Garlapati
Department of Biology, Georgia State University, Atlanta, Georgia.
Sushma Reddy
SR
Gundala
Department of Biology, Georgia State University, Atlanta, Georgia.
Kimberly
K
Myers
Department of Biology, Georgia State University, Atlanta, Georgia.
Ahmed
A
Ghareeb
Department of Biology, Georgia State University, Atlanta, Georgia.
Shristi
S
Bhattarai
Department of Biology, Georgia State University, Atlanta, Georgia.
Golnaz
G
Kamalinia
Department of Biology, Georgia State University, Atlanta, Georgia.
Sangina
S
Bristi
Department of Chemistry, Georgia State University, Atlanta, Georgia.
Dan
D
Su
Department of Chemistry, Georgia State University, Atlanta, Georgia.
Giovanni
G
Gadda
Department of Biology, Georgia State University, Atlanta, Georgia.
Padmashree C G
PCG
Rida
Department of Gynecologic Oncology, Northside Hospital Cancer Institute, Atlanta, Georgia.
Guilherme H
GH
Cantuaria
Department of Biology, Georgia State University, Atlanta, Georgia. raneja@gsu.edu.
Ritu
R
Aneja
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D019856:Ethanolamine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis / Q000737:chemistry; D008297:Male; D051379:Mice; D010714:Phosphatidylethanolamines / Q000096:biosynthesis*; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008055:Lipids; D010714:Phosphatidylethanolamines; C483858:phosphatidylethanolamine; D019856:Ethanolamine