title: Cystathionine-beta-synthase inhibition for colon cancer: Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach.
abstract: Colon cancer cells contain high levels of cystathionine-beta-synthase (CBS). Its product, hydrogen sulfide (H2S) promotes the growth and proliferation of colorectal tumor cells. In order to improve the antitumor efficacy of the prototypical CBS inhibitor aminooxyacetic acid (AOAA), we have designed and synthesized YD0171, a methyl ester derivative of AOAA. The antiproliferative effect of YD0171 exceeded the antiproliferative potency of AOAA in HCT116 human colon cancer cells. The esterase inhibitor paraoxon prevented the cellular inhibition of CBS activity by YD0171. YD0171 suppressed mitochondrial respiration and glycolytic function and induced G0/G1 arrest, but did not induce tumor cell apoptosis or necrosis. Metabolomic analysis in HCT116 cells showed that YD0171 affects multiple pathways of cell metabolism. The efficacy of YD0171 as an inhibitor of tumor growth was also tested in nude mice bearing subcutaneous HCT116 cancer cell xenografts. Animals were treated via subcutaneous injection of vehicle, AOAA (1, 3 or 9 mg/kg/day) or YD0171 (0.1, 0.5 or 1 mg/kg/day) for 3 weeks. Tumor growth was significantly reduced by 9 mg/kg/day AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/day. Thus, thein vivoefficacy of YD0171 is 9-times higher than that of AOAA. YD0171 (1 mg/kg/day) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/day) also reduced tumor growth in patient-derived tumor xenograft (PDTX) bearing athymic mice. YD0171 (3 mg/kg/day) induced the regression of established HCT116 tumorsin vivo. A 5-day safety study in mice demonstrated that YD0171 at 20 mg/kg/day (given in two divided doses) does not increase plasma markers of organ injury, nor does it induce histological alterations in the liver or kidney. YD0171 caused a slight elevation in plasma homocysteine levels. In conclusion, the prodrug approach improves the pharmacological profile of AOAA; YD0171 represents a prototype for CBS inhibitory anticancer prodrugs. By targeting colorectal cancer bioenergetics, an emerging important hallmark of cancer, the approach exemplified herein may offer direct translational opportunities.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Celia
authors.initials: C
authors.lastname: Chao
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: John R
authors.initials: JR
authors.lastname: Zatarain
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Ciro
authors.initials: C
authors.lastname: Coletta
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Amy A
authors.initials: AA
authors.lastname: Mrazek
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Nadiya
authors.initials: N
authors.lastname: Druzhyna
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Paul
authors.initials: P
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Judy L
authors.initials: JL
authors.lastname: Hellmich
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Antonia
authors.initials: A
authors.lastname: Asimakopoulou
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yanagi
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Gabor
authors.initials: G
authors.lastname: Olah
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Petra
authors.initials: P
authors.lastname: Szoleczky
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Gabor
authors.initials: G
authors.lastname: Törö
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Fredrick J
authors.initials: FJ
authors.lastname: Bohanon
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Minal
authors.initials: M
authors.lastname: Cheema
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Rachel
authors.initials: R
authors.lastname: Lewis
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: David
authors.initials: D
authors.lastname: Eckelbarger
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Akbar
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America|Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Katalin
authors.initials: K
authors.lastname: Módis
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Ashley
authors.initials: A
authors.lastname: Untereiner
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Bartosz
authors.initials: B
authors.lastname: Szczesny
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellmich
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, United States of America
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
keywords: Hydrogen sulfide; cell proliferation; cystathionine-beta-synthase; drug development; tumor growth