TY - JOUR
T1 - Cystathionine-β-synthase inhibition for colon cancer
T2 - Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach
AU - Chao, Celia
AU - Zatarain, John
AU - Ding, Ye
AU - Coletta, Ciro
AU - Mrazek, Amy A.
AU - Druzhyna, Nadiya
AU - Johnson, Paul
AU - Chen, Haiying
AU - Hellmich, Judy L.
AU - Asimakopoulou, Antonia
AU - Yanagi, Kazunori
AU - Olah, Gabor
AU - Szoleczky, Petra
AU - Törö, Gabor
AU - Bohanon, Fredrick J.
AU - Cheema, Minal
AU - Lewis, Rachel
AU - Eckelbarger, David
AU - Ahmad, Akbar
AU - Módis, Katalin
AU - Untereiner, Ashley
AU - Szczesny, Bartosz
AU - Papapetropoulos, Andreas
AU - Zhou, Jia
AU - Hellmich, Mark
AU - Szabo, Csaba
N1 - Funding Information:
This work was supported by R01CA175803 (CS, MRH), T32 DK007639- 24 (MRH), a pilot project supported by UL1TR001439 from the National Center for Advancing Translational Sciences, National Institutes of Health and the Cancer Prevention Research Institute of Texas grant DP150074 (MRH, CS). The authors thank Dr. Steve Stirdivant (Metabolon Inc.) for helpful discussions during the interpretation of the metabolomic analysis data; Dr. Laixin Wang (Novabioassays LLC) for his contributions to the water/ octanol partition study; Mr. Mark Griffin for the cell cycle analysis at the UTMB Flow Cytometry and Cell Sorting Core Facility and Dr. Andras Kiss (Semmelweis University, Department of Pathology, Budapest, Hungary) for the blinded evaluation of the histological slides from the safety study.
Publisher Copyright:
© 2016, Uninversity of Michigan. All rights reserved.
PY - 2016
Y1 - 2016
N2 - Colon cancer cells contain high levels of cystathionine-β-synthase (CBS). Its product, hydrogen sulfide (H2S), promotes the growth and proliferation of colorectal tumor cells. 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 or AOAA (0.1, 0.5 or 1 mg/kg/d) for 3 wks. Tumor growth was significantly reduced by 9 mg/kg/d AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/d. Thus, the in vivo efficacy of YD0171 is nine times higher than that of AOAA. YD0171 (1 mg/kg/d) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/d) also reduced tumor growth in patient-derived tumor xenograft bearing athymic mice. YD0171 (3 mg/kg/d) induced the regression of established HCT116 tumors in vivo. A 5-d safety study in mice demonstrated that YD0171 at 20 mg/kg/d (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.
AB - Colon cancer cells contain high levels of cystathionine-β-synthase (CBS). Its product, hydrogen sulfide (H2S), promotes the growth and proliferation of colorectal tumor cells. 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 or AOAA (0.1, 0.5 or 1 mg/kg/d) for 3 wks. Tumor growth was significantly reduced by 9 mg/kg/d AOAA, but not at the lower doses. YD0171 was more potent: tumor volume was significantly inhibited at 0.5 and 1 mg/kg/d. Thus, the in vivo efficacy of YD0171 is nine times higher than that of AOAA. YD0171 (1 mg/kg/d) attenuated tumor growth and metastasis formation in the intracecal HCT116 tumor model. YD0171 (3 mg/kg/d) also reduced tumor growth in patient-derived tumor xenograft bearing athymic mice. YD0171 (3 mg/kg/d) induced the regression of established HCT116 tumors in vivo. A 5-d safety study in mice demonstrated that YD0171 at 20 mg/kg/d (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.
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U2 - 10.2119/molmed.2016.00102
DO - 10.2119/molmed.2016.00102
M3 - Article
AN - SCOPUS:84987660384
VL - 22
SP - 361
EP - 379
JO - Molecular Medicine
JF - Molecular Medicine
SN - 1076-1551
ER -