Cystathionine-β-synthase inhibition for colon cancer

Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach

Celia Chao, John R. Zatarain, Ye Ding, Ciro Coletta, Amy A. Mrazek, Nadiya Druzhyna, Paul Johnson, Haiying Chen, Judy L. Hellmich, Antonia Asimakopoulou, Kazunori Yanagi, Gabor Olah, Petra Szoleczky, Gabor Törö, Fredrick J. Bohanon, Minal Cheema, Rachel Lewis, David Eckelbarger, Akbar Ahmad, Katalin Modis & 6 others Ashley Untereiner, Bartosz Szczesny, Andreas Papapetropoulos, Jia Zhou, Mark Hellmich, Csaba Szabo

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)361-379
Number of pages19
JournalMolecular Medicine
Volume22
DOIs
StatePublished - 2016

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Cystathionine
Aminooxyacetic Acid
Prodrugs
Colonic Neoplasms
Neoplasms
HCT116 Cells
Growth
Heterografts
Nude Mice
Colorectal Neoplasms
Paraoxon
Growth Inhibitors
Hydrogen Sulfide
Metabolomics
Homocysteine
Esterases
Subcutaneous Injections
Tumor Burden
Energy Metabolism
Respiration

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Cystathionine-β-synthase inhibition for colon cancer : Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach. / Chao, Celia; Zatarain, John R.; Ding, Ye; Coletta, Ciro; Mrazek, Amy A.; Druzhyna, Nadiya; Johnson, Paul; Chen, Haiying; Hellmich, Judy L.; Asimakopoulou, Antonia; Yanagi, Kazunori; Olah, Gabor; Szoleczky, Petra; Törö, Gabor; Bohanon, Fredrick J.; Cheema, Minal; Lewis, Rachel; Eckelbarger, David; Ahmad, Akbar; Modis, Katalin; Untereiner, Ashley; Szczesny, Bartosz; Papapetropoulos, Andreas; Zhou, Jia; Hellmich, Mark; Szabo, Csaba.

In: Molecular Medicine, Vol. 22, 2016, p. 361-379.

Research output: Contribution to journalArticle

Chao, C, Zatarain, JR, Ding, Y, Coletta, C, Mrazek, AA, Druzhyna, N, Johnson, P, Chen, H, Hellmich, JL, Asimakopoulou, A, Yanagi, K, Olah, G, Szoleczky, P, Törö, G, Bohanon, FJ, Cheema, M, Lewis, R, Eckelbarger, D, Ahmad, A, Modis, K, Untereiner, A, Szczesny, B, Papapetropoulos, A, Zhou, J, Hellmich, M & Szabo, C 2016, 'Cystathionine-β-synthase inhibition for colon cancer: Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach', Molecular Medicine, vol. 22, pp. 361-379. https://doi.org/10.2119/molmed.2016.00102
Chao, Celia ; Zatarain, John R. ; Ding, Ye ; Coletta, Ciro ; Mrazek, Amy A. ; Druzhyna, Nadiya ; Johnson, Paul ; Chen, Haiying ; Hellmich, Judy L. ; Asimakopoulou, Antonia ; Yanagi, Kazunori ; Olah, Gabor ; Szoleczky, Petra ; Törö, Gabor ; Bohanon, Fredrick J. ; Cheema, Minal ; Lewis, Rachel ; Eckelbarger, David ; Ahmad, Akbar ; Modis, Katalin ; Untereiner, Ashley ; Szczesny, Bartosz ; Papapetropoulos, Andreas ; Zhou, Jia ; Hellmich, Mark ; Szabo, Csaba. / Cystathionine-β-synthase inhibition for colon cancer : Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach. In: Molecular Medicine. 2016 ; Vol. 22. pp. 361-379.
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abstract = "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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T2 - Enhancement of the efficacy of aminooxyacetic acid via the prodrug approach

AU - Chao, Celia

AU - Zatarain, John R.

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 - Modis, Katalin

AU - Untereiner, Ashley

AU - Szczesny, Bartosz

AU - Papapetropoulos, Andreas

AU - Zhou, Jia

AU - Hellmich, Mark

AU - Szabo, Csaba

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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