Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition Concept
Upregulation of hydrogen sulfide (H<sub>2</sub>S) biosynthesis, at least in part related to the upregulation of cystathionine β-synthetase (CBS) in cancer cells, serves as a tumor-promoting factor and has emerged as a possible molecular target for antitumor drug development. To facilitat...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/8/1073 |
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| author | Mark R. Hellmich Celia Chao Katalin Módis Ye Ding John R. Zatarain Ketan Thanki Manjit Maskey Nadiya Druzhyna Ashley A. Untereiner Akbar Ahmad Yu Xue Haiying Chen William K. Russell Jianmei Wang Jia Zhou Csaba Szabo |
| author_facet | Mark R. Hellmich Celia Chao Katalin Módis Ye Ding John R. Zatarain Ketan Thanki Manjit Maskey Nadiya Druzhyna Ashley A. Untereiner Akbar Ahmad Yu Xue Haiying Chen William K. Russell Jianmei Wang Jia Zhou Csaba Szabo |
| author_sort | Mark R. Hellmich |
| collection | DOAJ |
| description | Upregulation of hydrogen sulfide (H<sub>2</sub>S) biosynthesis, at least in part related to the upregulation of cystathionine β-synthetase (CBS) in cancer cells, serves as a tumor-promoting factor and has emerged as a possible molecular target for antitumor drug development. To facilitate future clinical translation, we have synthesized a variety of novel CBS-targeting, esterase-cleavable prodrugs based on the structure of the prototypical CBS inhibitor aminooxyacetic acid (AOAA). The pharmacological properties of these compounds were evaluated in cell-free assays with recombinant human CBS protein, the human colon cancer cell line HCT116, and in vivo using various tumor-bearing mice models. The prodrug YD0251 (the isopropyl ester derivative of AOAA) was selected for detailed characterization. YD0251 exhibits improved antiproliferative efficacy in cell culture models when compared to AOAA. It is up to 18 times more potent than AOAA at suppressing HCT116 tumor growth in vivo and is effective when administered to tumor-bearing mice either via subcutaneous injection or oral gavage. Patient-derived xenografts (PDTXs) with higher levels of CBS protein grew significantly larger than tumors with lower levels, and YD0251 treatment inhibited the growth of PDTXs with elevated CBS, whereas it had no significant effect on PDTXs with low CBS protein levels. The toxicity of YD0251 was assessed in mice subjected to subchronic administration of supratherapeutic doses the inhibitor; no significant alteration in circulating markers of organ injury or histopathological alterations were noted, up to 60 mg/kg/day × 5 days. In preparation to a future theranostic concept (to match CBS inhibitor therapy to high-CBS expressors), we identified a potential plasma marker of CBS-expressing tumors. Colon cancer cells produced significant levels of lanthionine, a rare metabolic intermediate of CBS-mediated H<sub>2</sub>S biosynthesis; forced expression of CBS into non-transformed epithelial cells increased lanthionine biogenesis in vitro and in vivo (measured in the urine of tumor-bearing mice). These current results may be useful to facilitate the translation of a CBS inhibition-based antitumor concept into the clinical space. |
| first_indexed | 2024-03-10T08:59:30Z |
| format | Article |
| id | doaj.art-7a180ec2f5f14c47af1604b5f70b4469 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T08:59:30Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-7a180ec2f5f14c47af1604b5f70b44692023-11-22T06:54:22ZengMDPI AGBiomolecules2218-273X2021-07-01118107310.3390/biom11081073Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition ConceptMark R. Hellmich0Celia Chao1Katalin Módis2Ye Ding3John R. Zatarain4Ketan Thanki5Manjit Maskey6Nadiya Druzhyna7Ashley A. Untereiner8Akbar Ahmad9Yu Xue10Haiying Chen11William K. Russell12Jianmei Wang13Jia Zhou14Csaba Szabo15Department of Surgery, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Surgery, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Surgery, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Pharmacology and Toxicology, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Surgery, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Surgery, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Surgery, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Anesthesiology, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Anesthesiology, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Anesthesiology, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Pharmacology and Toxicology, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Pharmacology and Toxicology, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Biochemistry and Molecular Biology, University of Texas, Medical Branch, Galveston, TX 77555, USACollege of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USADepartment of Pharmacology and Toxicology, University of Texas, Medical Branch, Galveston, TX 77555, USADepartment of Anesthesiology, University of Texas, Medical Branch, Galveston, TX 77555, USAUpregulation of hydrogen sulfide (H<sub>2</sub>S) biosynthesis, at least in part related to the upregulation of cystathionine β-synthetase (CBS) in cancer cells, serves as a tumor-promoting factor and has emerged as a possible molecular target for antitumor drug development. To facilitate future clinical translation, we have synthesized a variety of novel CBS-targeting, esterase-cleavable prodrugs based on the structure of the prototypical CBS inhibitor aminooxyacetic acid (AOAA). The pharmacological properties of these compounds were evaluated in cell-free assays with recombinant human CBS protein, the human colon cancer cell line HCT116, and in vivo using various tumor-bearing mice models. The prodrug YD0251 (the isopropyl ester derivative of AOAA) was selected for detailed characterization. YD0251 exhibits improved antiproliferative efficacy in cell culture models when compared to AOAA. It is up to 18 times more potent than AOAA at suppressing HCT116 tumor growth in vivo and is effective when administered to tumor-bearing mice either via subcutaneous injection or oral gavage. Patient-derived xenografts (PDTXs) with higher levels of CBS protein grew significantly larger than tumors with lower levels, and YD0251 treatment inhibited the growth of PDTXs with elevated CBS, whereas it had no significant effect on PDTXs with low CBS protein levels. The toxicity of YD0251 was assessed in mice subjected to subchronic administration of supratherapeutic doses the inhibitor; no significant alteration in circulating markers of organ injury or histopathological alterations were noted, up to 60 mg/kg/day × 5 days. In preparation to a future theranostic concept (to match CBS inhibitor therapy to high-CBS expressors), we identified a potential plasma marker of CBS-expressing tumors. Colon cancer cells produced significant levels of lanthionine, a rare metabolic intermediate of CBS-mediated H<sub>2</sub>S biosynthesis; forced expression of CBS into non-transformed epithelial cells increased lanthionine biogenesis in vitro and in vivo (measured in the urine of tumor-bearing mice). These current results may be useful to facilitate the translation of a CBS inhibition-based antitumor concept into the clinical space.https://www.mdpi.com/2218-273X/11/8/1073hydrogen sulfideanticancerbiomarkerprodrug |
| spellingShingle | Mark R. Hellmich Celia Chao Katalin Módis Ye Ding John R. Zatarain Ketan Thanki Manjit Maskey Nadiya Druzhyna Ashley A. Untereiner Akbar Ahmad Yu Xue Haiying Chen William K. Russell Jianmei Wang Jia Zhou Csaba Szabo Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition Concept Biomolecules hydrogen sulfide anticancer biomarker prodrug |
| title | Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition Concept |
| title_full | Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition Concept |
| title_fullStr | Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition Concept |
| title_full_unstemmed | Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition Concept |
| title_short | Efficacy of Novel Aminooxyacetic Acid Prodrugs in Colon Cancer Models: Towards Clinical Translation of the Cystathionine β-Synthase Inhibition Concept |
| title_sort | efficacy of novel aminooxyacetic acid prodrugs in colon cancer models towards clinical translation of the cystathionine β synthase inhibition concept |
| topic | hydrogen sulfide anticancer biomarker prodrug |
| url | https://www.mdpi.com/2218-273X/11/8/1073 |
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