Journal
BIOMOLECULES
Volume 11, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/biom11081073
Keywords
hydrogen sulfide; anticancer; biomarker; prodrug
Categories
Funding
- Cancer Prevention Research Institute of Texas (CPRIT), Texas, USA [DP150074]
- National Institutes of Health, Bethesda, USA [R41CA213463, DK007639]
- Swiss Krebsliga [KLS-4504-08-2018]
- John D. Stobo, M.D. Distinguished Chair Endowment Fund at UTMB
- Department of Defense Career Development Award [W81XWH2010641]
- American Cancer Society Research Scholar Grant [RSG-21-027-01-CSM]
- CPRIT, Texas USA [RP190682]
- U.S. Department of Defense (DOD) [W81XWH2010641] Funding Source: U.S. Department of Defense (DOD)
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The upregulation of CBS in cancer cells has been identified as a tumor-promoting factor, leading to the synthesis of a novel CBS-targeting prodrug YD0251 with higher efficacy in inhibiting tumor growth compared to the prototypical CBS inhibitor AOAA. The prodrug was successful in suppressing tumor growth in vivo with low toxicity, and a potential plasma marker for CBS-expressing tumors was identified for potential future theranostic applications to match CBS inhibitor therapy with high-CBS expressors.
Upregulation of hydrogen sulfide (H2S) biosynthesis, at least in part related to the upregulation of cystathionine beta-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 x 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 H2S 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.
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