Abstract
Purpose
Transglutaminase 2 (TGase 2), a cross-linking enzyme, plays an important role in both pro-survival and anti-apoptosis during oncogenesis. For instance, TGase 2 induces NF-κB activation through I-κBα polymerization, which leads to the increase of pro-survival factors such as BCl-2. TGase 2 also suppresses apoptosis via depletion of caspase 3 and cathepsin D. Therefore, a specific TGase 2 inhibitor may become a very useful treatment for cancer showing high levels of TGase 2 expression.
Methods
By small-molecule library screening, we managed to locate a competitive TGase 2 inhibiting quinoxaline compound (GK13) from 50 other quinoxaline derivatives. The 50 compounds that were screened represent a thousand structurally diverse, potentially pharmaceutical heterocyclic compound libraries, including benzopyrans, oxadiazoles, thiadiazoles, and quinoxalines. By measuring GI50, TGI, and LC50 using SRB assay, GK13 was selected.
Results
In vitro enzyme kinetics using guinea pig liver TGase 2 showed that IC50 value was about 16.4 E−6 M. GK13 inhibits TGase 2-mediated I-κBα polymerization in a dose-dependent manner. LC50 of GK13 showed greater efficacy as 4.3E−4 M than LC50 of doxorubicin that showed efficacy as 3.87E−3 M in NCC72 composing 11 tissue origins and 72 cancer cell lines.
Conclusion
GK13 showed a possibility that quinoxaline derivatives may be effective for anti-cancer activity via TGase 2 inhibition.
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Acknowledgments
This work was supported by a research grant (NCC1110011-2) from the National Cancer Center in Korea to S.Y.K. and National R&D Program for Cancer Control (No. 1020050) in Korea to Y.D.G. We declare that none of the authors have a financial interest related to this work, and none of the authors have any financial support beyond the research grant mentioned above.
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Lee, SH., Kim, N., Kim, SJ. et al. Anti-cancer effect of a quinoxaline derivative GK13 as a transglutaminase 2 inhibitor. J Cancer Res Clin Oncol 139, 1279–1294 (2013). https://doi.org/10.1007/s00432-013-1433-1
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DOI: https://doi.org/10.1007/s00432-013-1433-1