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Novel conjugates with dual suppression of glutathione S-transferases and tryptophan-2,3-dioxygenase activities for improving hepatocellular carcinoma therapy.
Bioorg Chem 2019; 92:103191BC

Abstract

Tryptophan-2,3-dioxygenase (TDO) is an immune checkpoint enzyme expressed in human tumors and involved in immune evasion and tumor tolerance. While glutathione S-transferases (GSTs) are pharmacological targets for several cancer. Here we demonstrated the utility of NBDHEX (GSTs inhibitor) and TDO inhibitor by the combinatorial linker design. Two novel conjugates with different linkers were prepared to reverse tumor immune suppression. The conjugates displayed significant antitumor activity against TDO and GSTs expression of HepG2 cancer cells. Further study indicated that compound 4 could induce higher apoptotic effect than its mother compounds via a mitochondrial-dependent pathway, simultaneously more effective to inhibit TDO and GSTs protein expression. Further study indicated that 4 could decrease the production of kynurenine and deactivate aryl hydrocarbon receptor (AHR), leading to CD3+T-cell activation and proliferation to involve in antitumor immune response.

Authors+Show Affiliations

Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: 101011844@seu.edu.cn.Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China; Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31445192

Citation

Hua, Shixian, et al. "Novel Conjugates With Dual Suppression of Glutathione S-transferases and Tryptophan-2,3-dioxygenase Activities for Improving Hepatocellular Carcinoma Therapy." Bioorganic Chemistry, vol. 92, 2019, p. 103191.
Hua S, Wang X, Chen F, et al. Novel conjugates with dual suppression of glutathione S-transferases and tryptophan-2,3-dioxygenase activities for improving hepatocellular carcinoma therapy. Bioorg Chem. 2019;92:103191.
Hua, S., Wang, X., Chen, F., & Gou, S. (2019). Novel conjugates with dual suppression of glutathione S-transferases and tryptophan-2,3-dioxygenase activities for improving hepatocellular carcinoma therapy. Bioorganic Chemistry, 92, p. 103191. doi:10.1016/j.bioorg.2019.103191.
Hua S, et al. Novel Conjugates With Dual Suppression of Glutathione S-transferases and Tryptophan-2,3-dioxygenase Activities for Improving Hepatocellular Carcinoma Therapy. Bioorg Chem. 2019;92:103191. PubMed PMID: 31445192.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel conjugates with dual suppression of glutathione S-transferases and tryptophan-2,3-dioxygenase activities for improving hepatocellular carcinoma therapy. AU - Hua,Shixian, AU - Wang,Xinyi, AU - Chen,Feihong, AU - Gou,Shaohua, Y1 - 2019/08/10/ PY - 2019/02/07/received PY - 2019/07/01/revised PY - 2019/08/09/accepted PY - 2019/8/25/pubmed PY - 2019/8/25/medline PY - 2019/8/25/entrez KW - Anticancer KW - Chemo-immunotherapy KW - Glutathione S-transferase KW - Hepatocellular carcinoma KW - Tryptophan-2,3-dioxygenase SP - 103191 EP - 103191 JF - Bioorganic chemistry JO - Bioorg. Chem. VL - 92 N2 - Tryptophan-2,3-dioxygenase (TDO) is an immune checkpoint enzyme expressed in human tumors and involved in immune evasion and tumor tolerance. While glutathione S-transferases (GSTs) are pharmacological targets for several cancer. Here we demonstrated the utility of NBDHEX (GSTs inhibitor) and TDO inhibitor by the combinatorial linker design. Two novel conjugates with different linkers were prepared to reverse tumor immune suppression. The conjugates displayed significant antitumor activity against TDO and GSTs expression of HepG2 cancer cells. Further study indicated that compound 4 could induce higher apoptotic effect than its mother compounds via a mitochondrial-dependent pathway, simultaneously more effective to inhibit TDO and GSTs protein expression. Further study indicated that 4 could decrease the production of kynurenine and deactivate aryl hydrocarbon receptor (AHR), leading to CD3+T-cell activation and proliferation to involve in antitumor immune response. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/31445192/Novel_conjugates_with_dual_suppression_of_glutathione_S-transferases_and_tryptophan-2,3-dioxygenase_activities_for_improving_hepatocellular_carcinoma_therapy L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(19)30102-6 DB - PRIME DP - Unbound Medicine ER -