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Oncotarget. 2017 Nov 3;8(68):112610-112622. doi: 10.18632/oncotarget.22614. eCollection 2017 Dec 22.

Novel indazole-based small compounds enhance TRAIL-induced apoptosis by inhibiting the MKK7-TIPRL interaction in hepatocellular carcinoma.

Author information

1
Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea.
2
Bio and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
3
Department of Functional Genomics, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
4
Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea.
5
Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.

Abstract

Hepatocellular carcinoma (HCC) is one of the most malignant tumors. Although various treatments, such as surgery and chemotherapy, have been developed, a novel alternative therapeutic approach for HCC therapy is urgently needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent, but many cancer cells are resistant to TRAIL-induced apoptosis. To help overcome TRAIL resistance in HCC cancer cells, we have identified novel chemical compounds that act as TRAIL sensitizers. We first identified the hit compound, TRT-0002, from a chemical library of 6,000 compounds using a previously developed high-throughput enzyme-linked immunosorbent assay (ELISA) screening system, which was based on the interaction of mitogen-activated protein kinase kinase 7 (MKK7) and TOR signaling pathway regulator-like (TIPRL) proteins and a cell viability assay. To increase the efficacy of this TRAIL sensitizer, we synthesized 280 analogs of TRT-0002 and finally identified two lead compounds (TRT-0029 and TRT-0173). Co-treating cultured Huh7 cells with either TRT-0029 or TRT-0173 and TRAIL resulted in TRAIL-induced apoptosis due to the inhibition of the MKK7-TIPRL interaction and subsequent phosphorylation of MKK7 and c-Jun N-terminal kinase (JNK). In vivo, injection of these compounds and TRAIL into HCC xenograft tumors resulted in tumor regression. Taken together, our results suggest that the identified lead compounds serve as TRAIL sensitizers and represent a novel strategy to overcome TRAIL resistance in HCC.

KEYWORDS:

HCC; TIPRL; TRAIL sensitizer; apoptosis

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