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.
Highlights
Hepatocellular carcinoma (HCC) is a severe human malignant tumor [1]
Using an enzymelinked immunosorbent assay (ELISA) system consisting of purified recombinant TOR signaling pathway regulator-like (TIPRL) and mitogen-activated protein kinase kinase 7 (MKK7) proteins (Figure 1A) and the strategies shown in Figure 1B and 1C, we identified a novel chemical compound that inhibits the MKK7-TIPRL interaction
These initial hits were re-evaluated in triplicate, and unwanted hits, such as natural products having high molecular weights (M.W. > 1,000), which compounds that could be difficult to optimize into orally bioactive drugs, or compounds that could have interfered with the ELISA assay, were removed
Summary
Hepatocellular carcinoma (HCC) is a severe human malignant tumor [1]. a surgery is believed to be an essential treatment for HCC, liver function eventually declines in most patients, resulting in poor survival rates. Many emerging therapeutic methods are available to improve the survival rate of patients with HCC, such as curative therapy, palliative therapy and various systemic treatments. These strategies have not dramatically improved outcomes for patients with HCC, and many researchers and drug companies endeavor to develop alternative therapeutic approaches for the treatment of HCC [2, 3]. The binding of TRAIL to DR4/5 initiates an apoptosis signal by recruiting FAS-associated death domain (FADD) and DD, which activates poly ADP ribose polymerase (PARP) and caspases [5,6,7]. Many cancer cells are resistant to TRAIL-induced apoptosis, and these cells overexpress anti-apoptotic proteins (Bcl and Bcl-XL), antagonistic receptors (DcR1/2), and defective FADD. The mode of action (MOA) by which many of these natural/small compounds increase TRAIL-induced apoptosis and act as TRAIL sensitizers is not known
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
