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Published on: September 22, 2019
Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9
Keita Ogawa1, Tetsuhiro Chiba2, Masato Nakamura1
1Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Background/Aim:
MHC-class I-related chain A (MICA) functions as a ligand for natural killer group D, an activating receptor on natural killer (NK) cells, and its expression correlates with the carcinogenesis and progression of hepatocellular carcinoma (HCC). Although membranous MICA (mMICA) activates NK cells, soluble forms of MICA (sMICA), shed by cleaving enzymes, such as A disintegrin and metalloprotease (ADAM) 9, suppress NK cells. Therefore, the prevention of MICA shedding through the inhibition of ADAM9 has the potential to activate cancer immunity. Although we have discovered several ADAM inhibitors, many did not sufficiently activate NK cells without being cytotoxic, and, thus, new ADAM9 inhibitor candidates are needed.
Materials And Methods:
To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells.
Results:
CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells.
Conclusion:
CCL347 has potential as a novel therapeutic drug for HCC.
Insights
A novel compound, CCL347, effectively reduces soluble MHC-class I-related chain A (sMICA) in hepatocellular carcinoma (HCC) cells. This inhibition enhances natural killer (NK) cell activity against cancer, offering a promising new therapeutic avenue for HCC treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- MHC-class I-related chain A (MICA) expression is linked to hepatocellular carcinoma (HCC) development and progression.
- Soluble MICA (sMICA) suppresses natural killer (NK) cell activity, while membrane-bound MICA (mMICA) activates them.
- Inhibiting MICA shedding via ADAM9 could enhance anti-cancer immunity, but existing inhibitors often show cytotoxicity.
Purpose of the Study:
- To identify novel ADAM9 inhibitors for potential HCC therapy.
- To evaluate the efficacy of candidate compounds in reducing sMICA and enhancing NK cell function.
- To assess the safety profile of identified compounds regarding cytotoxicity.
Main Methods:
- A chemical library of 741 compounds was screened using a fluorescence assay to identify potential ADAM9 inhibitors.
- Hit compounds were analyzed for their effects on sMICA and mMICA levels in HCC cell lines via ELISA and flow cytometry.
- NK cell cytotoxicity was assessed through co-culture assays with HCC cells.
Main Results:
- CCL347, a symmetrical five-benzene-ring compound, was identified as a hit.
- CCL347 significantly reduced sMICA levels with minimal cytotoxicity.
- While mMICA was also reduced, CCL347 enhanced NK cell-mediated cytotoxicity against HCC cells.
Conclusions:
- CCL347 demonstrates potential as a novel therapeutic agent for HCC.
- Inhibiting MICA shedding with CCL347 may represent a viable strategy to boost anti-cancer immunity in HCC patients.
