Leukotriene receptor antagonists enhance HCC treatment efficacy by inhibiting ADAMs and suppressing MICA shedding

Abstract

In our previous genome-wide association study, we demonstrated the association between MHC class I-related chain A (MICA) and hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Increasing membrane-bound MICA (mMICA) in cancer cells by reducing MICA sheddases facilitates natural killer (NK) cell-mediated cytotoxicity. Our recent study clarified that A disintegrin and metalloproteases (ADAM), including ADAM9, are MICA sheddases in HCC, and that the suppression of ADAMs increases mMICA, demonstrating the rationality of mMICA-NK targeted therapy. Furthermore, we showed that regorafenib suppresses ADAM9 transcriptionally and translationally. A library of FDA-approved drugs was screened for more efficient inhibitors of ADAM9. Flow cytometry evaluation of the expression of mMICA after treatment with various candidate drugs identified leukotriene receptor antagonists as potential ADAM9 inhibitors. Furthermore, leukotriene receptor antagonists alone or in combination with regorafenib upregulated mMICA, which was in turn downregulated by leukotriene C4 and D4 via ADAM9 function. Our study demonstrates that leukotriene receptor antagonists could be developed as novel drugs for immunological control and suppression of ADAM9 in HCC. Further, leukotriene receptor antagonists should be explored as combination therapy partners with conventional multi-kinase inhibitors for developing therapeutic strategies with enhanced efficacies for HCC management and treatment. Keywords A disintegrin and metalloprotease 9 • Hepatocellular carcinoma • MHC class I-related chain A • Regorafenib • Leukotriene D4 Abbreviations ADAM A disintegrin and metalloprotease CCK8 Cell Counting Kit-8 HCC Hepatocellular carcinoma MICA MHC class I polypeptide-related sequence A MKIs Multi-kinase inhibitors. mMICA Membrane-bound MICA MMP Matrix metalloprotease NK Natural killer SEM Standard error of the mean sMICA Soluble MICA

Cysteinyl Leukotriene Pathway and Cancer

“…In a recent study using human hepatoma cell lines, CysLT antagonists (pranlukast and montelukast) inhibited ADAM9 activity and upregulated level of membrane-bound MHC class I-related chain A (mMICA), which might facilitate natural killer cell-mediated cytotoxicity, suggesting the potential of using leukotriene receptor antagonists along with regorafenib in the treatment of hepatoma [ 63 ].…”

A Rh(II)- or Ag(I)-Catalyzed Formal C–O Bond Insertion of Cyclic Hemiaminal with Aryl Diazoacetate

“…Reagents and conditions: 1 (1.0 mmol 1.0 equiv), 2 (1.5 mmol, 1.5 equiv), and AgOTf (10 mol%) in anhydrous DCM (5.0 mL) at room temperature for 2.0 h. The dr values were determined based on 1 H NMR analysis of the crude reaction mixture; isolated yields are given. Reagents and conditions: 4 (1.0 mmol, 1.0 equiv), 2 (1.5 mmol, 1.5 equiv), and Rh 2 (OAc) 4 (2.0 mol%) in anhydrous DCE (5.0 mL) at room temperature for 2.0 h. Thedr values were determined based on 1 H NMR analysis of the crude reaction mixture; isolated yields are given. Moreover, the effect of representative products 3 and 5 on cell viability was evaluated via CCK8 assay in HCT116 (colon cancer), MCF-7 (breast cancer), and A549 (lung adenocarcinoma) human cancer cell lines (see Table S2 in the Supporting Information for details).…”

“…-Hydroxyl--amino acid derivatives are ubiquitous structural units that are widely present in natural products and bioactive compounds (Figure 1), 1 such as Paclitaxel, 2 Mitosis inhibitor, 3 Leukotriene antagonists, 4 and sGC activators. 5 The importance of -hydroxyl--amino acids in medicine chemistry has stimulated tremendous efforts to develop a variety of catalytic methods for their synthesis, especially for those containing a tertiary/quaternary carbon center at the -position due to their unique structure and diverse biologic properties.…”

“…Scheme 3 Scope for the synthesis of six-membered N-heterocycles 5. Reagents and conditions: 4 (1.0 mmol, 1.0 equiv), 2 (1.5 mmol, 1.5 equiv), and Rh 2 (OAc)4 (2.0 mol%) in anhydrous DCE (5.0 mL) at room temperature for 2.0 h. Thedr values were determined based on 1 H NMR analysis of the crude reaction mixture; isolated yields are given.…”

An Overview of ADAM9: Structure, Activation, and Regulation in Human Diseases

“…This effect partially explained the clinical superiority of regorafenib over sorafenib [ 126 ]. Leukotriene receptor antagonists, pranlukast, and montelukast were reported to inhibit the enzymatic activity of ADAM9 in vitro and enhanced mMICA levels in HCC cells [ 127 ].…”