A Unique Anti-Cancer 3-Styrylchromone Suppresses Inflammatory Response via HMGB1-RAGE Signaling

Abstract

High mobility group box 1 (HMGB1)-receptor for advanced glycation endo-products (RAGE) axis serves as a key player in linking inflammation and carcinogenesis. Recently, papaverine was revealed to suppress the HMGB1-RAGE inflammatory signaling pathway and cancer cell proliferation. Therefore, a dual suppressor targeting this axis is expected to become a new type of therapeutic agent to treat cancer. Methods: Papaverine 3D pharmacophore mimetic compounds were selected by the LigandScout software from our in-house, anti-cancer chemical library and assessed for their anti-inflammatory activities by a HMGB1-RAGE-mediated interleukin-6 production assay using macrophage-like RAW264.7 cells. Molecular-biological analyses, such as Western blotting, were performed to clarify the mechanism of action. Results: A unique 6-methoxy-3-hydroxy-styrylchromone was found to possess potent anti-inflammatory and anti-cancer activities via the suppression of the HMGB1-RAGE-extracellular signal-regulated kinase 1/2 signaling pathway. Furthermore, the 3D pharmacophore-activity relationship analyses revealed that the hydroxyl group at the C4′ position of the benzene ring in a 3-styryl moiety was significant in its dual suppressive effects. Conclusions: These findings indicated that this compound may provide a valuable scaffold for the development of a new type of anti-cancer drug possessing anti-inflammatory activity and as a tool for understanding the link between inflammation and carcinogenesis.

A Dual Anti-Inflammatory and Anti-Proliferative 3-Styrylchromone Derivative Synergistically Enhances the Anti-Cancer Effects of DNA-Damaging Agents on Colon Cancer Cells by Targeting HMGB1-RAGE-ERK1/2 Signaling

“…The above results indicate that the C6 strongly suppresses HMGB1-induced pro-inflammatory responses in the macrophages by attenuating the HMGB1-RAGE pro-inflammatory signaling pathway. Through the extracellular binding of HMGB1 to RAGE, the cytoplasmic tail of RAGE interacts with key factors, which activate downstream RAGE mediators, such as ERK1/2 and c-Jun N-terminal kinase (JNK), in the regulation of pro-inflammatory cytokine production [ 59 ]. Thus, whether C6 regulates the activation of downstream pro-inflammatory RAGE signaling, the activation of ERK1/2 was examined using HMGB1-stimulated RAW264.7 cells.…”

“…In silico 3D pharmacophore search was performed with LigandScout software [ 78 ]. All compounds were constructed by Chem-Draw Professional 18.0 and converted to 3D conformations by the optimization program in LigandScout software [ 59 , 79 , 80 ]. The degrees of 3D similarity of small molecular compounds are proportional to the calculated 3D PFS values, and the 0.5 threshold (half 3D similarity) is a good choice.…”

“…Mouse macrophage-like RAW264.7 cells and human colorectal cancer HCT116 cells were purchased from American Type Culture Collection (Manassas, VA, USA). The cells were cultured in DMEM supplemented with 10% fetal bovine serum (FBS) (Biosera Europe, Nuaillé, France) and 1% penicillin-streptomycin (Nacalai Tesque, Inc., Kyoto, Japan) in a humidified atmosphere containing 5% CO 2 at 37 °C without antibiotics [ 54 , 55 , 59 , 60 , 64 ].…”

“…The WST-8-based colorimetric assay was used to assess cell viability using a SYNERGY HTX multimode plate reader (BioTek Instruments, Inc., Winooski, VT, USA) according to the manufacturer’s protocols [ 54 , 55 , 59 , 60 , 64 ].…”

“…The combination of papaverine and TMZ significantly delayed tumor growth in a U87MG xenograft mouse model [ 57 ]. Interestingly, we recently found that some 3-styrylchromone derivatives, which have already been identified to have anti-cancer activities [ 58 ], have weak anti-inflammatory activities via the suppression of HMGB1-RAGE [ 59 ] and lipopolysaccharide-Toll-like receptor (TLR)4 [ 60 ] signaling pathways in macrophage-like RAW264.7 cells. Thus, it is expected that papaverine-mimetic 3-styrylchromone derivatives, which possess both potent anti-inflammatory and anti-cancer activities targeting the HMGB1-RAGE axis, may become valuable leads for developing a new type of anti-cancer pharmaceutical.…”