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

Abstract

The current anti-cancer treatments are not enough to eradicate tumors, and therefore, new modalities and strategies are still needed. Most tumors generate an inflammatory tumor microenvironment (TME) and maintain the niche for their development. Because of the critical role of inflammation via high-mobility group box 1 (HMGB1)–receptor for advanced glycation end-products (RAGE) signaling pathway in the TME, a novel compound possessing both anti-cancer and anti-inflammatory activities by suppressing the HMGB1-RAGE axis provides an effective strategy for cancer treatment. A recent work of our group found that some anti-cancer 3-styrylchromones have weak anti-inflammatory activities via the suppression of this axis. In this direction, we searched such anti-cancer molecules possessing potent anti-inflammatory activities and discovered 7-methoxy-3-hydroxy-styrylchromone (C6) having dual suppressive activities. Mechanism-of-action studies revealed that C6 inhibited the increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) under the stimulation of HMGB1-RAGE signaling and thereby suppressed cytokine production in macrophage-like RAW264.7 cells. On the other hand, in colorectal cancer HCT116 cells, C6 inhibited the activation of ERK1/2, cyclin-dependent kinase 1, and AKT, down-regulated the protein level of XIAP, and up-regulated pro-apoptotic Bax and caspase-3/7 expression. These alterations are suggested to be involved in the C6-induced suppression of cell cycle/proliferation and initiation of apoptosis in the cancer cells. More importantly, in cancer cells, the treatment of C6 potentiates the anti-cancer effects of DNA-damaging agents. Thus, C6 may be a promising lead for the generation of a novel class of cancer therapeutics.

A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs

“…We recently reported that Compound B potently inhibited the HMGB1-stimulated IL-6 production in mouse macrophage-like cells RAW264.7, suggesting dual suppressive actions: anti-inflammatory and anti-cancer activities [ 36 ]. Compound B (10 μM) failed to inhibit the following kinases (ABL, CSK, EDFR, EPHA2, EPHB4, FGFR1, FLT3, IGF1R, ITK, JAK3, KDR, LCK, MET, PDGFRα, PYK2, SRC, SYK, TIE2, TRKA, TYRO3) (unpublished data).…”

AGEs and RAGE: metabolic and molecular signatures of the glycation-inflammation axis in malignant or metastatic cancers

“…In many tumours, stromal cells incite CAFs and vascular endothelial cells, and employ multiple supportive immune cells like TAMs and MDSCs, ultimately creating an immuno-suppressive and inflammatory tumour micro-milieu. The crosstalk between cancer cells and immune cells drive tumour progression through RAGE-mediated active expression of inflammatory cytokines—IL-6, IL-1β, TNF-α, other cytokines and chemokines, which elicit the secretion of pro-inflammatory RAGE ligands, comprising HMGB1 and S100 family of proteins [ 83 ]. HMGB1 released from immune cells in a persistent inflammatory milieu instigate chemokines and cytokines, which mediate the CAFs, MDSCs and TAMs to create inflammatory and immuno-suppressive onco-milieu by preventing the entry or T-cells and natural killer (NK) cells, conducive for the evasion of immune detection, thereby facilitating unchecked tumour growth.…”

“…Papaverine elicited considerable suppression of RAGE-reliant cell proliferation, invasion and migration, RAGE-reliant NF-κB activation and RAGE expression in HT1080 human fibrosarcoma cells. Furthermore, papaverine-mimetic 3-styrylchromone derivative developed recently by Tanuma et al [ 83 ] exhibited anti-inflammatory, anti-proliferative and anti-cancer effects via suppression of HMGB1-RAGE-ERK 1/2 signalling; anti-apoptotic effects via augmented pro-apoptotic Bax and caspase-3/7 expression in HCT116 colon cancer cells, both individually and in synergistic combination with DNA damaging agents. Hence we suggest that papaverine, scutellarein including many AGE inhibitors/anti-glycation agents (shown in Table 3 ) like curcumin, quercetin, withaferin A, and other plant-based agents could be developed as novel molecular lead compounds with inherent potential in anticancer therapeutics simultaneously non-toxic to healthy cells.…”

Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider

“…A novel molecule, recently discovered by Tanuma et al [ 82 ], 7-methoxy-3-hydroxy-styrylchromone (c6), is not only an effective suppressor of cell cycle/proliferation but also an initiator of apoptosis in cancer cells, and a promising potentiator of the anticancer effects of DNA-damaging antineoplastic agents.…”