Targeting DNA Binding for NF-κB as an Anticancer Approach in Hepatocellular Carcinoma

Abstract

Quinoline core has been shown to possess a promising role in the development of anticancer agents. However, the correlation between its broad spectrum of bioactivity and the underlying mechanism of actions is poorly understood. The present study, with the use of bioinformatics approaches, reported a series of designed molecules which integrated quinoline core and sulfonyl moiety, with the objective of evaluating the substituent and linker effects on anticancer activities and associated mechanistic targets. We identified potent compounds (1h, 2h, 5 and 8) exhibiting significant anticancer effects towards liver cancer cells (Hep3B) with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) relative values of cytotoxicity below 0.40, a value in the range of doxorubicin positive control with the value of 0.12. Bulky substituents and the presence of bromine atom, as well as the presence of sulfonamide linkage, are likely the favorable structural components for molecules exerting a strong anticancer effect. To the best of our knowledge, our findings obtained from chemical synthesis, in vitro cytotoxicity, bioinformatics-based molecular docking analysis (similarity ensemble approach, SEA),and electrophoretic mobility shift assay provided the first evidence in correlation to the anticancer activities of the selected compound 5 with the modulation on the binding of transcription factor NF-κB to its target DNA. Accordingly, compound 5 represented a lead structure for the development of quinoline-based NF-κB inhibitors and this work added novel information on the understanding of the mechanism of action for bioactive sulfonyl-containing quinoline compounds against hepatocellular carcinoma.

Curcumin: a therapeutic strategy in cancers by inhibiting the canonical WNT/β-catenin pathway

“…Several studies have examined the relationship between chronic inflammation and cancer [5, 6] and indeed have highlighted the promising role of anti-inflammatory treatments for cancer [7]. Chronic inflammation is responsible for the different stages observed in cancers, such as invasion, angiogenesis, proliferation and metastasis [8–10].…”

“…Since few years, the combination formed by oxidative stress and chronic inflammation is involved in the initiation of cancer [12]. Reactive oxygen species production (ROS) is increased by the activation of inflammatory factors [13] and thus also participates in the process of invasion, proliferation, angiogenesis and then metastasis [14]. The canonical WNT/β-catenin pathway controls several other pathways involved in development and tissue homeostasis.…”

“…It is well known that the human body is capable of self-healing after a short-term inflammatory response, but a long-term chronic inflammation could lead to initiation of the cancer process. Many studies have shown that inflammatory factors (including interleukins, TNF-α, NF-ϰB) and the ROS production-induced inflammation infiltrate the inflammatory microenvironment leading to DNA damages and ultimately initiation of cancer [21]. By acting on several signaling pathways, especially the WNT/β-catenin pathway, curcumin can have anticancer effect by inhibiting chronic inflammation and oxidative stress [22].…”

“…The over-activated PI3K/Akt pathway observed in the cancer process is stimulated by ROS production [100]. PTEN is the main inhibitor of the PI3K/Akt pathway [101].…”

“…The recent anti-tumorigenic role of curcumin in human leukemic cells may confirmed the presence of oxidized curcumin metabolites [188]. Indeed, curcumin is known to be a natural component presenting antioxidant effects [190]. Due to its chemical structure, curcumin is indeed a scavenger of ROS and RNS [191].…”