Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo

Abstract

Substantial evidence indicates that aspirin and related non-steroidal anti-inflammatory drugs (NSAIDs) have potential as chemopreventative/therapeutic agents. However, these agents cannot be universally recommended for prevention purposes due to their potential side-effect profiles. Here, we compared the growth inhibitory and mechanistic activity of aspirin to two novel analogues, diaspirin (DiA) and fumaryl diaspirin (F-DiA). We found that the aspirin analogues inhibited cell proliferation and induced apoptosis of colorectal cancer cells at significantly lower doses than aspirin. Similar to aspirin, we found that an early response to the analogues was a reduction in levels of cyclin D1 and stimulation of the NF-κB pathway. This stimulation was associated with a significant reduction in basal levels of NF-κB transcriptional activity, in keeping with previous data for aspirin. However, in contrast to aspirin, DiA and F-DiA activity was not associated with nucleolar accumulation of RelA. For all assays, F-DiA had a more rapid and significant effect than DiA, identifying this agent as particularly active against colorectal cancer. Using a syngeneic colorectal tumour model in mice, we found that, while both agents significantly inhibited tumour growth in vivo, this effect was particularly pronounced for F-DiA. These data identify two compounds that are active against colorectal cancer in vitro and in vivo. They also identify a potential mechanism of action of these agents and shed light on the chemical structures that may be important for the antitumour effects of aspirin.

Integrative genomic analyses of the RNA-binding protein, RNPC1, and its potential role in cancer prediction

“…NF-κB is composed of NFKB1 or NFKB2 bound to either REL, RELA or RELB. NF-κB is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to a number of biological processes, such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis (49)(50)(51)(52). C/EBPα is required for the proper control of adipogenesis, glucose metabolism, granulocytic differentiation, lung development and the development of various types of cancer (53,54).…”

Downregulation of miR-518a-3p activates the NIK-dependent NF-κB pathway in colorectal cancer

“…In the majority of tumor cells, constitutive activation of nuclear factor-κB (NF-κB) is often observed ( 2 ). The abnormal activation of NF-κB contributes to significant cell proliferation and migration in CRC and in other types of cancer ( 3 ), and the inhibition of NF-κB activity has been shown to significantly reduce cancer cell growth and enhance cell apoptosis, indicating that NF-κB members are potential therapeutic targets in tumors ( 4 ). Mammalian NF-κB members mainly include p65 (RelA), p105/p50, RelB, p100/p52 and c-Rel ( 5 ), and two distinct pathways are involved in the regulation of NF-κB activation: the canonical and the non-canonical pathways.…”

Synthesis of Tolmetin Hydrazide–Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells

“…Cancer cells use different mechanisms including extrinsic and intrinsic pathways to escape apoptosis. The evidence obtained in recent years indicates that many non‐steroidal anti‐inflammatory drugs (NSAIDs) have anti‐proliferative activity in tumor cells . In the current study, we also investigated whether the anti‐cancer effects of compound 4g and tolmetin occurred via the apoptotic pathway and, if so, which signaling pathway that initiates apoptosis was activated in host defence.…”