A novel mechanism for the anticancer activity of aspirin and salicylates

Abstract

Epidemiological studies indicate that long-term aspirin usage reduces the incidence of colorectal cancer (CRC) and may protect against other non-CRC associated adenocarcinomas, including oesophageal cancer. A number of hypotheses have been proposed with respect to the molecular action of aspirin and other non-steroidal anti-inflammatory drugs in cancer development. The mechanism by which aspirin exhibits toxicity to CRC has been previously investigated by synthesising novel analogues and derivatives of aspirin in an effort to identify functionally significant moieties. Herein, an early effect of aspirin and aspirin-like analogues against the SW480 CRC cell line was investigated, with a particular focus on critical molecules in the epidermal growth factor (EGF) pathway. The present authors proposed that aspirin, diaspirin and analogues, and diflunisal (a salicylic acid derivative) may rapidly perturb EGF and EGF receptor (EGFR) internalisation. Upon longer incubations, the diaspirins and thioaspirins may inhibit EGFR phosphorylation at Tyr1045 and Tyr1173. It was additionally demonstrated, using a qualitative approach, that EGF internalisation in the SW480 cell line may be directed to endosomes by fumaryldiaspirin using early endosome antigen 1 as an early endosomal marker and that EGF internalisation may also be perturbed in oesophageal cell lines, suggestive of an effect not only restricted to CRC cells. Taken together and in light of our previous findings that the aspirin-like analogues can affect cyclin D1 expression and nuclear factor-κB localisation, it was hypothesized that aspirin and aspirin analogues significantly and swiftly perturb the EGFR axis and that the protective activity of aspirin may in part be explained by perturbed EGFR internalisation and activation. These findings may also have implications in understanding the inhibitory effect of aspirin and salicylates on wound healing, given the critical role of EGF in the response to tissue trauma.

Comprehensive Volatilome and Metabolome Signatures of Colorectal Cancer in Urine: A Systematic Review and Meta-Analysis

“…Therefore, prior to surgery, patients had less excretion of salicyluric acid, which is the glycine conjugate of salicylic acid, a component of aspirin. Some studies have suggested that aspirin has a chemoprotective role in colorectal cancer, where salicyluric acid and its derivatives are metabolized by colon cells and exert a protective effect [ 71 , 72 ]. One compound found to be upregulated pre- and post-surgery, L-pyroglutamic acid, was also upregulated in CRC and advanced adenoma compared to controls.…”

Diflunisal targets the HMGB 1/ CXCL 12 heterocomplex and blocks immune cell recruitment

“…Salicylates and their derivatives are potent and widely used nonsteroidal anti‐inflammatory drugs with a wide spectrum of modulating activities, comprising inhibition of cyclooxygenases and of NF‐kB , allosteric activation of AMP kinase (AMPK) , alteration of mTOR signaling , perturbation of EGFR internalization , and inhibition of CBP/p300 acetyltransferase activity . Recently, we showed that salicylates also inhibit signaling by HMGB1 .…”

Prognostic significance of BIRC7/Livin, Bcl-2, p53, Annexin V, PD-L1, DARC, MSH2 and PMS2 in colorectal cancer treated with FOLFOX chemotherapy with or without aspirin

“…Conversely, small interfering RNA (siRNA) transfection has been reported to downregulate BIRC7/Livin expression towards apoptotic induction in CRC in vitro and in vivo [60]. Aspirin reduces CRC growth via different mechanisms such as, inhibition of cyclooxygenase-2, dysregulation of NFκβ and Wnt-β-catenin signalling pathways, activation of EGFR pathway, host immune response modulation and up-regulation of tumour suppression genes [61][62][63]. Our findings using the TCGA showed a higher expression of BIRC7/Livin in Whites and Asians compared with African-Americans.…”