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Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo
Claudius, AK Kankipati, CS Kilari, RS Hassan, S Guest, K Russell, ST Perry, CJ Stark, LA Nicholl, ID
Claudius, AK
Kankipati, CS
Kilari, RS
Hassan, S
Guest, K
Russell, ST
Perry, CJ
Stark, LA
Nicholl, ID
Editors
Other contributors
Affiliation
Epub Date
Issue Date
2014-07-31
Submitted date
Subjects
Cell Line, Tumor
Animals
Humans
Mice
Mice, Nude
Adenocarcinoma
Colorectal Neoplasms
Aspirin
NF-kappa B
Anti-Inflammatory Agents, Non-Steroidal
Drug Screening Assays, Antitumor
Xenograft Model Antitumor Assays
Signal Transduction
Cell Cycle
Apoptosis
Cell Proliferation
Transcription Factor RelA
Cyclin D
Animals
Humans
Mice
Mice, Nude
Adenocarcinoma
Colorectal Neoplasms
Aspirin
NF-kappa B
Anti-Inflammatory Agents, Non-Steroidal
Drug Screening Assays, Antitumor
Xenograft Model Antitumor Assays
Signal Transduction
Cell Cycle
Apoptosis
Cell Proliferation
Transcription Factor RelA
Cyclin D
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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.
Citation
Claudius, A-K., Kankipati, C. S., Kilari, R. S., Hassan, S., Guest, K., Russell, S. T., ... Nicholl, I. D. (2014). Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo. Oncology Reports, 32(4), 1670-1680. https://doi.org/10.3892/or.2014.3373
Publisher
Journal
Research Unit
PubMed ID
25109257
PubMed Central ID
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Type
Journal article
Language
en
Description
Series/Report no.
ISSN
EISSN
1791-2431
ISBN
ISMN
Gov't Doc #
Sponsors
This project was supported by funding from the Research Institute in Healthcare Science, University of Wolverhampton (IDN) and by the AICR (10-0158) (LAS).