Abstract
BackgroundThe link between inflammation and cancer has been confirmed by the use of anti-inflammatory therapies in cancer prevention and treatment. 5-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells. Studies also revealed that metformin induced apoptosis in several cancer cell lines.MethodsWe investigated the combinatory effect of 5-ASA and metformin on HCT-116 and Caco-2 CRC cell lines. Apoptotic markers were determined using western blotting. Expression of pro-inflammatory cytokines was determined by RT-PCR. Inflammatory transcription factors and metastatic markers were measured by ELISA.ResultsMetformin enhanced CRC cell death induced by 5-ASA through significant increase in oxidative stress and activation of apoptotic machinery. Moreover, metformin enhanced the anti-inflammatory effect of 5-ASA by decreasing the gene expression of IL-1β, IL-6, COX-2 and TNF-α and its receptors; TNF-R1 and TNF-R2. Significant inhibition of activation of NF-κB and STAT3 transcription factors, and their downstream targets was also observed. Metformin also enhanced the inhibitory effect of 5-ASA on MMP-2 and MMP-9 enzyme activity, indicating a decrease in metastasis.ConclusionThe current data demonstrate that metformin potentiates the antitumor effect of 5-ASA on CRC cells suggesting their potential use as an adjuvant treatment in CRC.
Highlights
The link between inflammation and cancer has been confirmed by the use of anti-inflammatory therapies in cancer prevention and treatment. 5-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells
Exaggerated increase in oxidative stress upon combined treatment with metformin and 5-ASA Combination of subIC50 concentrations of both drugs produced a pronounced increase in MDA level (Fig. 2a) and a greater decrease in the intracellular GSH level than each drug alone (Fig. 2b)
In Caco-2 cells the combination of metformin and 5-ASA resulted in a significant increase in MDA level of 3 folds compared to, 1.9 and 1.75 folds produced by either of the treatments
Summary
The link between inflammation and cancer has been confirmed by the use of anti-inflammatory therapies in cancer prevention and treatment. 5-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells. 5-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells. Mesalamine [5-aminosalicylic acid (5-ASA)] is the drug of choice in IBD, mainly UC, for maintenance of remission and treatment of mild relapses. It is a weak COX and LOX inhibitor as it is structurally related to NSAIDs, but unlike these compounds it has low systemic resorption and very few side effects even at high doses for long time periods [9]. Epidemiological investigations suggested that long term 5-ASA consumption decreases the risk of developing CRC in IBD patients [10, 11]. The antiproliferative and pro-apoptotic effects of 5-ASA on several
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