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Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines.

Saber MM, Galal MA, Ain-Shoka AA, Shouman SA - BMC Cancer (2016)

Bottom Line: 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.Metformin also enhanced the inhibitory effect of 5-ASA on MMP-2 and MMP-9 enzyme activity, indicating a decrease in metastasis.The 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.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. mona.magdy@pharma.cu.edu.eg.

ABSTRACT

Background: 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. Studies also revealed that metformin induced apoptosis in several cancer cell lines.

Methods: We 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.

Results: Metformin 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.

Conclusion: The 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.

No MeSH data available.


Related in: MedlinePlus

Western blot for Bcl-2 and Bax levels in (a) Caco-2 and (b) HCT-116 cells after treatment with metformin, 5-ASA or their combination. One representative western blot of three independent experiments is shown. Effect of treatment of Caco-2 and HCT-116 cells for 48 h with subIC50 concentrations of metformin, 5-ASA or the combination of both drugs on (c) Bcl-2 level (d) Bax level. All data are expressed as mean ± SD of 3 separate experiments. The statistical significance of the results was analyzed using one way ANOVA followed by Tukey-Kramer multiple comparison test. a Significantly different from control, b from metformin and c from 5-ASA (P <0.05)
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Fig3: Western blot for Bcl-2 and Bax levels in (a) Caco-2 and (b) HCT-116 cells after treatment with metformin, 5-ASA or their combination. One representative western blot of three independent experiments is shown. Effect of treatment of Caco-2 and HCT-116 cells for 48 h with subIC50 concentrations of metformin, 5-ASA or the combination of both drugs on (c) Bcl-2 level (d) Bax level. All data are expressed as mean ± SD of 3 separate experiments. The statistical significance of the results was analyzed using one way ANOVA followed by Tukey-Kramer multiple comparison test. a Significantly different from control, b from metformin and c from 5-ASA (P <0.05)

Mentions: The increase in caspase-3 activity was accompanied by increased apoptotic Bax levels and decreased expression of the anti-apoptotic Bcl-2 protein in both cell lines (Fig. 3), following treatment with 5-ASA, metformin or their combination after 48 h. The combination group showed the most significant change in Bax levels, as compared to individual treatments where it produced a 16 and 13 folds increase in Caco-2 and HCT-116 cells, respectively. On the other hand, the anti-apoptotic Bcl-2 expression decreased by 85 % and 80 % in Caco-2 and HCT-116 cells after combination treatment.Fig. 3


Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines.

Saber MM, Galal MA, Ain-Shoka AA, Shouman SA - BMC Cancer (2016)

Western blot for Bcl-2 and Bax levels in (a) Caco-2 and (b) HCT-116 cells after treatment with metformin, 5-ASA or their combination. One representative western blot of three independent experiments is shown. Effect of treatment of Caco-2 and HCT-116 cells for 48 h with subIC50 concentrations of metformin, 5-ASA or the combination of both drugs on (c) Bcl-2 level (d) Bax level. All data are expressed as mean ± SD of 3 separate experiments. The statistical significance of the results was analyzed using one way ANOVA followed by Tukey-Kramer multiple comparison test. a Significantly different from control, b from metformin and c from 5-ASA (P <0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4759732&req=5

Fig3: Western blot for Bcl-2 and Bax levels in (a) Caco-2 and (b) HCT-116 cells after treatment with metformin, 5-ASA or their combination. One representative western blot of three independent experiments is shown. Effect of treatment of Caco-2 and HCT-116 cells for 48 h with subIC50 concentrations of metformin, 5-ASA or the combination of both drugs on (c) Bcl-2 level (d) Bax level. All data are expressed as mean ± SD of 3 separate experiments. The statistical significance of the results was analyzed using one way ANOVA followed by Tukey-Kramer multiple comparison test. a Significantly different from control, b from metformin and c from 5-ASA (P <0.05)
Mentions: The increase in caspase-3 activity was accompanied by increased apoptotic Bax levels and decreased expression of the anti-apoptotic Bcl-2 protein in both cell lines (Fig. 3), following treatment with 5-ASA, metformin or their combination after 48 h. The combination group showed the most significant change in Bax levels, as compared to individual treatments where it produced a 16 and 13 folds increase in Caco-2 and HCT-116 cells, respectively. On the other hand, the anti-apoptotic Bcl-2 expression decreased by 85 % and 80 % in Caco-2 and HCT-116 cells after combination treatment.Fig. 3

Bottom Line: 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.Metformin also enhanced the inhibitory effect of 5-ASA on MMP-2 and MMP-9 enzyme activity, indicating a decrease in metastasis.The 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.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. mona.magdy@pharma.cu.edu.eg.

ABSTRACT

Background: 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. Studies also revealed that metformin induced apoptosis in several cancer cell lines.

Methods: We 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.

Results: Metformin 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.

Conclusion: The 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.

No MeSH data available.


Related in: MedlinePlus