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Indomethacin-enhanced anticancer effect of arsenic trioxide in A549 cell line: involvement of apoptosis and phospho-ERK and p38 MAPK pathways.

Mandegary A, Torshabi M, Seyedabadi M, Amirheidari B, Sharif E, Ghahremani MH - Biomed Res Int (2013)

Bottom Line: Treatment of cells with combinations of clinically relevant concentrations of ATO and Indo resulted in greater growth inhibition and apoptosis induction than did either agent alone.Caspase-3 activity was considerably high in the presence of ATO and Indo but showed no difference in single or combination use.Phosphorylation of p38 and ERK1/2 was remarkable in the concurrent presence of both drugs.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran.

ABSTRACT

Background: Focusing on novel drug combinations that target different pathways especially apoptosis and MAPK could be a rationale for combination therapy in successful treatment of lung cancer. Concurrent use of cyclooxygenase (COX) inhibitors with arsenic trioxide (ATO) might be a possible treatment option.

Methods: Cytotoxicity of ATO, dexamethasone (Dex), celecoxib (Cel), and Indomethacin (Indo) individually or in combination was determined at 24, 48, and 72 hrs in A549 lung cancer cells. The COX-2 gene and protein expression, MAPK pathway proteins, and caspase-3 activity were studied for the most cytotoxic combinations.

Results: The IC50s of ATO and Indo were 68.7 μmol/L and 396.5 μmol/L, respectively. Treatment of cells with combinations of clinically relevant concentrations of ATO and Indo resulted in greater growth inhibition and apoptosis induction than did either agent alone. Caspase-3 activity was considerably high in the presence of ATO and Indo but showed no difference in single or combination use. Phosphorylation of p38 and ERK1/2 was remarkable in the concurrent presence of both drugs.

Conclusions: Combination therapy with ATO and Indo exerted a very potent in vitro cytotoxic effect against A549 lung cancer cells. Activation of ERK and p38 pathways might be the mechanism of higher cytotoxic effect of ATO-Indo combination.

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Related in: MedlinePlus

The effects of ATO and Indo and their combinations on the expression of COX-2 mRNA. (a) RT-PCR reaction products were resolved on 1% agarose gel and stained with Ethidium bromide. (b) Densitometric analyses of COX-2 mRNA expression is presented as the band's density to control (β-actin) of three independent experiments (Mean ± SE, n = 3). (c) The effect of Indo alone (light columns) and combination with ATO 2 μM (dark columns) on COX-2 expression.
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fig4: The effects of ATO and Indo and their combinations on the expression of COX-2 mRNA. (a) RT-PCR reaction products were resolved on 1% agarose gel and stained with Ethidium bromide. (b) Densitometric analyses of COX-2 mRNA expression is presented as the band's density to control (β-actin) of three independent experiments (Mean ± SE, n = 3). (c) The effect of Indo alone (light columns) and combination with ATO 2 μM (dark columns) on COX-2 expression.

Mentions: Considering the role of COX-2 and COX inhibition in lung cancer [26], we have assessed the mRNA expression of COX-2 with different concentrations of ATO as well as ATO 2 μM combination with Indo. Figure 4(a) shows that ATO has decreased the COX-2 expression in a dose-dependent manner (Figures 4(a) and 4(b)) and at ATO 10 μM there is 50% reduction in COX-2 expression. Treatment of A549 cells with Indo has increased the COX-2 expression dose-dependently (Figure 4(c)). The Indo-induced COX-2 expression has been inhibited by addition of ATO 2 μM to the cells (Figure 4(c)).


Indomethacin-enhanced anticancer effect of arsenic trioxide in A549 cell line: involvement of apoptosis and phospho-ERK and p38 MAPK pathways.

Mandegary A, Torshabi M, Seyedabadi M, Amirheidari B, Sharif E, Ghahremani MH - Biomed Res Int (2013)

The effects of ATO and Indo and their combinations on the expression of COX-2 mRNA. (a) RT-PCR reaction products were resolved on 1% agarose gel and stained with Ethidium bromide. (b) Densitometric analyses of COX-2 mRNA expression is presented as the band's density to control (β-actin) of three independent experiments (Mean ± SE, n = 3). (c) The effect of Indo alone (light columns) and combination with ATO 2 μM (dark columns) on COX-2 expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3842073&req=5

fig4: The effects of ATO and Indo and their combinations on the expression of COX-2 mRNA. (a) RT-PCR reaction products were resolved on 1% agarose gel and stained with Ethidium bromide. (b) Densitometric analyses of COX-2 mRNA expression is presented as the band's density to control (β-actin) of three independent experiments (Mean ± SE, n = 3). (c) The effect of Indo alone (light columns) and combination with ATO 2 μM (dark columns) on COX-2 expression.
Mentions: Considering the role of COX-2 and COX inhibition in lung cancer [26], we have assessed the mRNA expression of COX-2 with different concentrations of ATO as well as ATO 2 μM combination with Indo. Figure 4(a) shows that ATO has decreased the COX-2 expression in a dose-dependent manner (Figures 4(a) and 4(b)) and at ATO 10 μM there is 50% reduction in COX-2 expression. Treatment of A549 cells with Indo has increased the COX-2 expression dose-dependently (Figure 4(c)). The Indo-induced COX-2 expression has been inhibited by addition of ATO 2 μM to the cells (Figure 4(c)).

Bottom Line: Treatment of cells with combinations of clinically relevant concentrations of ATO and Indo resulted in greater growth inhibition and apoptosis induction than did either agent alone.Caspase-3 activity was considerably high in the presence of ATO and Indo but showed no difference in single or combination use.Phosphorylation of p38 and ERK1/2 was remarkable in the concurrent presence of both drugs.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran.

ABSTRACT

Background: Focusing on novel drug combinations that target different pathways especially apoptosis and MAPK could be a rationale for combination therapy in successful treatment of lung cancer. Concurrent use of cyclooxygenase (COX) inhibitors with arsenic trioxide (ATO) might be a possible treatment option.

Methods: Cytotoxicity of ATO, dexamethasone (Dex), celecoxib (Cel), and Indomethacin (Indo) individually or in combination was determined at 24, 48, and 72 hrs in A549 lung cancer cells. The COX-2 gene and protein expression, MAPK pathway proteins, and caspase-3 activity were studied for the most cytotoxic combinations.

Results: The IC50s of ATO and Indo were 68.7 μmol/L and 396.5 μmol/L, respectively. Treatment of cells with combinations of clinically relevant concentrations of ATO and Indo resulted in greater growth inhibition and apoptosis induction than did either agent alone. Caspase-3 activity was considerably high in the presence of ATO and Indo but showed no difference in single or combination use. Phosphorylation of p38 and ERK1/2 was remarkable in the concurrent presence of both drugs.

Conclusions: Combination therapy with ATO and Indo exerted a very potent in vitro cytotoxic effect against A549 lung cancer cells. Activation of ERK and p38 pathways might be the mechanism of higher cytotoxic effect of ATO-Indo combination.

Show MeSH
Related in: MedlinePlus