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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

Effect of different concentrations of ATO (a), Cel (b), Indo (c), and Dex (d) on the growth of A549 cell line (Mean ± SE, n = 4).
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fig2: Effect of different concentrations of ATO (a), Cel (b), Indo (c), and Dex (d) on the growth of A549 cell line (Mean ± SE, n = 4).

Mentions: ATO-induced inhibition of cell growth in A549 is illustrated in Figure 1. To explain further, a decrease in viability along with dose increments and time extensions is evident. Since the 24 and 48 hrs treatments had no significant cytotoxicity, assays were focused on the 72 hrs treatment. The dose-response curve of ATO, Cel, Indo, and Dex on cell proliferation at 72 hrs is shown in Figure 2. All the drugs, except Dex, induced cytotoxicity in a dose-dependent manner at 72 hrs. The calculated IC50s (concentration causing 50% growth inhibition) of agents were 68.7, 98.2, and 396.5 μM for ATO, Cel, and Indo, respectively. Dex did not inhibit cell growth up to 200 μM (Figure 2).


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)

Effect of different concentrations of ATO (a), Cel (b), Indo (c), and Dex (d) on the growth of A549 cell line (Mean ± SE, n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: Effect of different concentrations of ATO (a), Cel (b), Indo (c), and Dex (d) on the growth of A549 cell line (Mean ± SE, n = 4).
Mentions: ATO-induced inhibition of cell growth in A549 is illustrated in Figure 1. To explain further, a decrease in viability along with dose increments and time extensions is evident. Since the 24 and 48 hrs treatments had no significant cytotoxicity, assays were focused on the 72 hrs treatment. The dose-response curve of ATO, Cel, Indo, and Dex on cell proliferation at 72 hrs is shown in Figure 2. All the drugs, except Dex, induced cytotoxicity in a dose-dependent manner at 72 hrs. The calculated IC50s (concentration causing 50% growth inhibition) of agents were 68.7, 98.2, and 396.5 μM for ATO, Cel, and Indo, respectively. Dex did not inhibit cell growth up to 200 μM (Figure 2).

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