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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

Western blot analysis of COX-2, Akt, ERK1/2, p38, JNK, and Bax proteins in A549 cells treated with ATO, Indo, Dex, ATO + Indo, and ATO + Dex combinations.
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fig5: Western blot analysis of COX-2, Akt, ERK1/2, p38, JNK, and Bax proteins in A549 cells treated with ATO, Indo, Dex, ATO + Indo, and ATO + Dex combinations.

Mentions: To address the role of proteins involved in the apoptosis and survival, the expression of Akt, ERK1/2, p38, JNK, and Bax proteins was determined by western blotting analysis. The expression of COX-2 protein decreased dose-dependently by ATO especially in the dose of 50 μM (Figure 5). Indo alone did not change the expression of COX-2 protein. However, combination of ATO 2 μM and Indo (2 and 10 μM) decreased the COX-2 protein expression. ERK1/2 and p38 proteins levels were decreased with 50 μM ATO treatment but remained unchanged with other treatments. Akt, Bax, and JNK seemed to be unchanged with different treatments.


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)

Western blot analysis of COX-2, Akt, ERK1/2, p38, JNK, and Bax proteins in A549 cells treated with ATO, Indo, Dex, ATO + Indo, and ATO + Dex combinations.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Western blot analysis of COX-2, Akt, ERK1/2, p38, JNK, and Bax proteins in A549 cells treated with ATO, Indo, Dex, ATO + Indo, and ATO + Dex combinations.
Mentions: To address the role of proteins involved in the apoptosis and survival, the expression of Akt, ERK1/2, p38, JNK, and Bax proteins was determined by western blotting analysis. The expression of COX-2 protein decreased dose-dependently by ATO especially in the dose of 50 μM (Figure 5). Indo alone did not change the expression of COX-2 protein. However, combination of ATO 2 μM and Indo (2 and 10 μM) decreased the COX-2 protein expression. ERK1/2 and p38 proteins levels were decreased with 50 μM ATO treatment but remained unchanged with other treatments. Akt, Bax, and JNK seemed to be unchanged with different treatments.

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