Synergy of theophylline reduces necrotic effect of berberine, induces cell cycle arrest and PARP, HMGB1, Bcl-2 family mediated apoptosis in MDA-MB-231 breast cancer cells - 25/08/18
, Mahdieh Razmi a, Soudabeh Fallah bBienvenue sur EM-consulte, la référence des professionnels de santé.
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Graphical abstract |
Highlights |
• | Theophylline synergistically enhanced apoptosis, reduced necrosis induced by berberine in MDA-MB-231 breast cancer cells. |
• | Combination of theophylline and berberine reduced HMGB1 content/expression, MMP-9 expression and arrested the cells at G2/M phase. |
• | In the cells treated with BBR + TH, Bax expression level and PARP cleavage were increased while Bcl2 expression was reduced. |
• | Combination of exogenous cAMP represented similar effect on berberine toxicity compared to theophylline. |
Abstract |
Berberine, is a plant alkaloid, proved to have anticancer effect on various cancers. Theophylline (TH), a natural product, is widely used in the treatment of respiratory difficulties. The present study designed to elucidate the effects of theophylline and berberine combination on breast cancer cells cytotoxicity, gene expression and cell cycle. MTT assay revealed that berberine inhibited MDA-MB-231 breast cancer cells viability in a time and dose dependent manner (IC50 of 100 μM) but theophylline had no considerably effect on the cells. Combined treatment of berberine and theophylline showed a synergistic anti-proliferation effect, IC50 of berberine reduced to 50 μM and the cells were arrested at G2/M phase. Combined treatment of Berberine and theophylline reduced extracellular level of HMGB1 and down regulated HMGB1 and MMP-9 mRNA expression. The results of flow cytometry using annexin/PI staining of the cells, HMGB1 release, and poly ADP ribose polymerase cleavage demonstrated that theophylline attenuated necrotic effect of berberine and increased the level of apoptotic cell death. Enhancement of Bax content detected by ELISA and upregulation of Bax mRNA expression, down-regulation of Bcl-2 expression and increase of anion superoxide production confirmed induction of apoptosis via intrinsic apoptotic pathway. Replacement of theophylline with exogenous cyclic AMP in combination treatment represented similar effect on berberine cytotoxicity. From the results it is concluded that synergistic anticancer effect of theophylline and berberine suggests that combination of these two drugs may be an effective therapeutic agent against breast cancer cell.
Le texte complet de cet article est disponible en PDF.Abbreviations : TH, BBR, MTT, HRP-IgG, PARP, HMGB1, MMP-9, cAMP, FBS, PCA, TCA, SDS, PAGE, DMSO
Keywords : Combination, Berberine, Theophylline, Cell death, HMGB1, Bcl2 family
Plan
Vol 106
P. 858-867 - octobre 2018 Retour au numéro
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