PubMed İndeksli Yayınlar / PubMed Indexed Publications

Permanent URI for this collectionhttps://hdl.handle.net/11413/6357

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DENSpm overcame Bcl-2 mediated resistance against Paclitaxel treatment in MCF-7 breast cancer cells via activating polyamine catabolic machinery
(Elsevier France-Editions Scientifiques Medicales Elsevier, 23 Rue Linois, 75724 Paris, France, 2016-12) Akyol, Zeynep; Çoker Gürkan, Ajda; Palavan Ünsal, Zeynep Narçın; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 125860; 113920; 156421; 6125
Purpose: The Bcl-2 mediated resistance is one of the most critical obstacle in cancer therapy. Conventional chemotherapeutics such as Paclitaxel, a commonly used in the treatment of metastatic breast cancer, is not sufficient to overcome Bcl-2 mediated drug resistance mechanism. Thus, combinational drug regimes are favored by researchers to overcome resistance phenotype against drugs. N1, N11-diethylnorspermine (DENSpm), a polyamine analogue, which is a promising drug candidate induced-cell cycle arrest and apoptosis in various cancer cells such as prostate, melanoma, colon and breast cancer cells via activated polyamine catabolism and reactive oxygen generation. Recent studies indicated the potential therapeutic role of DENSpm in phase I and II trials in breast cancer cases. Although the molecular targets of Paclitaxel in apoptotic cell death mechanism is well documented, the therapeutic effect of DENSpm and Paclitaxel in breast cancer cells has not been investigated yet. In this study, our aim was to determine the time dependent effect of DENSpm and Paclitaxel on apoptotic cell death via determination of polyamine metabolism related targets in wt and Bcl-2 overexpressing MCF-7 breast cancer cells. Results: In our experimental study, Paclitaxel decreased cell viability in dose-dependent manner within 24 h. Co-treatment of Paclitaxel (30 nM) with DENSpm (20 mu M) further increased the cytoxicity of Paclitaxel (30 nM) compared to alone Paclitaxel (30 nM) treatment in MCF-7 Bcl-2+ breast cancer cells. In addition, we determined that resistance against Paclitaxel-induced apoptotic cell death in Bcl-2 overexpressed MCF-7 cells was overcome due to activation of polyamine catabolic pathway, which caused depletion of polyamines. Conclusions: DENSpm combinational treatment might increase the effect of low cytotoxic paclitaxel in drug-resistant breast cancer cases. (C) 2016 Elsevier Masson SAS. All rights reserved.
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Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl-2 through activation of autophagy in MCF-7 cells
(Elsevier France-Editions Scientifiques Medicales Elsevier, 23 Rue Linois, 75724 Paris, France, 2015-04) Akkoç, Yunus; Berrak, Özge; Çoker Gürkan, Ajda; Palavan Ünsal, Zeynep Narçın; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 113920; 156421; 125860; 6125
Curcumin is a natural anti-cancer agent derived from turmeric (Curcuma longa). Curcumin triggers intrinsic apoptotic cell death by activating mitochondrial permeabilization due to the altered expression of pro-and anti-apoptotic Bcl-2 family members. Phosphoinositol-3-kinase (PI3K) and Akt, key molecular players in the survival mechanism, have been shown to be associated with the Bcl-2 signaling cascade; therefore, evaluating the therapeutic efficiency of drugs that target both survival and the apoptosis mechanism has gained importance in cancer therapy. We found that Bcl-2 overexpression is a limiting factor for curcumin-induced apoptosis in highly metastatic MCF-7 breast cancer cells. Forced overexpression of Bcl-2 also blocked curcumin-induced autophagy in MCF-7 cells, through its inhibitory interactions with Beclin-1. Pre-treatment of PI3K inhibitor LY294002 enhanced curcumin-induced cell death, apoptosis, and autophagy via modulating the expression of Bcl-2 family members and autophagosome formation in MCF-7 breast cancer cells. Atg7 silencing further increased apoptotic potential of curcumin in the presence or absence of LY294002 in wt and Bcl-2+ MCF-7 cells. The findings of this study support the hypothesis that blocking the PI3K/Akt pathway may further increased curcumin-induced apoptosis and overcome forced Bcl-2 expression level mediated autophagic responses against curcumin treatment in MCF-7 cells. (C) 2015 Elsevier Masson SAS. All rights reserved.
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The inhibition of PI3K and NF kappa B promoted curcumin-induced cell cycle arrest at G2/M via altering polyamine metabolism in Bcl-2 overexpressing MCF-7 breast cancer cells
(Elsevier France-Editions Scientifiques Medicales Elsevier, 23 Rue Linois, 75724 Paris, France, 2016-02) Akkoç, Yunus; Çoker Gürkan, Ajda; Palavan Ünsal, Zeynep Narçın; Berrak, Özge; ARISAN, ELİF DAMLA; YERLİKAYA, PINAR OBAKAN; 113920; 125860; 156421; 6125
Bcl-2 protein has been contributed with number of genes which are involved in oncogenesis. Among the many targets of Bcl-2, NF kappa B have potential role in induction of cell cycle arrest. Curcumin has potential therapeutic effects against breast cancer through multiple signaling pathways. In this study, we investigated the role of curcumin in induction of cell cycle arrest via regulating of NF kappa B and polyamine biosynthesis in wt and Bcl-2+ MCF-7 cells. To examine the effect of curcumin on cell cycle regulatory proteins, PI3K/Akt, NF kappa B pathways and polyamine catabolism, we performed immunoblotting assay. In addition, cell cycle analysis was performed by flow cytometry. The results indicated that curcumin induced cell cycle arrest at G2/M phase by downregulation of cyclin B1 and Cdc2 and inhibited colony formation in MCF-7 wt cells. However, Bcl-2 overexpression prevented the inhibition of cell cycle associated proteins after curcumin treatment. The combination of LY294002, PI3K inhibitor, and curcumin induced cell cycle arrest by decreasing CDK4, CDK2 and cyclin E2 in Bcl-2+ MCF-7 cells. Moreover, LY294002 further inhibited the phosphorylation of Akt in Bcl-2+ MCF-7 cells. Curcumin could suppress the nuclear transport of NF kappa B through decreasing the interaction of P-I kappa B-NF kappa B. The combination of wedelolactone, NF kappa B inhibitor, and curcumin acted different on SSAT expression in wt MCF-7 and Bcl-2+ MCF-7 cells. NF kappa B inhibition increased the SSAT after curcumin treatment in Bcl2 overexpressed MCF-7 cells. Inhibition of NF kappa B activity as well as suppression of ROS generation with NAC resulted in the partial relief of cells from G2/M checkpoint after curcumin treatment in wt MCF7 cells. In conclusion, the potential role of curcumin in induction of cell cycle arrest is related with NF kappa B-regulated polyamine biosynthesis. (C) 2015 Elsevier Masson SAS. All rights reserved.

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