title: DENSpm overcame Bcl-2 mediated resistance against Paclitaxel treatment in MCF-7 breast cancer cells via activating polyamine catabolic machinery.
abstract: OBJECTIVE
  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 24h. Co-treatment of Paclitaxel (30nM) with DENSpm (20μM) further increased the cytoxicity of Paclitaxel (30nM) compared to alone Paclitaxel (30nM) 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.
authors.affiliation: Istanbul Kültür University, Science and Letters Faculty, Molecular Biology and Genetics Department, Atakoy Campus, 34156, Bakirkoy, Istanbul, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Akyol
authors.affiliation: Istanbul Kültür University, Science and Letters Faculty, Molecular Biology and Genetics Department, Atakoy Campus, 34156, Bakirkoy, Istanbul, Turkey. Electronic address: a.coker@iku.edu.tr.
authors.forename: Ajda
authors.initials: A
authors.lastname: Çoker-Gürkan
authors.affiliation: Istanbul Kültür University, Science and Letters Faculty, Molecular Biology and Genetics Department, Atakoy Campus, 34156, Bakirkoy, Istanbul, Turkey.
authors.forename: Elif Damla
authors.initials: ED
authors.lastname: Arisan
authors.affiliation: Istanbul Kültür University, Science and Letters Faculty, Molecular Biology and Genetics Department, Atakoy Campus, 34156, Bakirkoy, Istanbul, Turkey.
authors.forename: Pınar
authors.initials: P
authors.lastname: Obakan-Yerlikaya
authors.affiliation: Istanbul Kültür University, Science and Letters Faculty, Molecular Biology and Genetics Department, Atakoy Campus, 34156, Bakirkoy, Istanbul, Turkey.
authors.forename: Narçin
authors.initials: N
authors.lastname: Palavan-Ünsal
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D017239:Paclitaxel / Q000008:administration & dosage*; D011073:Polyamines / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D011073:Polyamines; D019253:Proto-Oncogene Proteins c-bcl-2; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine; D017239:Paclitaxel
keywords: Apoptosis; Breast cancer; DENSpm; Paclitaxel; Polyamine