title: Arsenic Trioxide Promotes Paclitaxel Cytotoxicity in Resistant Breast Cancer Cells.
abstract: A partial response or resistance to chemotherapeutic agents is considered as a main obstacle in treatment of patients with cancer, including breast cancer. Refining taxane-based treatment procedures using adjuvant or combination treatment is a novel strategy to increase the efficiency of chemotherapy. PPM1D is a molecule activated by reactive oxygen species. whose expression is reported to modulate the recruitment of DNA repair molecules. In this study we examined the impact of arsenic trioxide on efficacy of paclitaxel-induced apoptosis in paclitaxel-resistant MCF-7 cells. We also investigated the expression of PPM1D and TP53 genes in response to this combination treatment. Resistant cells were developed from the parent MCF-7 cell line by applying increasing concentrations of paclitaxel. MTT assays were applied to determine the rate of cell survival. DAPI staining using fluorescent microscopy was employed to study apoptotic bodies. Real-time RT-PCR analysis was also applied to determine PPM1D mRNA levels. Our results revealed that combination of arsenic trioxide and paclitaxel elevates the efficacy of the latter in induction of apoptosis in MCF-7/PAC resistant cells. Applying arsenic trioxide also caused significant decreases in PPM1D mRNA levels (p<0.05). Our findings suggest that arsenic trioxide increases paclitaxel-induced apoptosis by down regulation of PPM1D expression. PPM1D dependent signaling can be considered as a novel target to improve the efficacy of chemotherapeutic agents in resistant breast cancer cells.
authors.affiliation: Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran E-mail : drnsamadi@yahoo.com ; msaeidhejazi@yahoo.com.
authors.forename: Tayebeh Oghabi
authors.initials: TO
authors.lastname: Bakhshaiesh
authors.forename: Marzie
authors.initials: M
authors.lastname: Armat
authors.forename: Dariush
authors.initials: D
authors.lastname: Shanehbandi
authors.forename: Simin
authors.initials: S
authors.lastname: Sharifi
authors.forename: Behzad
authors.initials: B
authors.lastname: Baradaran
authors.forename: Mohammad Saeed
authors.initials: MS
authors.lastname: Hejazi
authors.forename: Nasser
authors.initials: N
authors.lastname: Samadi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D000071636:Protein Phosphatase 2C; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D001152:Arsenicals; D010087:Oxides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D017239:Paclitaxel; D000077237:Arsenic Trioxide