title: PI3K/Akt inhibition and down-regulation of BCRP re-sensitize MCF7 breast cancer cell line to mitoxantrone chemotherapy.
abstract: OBJECTIVE
  Multidrug resistance (MDR) of cancer cells is a major obstacle to successful chemotherapy. Overexpression of breast cancer resistance protein (BCRP) is one of the major causes of MDR. In addition, it has been shown that PI3K/Akt signaling pathway involves in drug resistance. Therefore, we evaluated the effects of novel approaches including siRNA directed against BCRP and targeted therapy against PI3K/Akt signaling pathway using LY294002 (LY) to re-sensitize breast cancer MCF7 cell line to mitoxantrone (MTX) chemotherapy.
  
  
  METHODS
  Anticancer effects of MTX, siRNA, and LY alone and in combination were evaluated in MCF7 cells using MTT cytotoxicity assay and flow cytometry analysis of cell cycle distribution and apoptosis induction.
  
  
  RESULTS
  MTT and apoptosis assays showed that both MTX and LY inhibited cell proliferation and induced apoptosis in MCF7 cells. Results indicated that inhibition of BCRP by siRNA or PI3K/Akt signaling pathway by LY significantly increased sensitivity of MCF7 cells to antiproliferation and apoptosis induction of MTX. Furthermore, MTX showed G2/M arrest, whereas LY induced G0/G1 arrest in cell cycle distribution of MCF7 cells. Combination of siRNA or LY with MTX chemotherapy significantly increased accumulation of MCF7 cells in the G2/M phase of cell cycle.
  
  
  CONCLUSIONS
  Combination of MTX chemotherapy with BCRP siRNA and PI3K/Akt inhibition can overcome MDR in breast cancer cells. This study furthermore suggests that novel therapeutic approaches are needed to enhance anticancer effects of available drugs in breast cancer.
authors.affiliation: Molecular Research Laboratory, Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran ; Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Komeili-Movahhed
authors.affiliation: Molecular Research Laboratory, Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shamileh
authors.initials: S
authors.lastname: Fouladdel
authors.affiliation: Molecular Research Laboratory, Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Elmira
authors.initials: E
authors.lastname: Barzegar
authors.affiliation: Molecular Research Laboratory, Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Shekoufeh
authors.initials: S
authors.lastname: Atashpour
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran ; Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hossein Ghahremani
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed
authors.initials: S
authors.lastname: Nasser Ostad
authors.affiliation: Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Madjd
authors.affiliation: Molecular Research Laboratory, Department of Pharmacology and Toxicology, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ebrahim
authors.initials: E
authors.lastname: Azizi
keywords: BCRP; Breast cancer; Combination therapy; Mitoxantrone; PI3K/Akt; siRNA