title: D-alpha-tocopheryl polyethylene glycol succinate (TPGS) induces cell cycle arrest and apoptosis selectively in Survivin-overexpressing breast cancer cells.
abstract: D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is a vitamin E derivative that has been intensively applied as a vehicle for drug delivery systems to enhance drug solubility and increase the oral bioavailability of anti-cancer drugs. Recently, it has been reported that TPGS acts as an anti-cancer agent alone or synergistically with chemotherapeutic drugs and increases the efficacy of nanoparticle formulations. In this study, we investigated the antitumor efficacy and the molecular mechanism of action of TPGS in breast cancer cell lines. Our results show that TPGS can induce G1/S cell cycle arrest and apoptosis in breast cancer cell lines (MCF-7 and MDA-MB-231) but not in "normal" (non-tumorigenic) immortalized cells (MCF-10A and MCF-12F). An investigation of the molecular mechanism of action of TPGS reveals that induction of G1/S phase cell cycle arrest is associated with upregulation of P21 and P27Kip1 proteins. Induction of apoptosis by TPGS involves the inhibition of phospho-AKT and the downregulation of the anti-apoptotic proteins Survivin and Bcl-2. Interestingly, our results also suggest that TPGS induces both caspase -dependent and -independent apoptotic signaling pathways and that this vitamin E derivative is selectively cytotoxic in breast cancer cell lines. When compared to the Survivin inhibitor YM155, TPGS was shown to be more selective for cancer cell growth inhibition. Overall our results suggest that TPGS may not only be useful as a carrier molecule for drug delivery, but may also exert intrinsic therapeutic effects suggesting that it may promote a synergistic interaction with formulated chemotherapeutic drugs.
authors.affiliation: Department of Biological Sciences, Faculty of Pure and Applied Sciences, University of Cyprus, 1678, Nicosia, Cyprus. Electronic address: neophytou.christiana@ucy.ac.cy.
authors.forename: Christiana M
authors.initials: CM
authors.lastname: Neophytou
authors.affiliation: St. George's University of London Medical School at the University of Nicosia, 46 Makedonitissas Ave., 1700 Nicosia, Cyprus. Electronic address: constantinou.co@unic.ac.cy.
authors.forename: Constantina
authors.initials: C
authors.lastname: Constantinou
authors.affiliation: Department of Biological Sciences, Faculty of Pure and Applied Sciences, University of Cyprus, 1678, Nicosia, Cyprus. Electronic address: papageo@ucy.ac.cy.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.affiliation: Department of Biological Sciences, Faculty of Pure and Applied Sciences, University of Cyprus, 1678, Nicosia, Cyprus. Electronic address: andreasc@ucy.ac.cy.
authors.forename: Andreas I
authors.initials: AI
authors.lastname: Constantinou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D000077022:Survivin; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C107489:BIRC5 protein, human; D017931:DNA Primers; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D014810:Vitamin E; D011092:Polyethylene Glycols; C014225:tocophersolan
keywords: AKT pathway; Apoptosis; Breast cancer; Cell cycle; Survivin; Vitamin E