title: Purified cranberry proanthocyanidines (PAC-1A) cause pro-apoptotic signaling,             ROS generation, cyclophosphamide retention and cytotoxicity in high-risk neuroblastoma             cells.
abstract: Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry             generated PAC-1A which selectively affected the viability of various neuroblastoma             (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused             a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased             generation of reactive oxygen species (ROS) which was directly correlated to the             modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the             expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic             (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK             and downregulated expression or activity of PI3K/AKT/mTOR pathway components.             PAC-1A increased the cellular uptake/retention of cyclophosphamide (CP). PAC-1A             and CP synergistically increased cytotoxicity and expression of pro-apoptotic             markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels.             Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells             include delay of cell cycle progression and induction of cell death via TNF-family             death receptor activity, thus, targeting both the extrinsic and intrinsic pathway             of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated             with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation             of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic             potential to treat a broad spectrum of NBs including highly malignant tumors that             show resistance to standard chemotherapeutics and apoptotic stimuli.
authors: Department of Plant Biology, Rutgers University, New Brunswick,                     NJ 08901, USA.
authors: Ajay P
authors: AP
authors: Singh
authors: Thilo S
authors: TS
authors: Lange
authors: Kyu K
authors: KK
authors: Kim
authors: Laurent
authors: L
authors: Brard
authors: Timothy
authors: T
authors: Horan
authors: Richard G
authors: RG
authors: Moore
authors: Nicholi
authors: N
authors: Vorsa
authors: Rakesh K
authors: RK
authors: Singh
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000235:genetics; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000493:pharmacokinetics*; D004357:Drug Synergism; D005638:Fruit / Q000737:chemistry; D020868:Gene Silencing / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology; D044945:Proanthocyanidins / Q000302:isolation & purification / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D029799:Vaccinium macrocarpon / Q000737:chemistry*
chemical_list: D010936:Plant Extracts; D044945:Proanthocyanidins; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D003520:Cyclophosphamide; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020169:Caspases; D005978:Glutathione