title: Indirubin-3'-oxime induces mitochondrial dysfunction and triggers growth             inhibition and cell cycle arrest in human neuroblastoma cells.
abstract: Neuroblastoma is the most common extracranial solid tumor found in infancy             and childhood. Current multimodal therapies such as surgery, chemotherapy, radiotherapy             and stem cell transplantation often cause inevitable severe side-effects, therefore,             it is necessary to develop novel drugs with higher efficacy on neuroblastoma cells             and minimal side-effects on normal cells. Indirubin-3'-oxime (I3M), an indigo             alkaloid, was found to exhibit potent antitumor activities on various types of             cancer cells. However, its modulatory effects on human neuroblastoma and the underlying             mechanisms remain poorly understood. As mitochondrial biogenesis and function             play critical roles in cell growth and survival, in the present study the effects             of I3M on mitochondrial functions and their correlation to the anticancer effect             of I3M on human neuroblastoma cells were investigated. I3M was found to inhibit             the growth of the human neuroblastoma LA-N-1, SH-SY5Y and SK-N-DZ cells in a dose-             and time-dependent manner, but exhibited little, if any, direct cytotoxicity on             normal cells. Mechanistic studies showed that I3M specifically decreased the expression             of the mitochondrial regulators ERRγ and PGC-1β and resulted in decreased mitochondrial             mass and altered mitochondrial function characterized by a reduction in mitochondrial             membrane potential and elevation of reactive oxygen species levels in LA-N-1 cells.             I3M also increased the level of CDK inhibitor p27Kip1 and reduced the levels of             CDK2 and cyclin E in LA-N-1 cells, leading to cell cycle arrest at the G0/G1 phase.             Collectively, these results suggest that mitochondrial dysfunction might be an             important mechanism underlying the I3M-induced cell cycle arrest.
authors.affiliation: Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, PR China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Liao
authors.forename: Kwok-Nam
authors.initials: KN
authors.lastname: Leung
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010091:Oximes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D010091:Oximes; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C474021:indirubin-3'-monoxime