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All-trans-Retinoic Acid-induced Apoptosis in Human Medulloblastoma

Activation of Caspase-3/Poly(ADP-ribose) Polymerase 1 Pathway¹

Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140 [K. G.], and Division of Neuro-Oncology, The Children’s Hospital of Philadelphia [P. C. P., C. D. R.] and Department of Neurosurgery, University of Pennsylvania [L. N. S., C. D. R.], Philadelphia, Pennsylvania 19104

ABSTRACT

Current treatments for childhood brain tumor medulloblastoma (MB), radiation and chemotherapy, lead to undesirable side effects. Identification of antitumor agents that reduce the toxicity will thus have significant therapeutic value. In this study, we investigated all-trans-retinoic acid (ATRA) as an antitumor agent. Although high concentrations (1–10 µM) of retinoic acid derivatives are generally needed for significant antitumor effects in many cancer cells, we observed that pharmacologically relevant concentrations of ATRA were effective in inducing cell death in human MB cells. Using 10-fold lower concentrations (100–500 nM), we found that ATRA inhibits MB (DAOY, D283, D425, and D458) cell proliferation as determined by cell viability [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and bromodeoxyuridine incorporation assays. Furthermore, 100 nM ATRA was potent in inhibiting the anchorage-independent growth of the sensitive cell lines (D283, D425, and D458) in soft agar assays. We also demonstrate that the ATRA-induced decrease in cell viability was due to increased cell death by apoptosis, which was accompanied by a 20-fold induction of caspase-3 activity in the most sensitive cell line, D458. By contrast, induction of caspase-3 was only 2-fold in the relatively insensitive DAOY cells. Furthermore, ATRA-induced cell death in D283, D425, and D458 cells was accompanied by activation of caspase-3, a key executioner of apoptosis. We also demonstrate that activated caspase-3 resulted in cleavage of 116-kDa poly(ADP-ribose) polymerase 1 to its signature fragments (85 and 29 kDa). Pretreatment with a specific caspase-3 inhibitor, DEVD-CHO, significantly reduced ATRA-induced apoptotic cell death. Thus, we demonstrate for the first time that low concentrations of ATRA inhibit MB cell proliferation and induce apoptotic cell death in part by activating caspase-3/poly(ADP-ribose) polymerase 1 effector pathway, and we show that retinoic acids and novel retinoids are potential antitumor agents in MB therapy.

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