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Ukrain modulates glial fibrillary acidic protein, but not connexin 43 expression, and induces apoptosis in human cultured glioblastoma cells

Gagliano, Nicolettaa; Moscheni, Claudiaa; Torri, Carloa; Donetti, Elenaa; Magnani, Ivanab; Costa, Francescoa; Nowicky, Wassilc; Gioia, Magdaa

doi: 10.1097/CAD.0b013e32808bf9ec
PRECLINICAL REPORTS

Glioblastoma is a highly malignant tumor, characterized by an unfavorable prognosis even in response to multidisciplinary treatment strategies, owing to its high-invasive phenotype. Ukrain, a semisynthetic thiophosphoric acid derivative of the purified alkaloid chelidonine, has been used in the therapy of several solid tumors, but little is known about its effect on glioblastoma and, in general, about the molecular mechanisms responsible for its effects. In particular, we previously demonstrated that Ukrain modulates the expression of genes and proteins involved in tumor invasion, and here we investigate some unreported effects of Ukrain on human cultured glioblastoma cells. We used morphological and molecular biology methods to analyze the expression and the intracellular distribution pattern of glial fibrillary acidic protein, the expression of the gap junction protein connexin 43 and the apoptotic effect in human glioblastoma cells treated with 0.1, 1 and 10 μmol/l Ukrain for 72 h. After treatment with 10 μmol/l Ukrain, glial fibrillary acidic protein fluorescence increased and a higher number of cells displayed glial fibrillary acidic protein organized into a filamentous state. Western blot analysis of glial fibrillary acidic protein confirmed that Ukrain tended to upregulate the protein. Connexin 43 was not modulated by Ukrain both at the mRNA and at the protein level. Ukrain-induced apoptotic rate was 4.63, 10.9 and 28.9% after 0.1, 1 and 10 μmol/l Ukrain, respectively, likely mediated by cytochrome c release in the cytoplasm. Considered as a whole, these findings provide new information to complete the understanding of the mechanisms of Ukrain antitumor and chemopreventive effect, and support the possible potential of Ukrain for the therapy of brain tumors.

aDepartment of Human Morphology

bUniversity of Milan and Division of Medical Genetics, San Paolo School of Medicine, University of Milan, Italy

cUkrainian Anti-Cancer Institute, Vienna, Austria

Correspondence to Dr Nicoletta Gagliano, PhD, Department of Human Morphology, University of Milan, Via Fratelli Cervi 93, 20090 Segrate, Milano, Italy

Tel: +39 02 50330462; fax: +39 02 50330452;

e-mail: nicoletta.gagliano@unimi.it

Sponsorship: This study was supported by Nowicky Pharma.

Received 5 December 2006 Revised form accepted 6 January 2007

© 2007 Lippincott Williams & Wilkins, Inc.