title: Reduced expression of the retinoblastoma protein shows that the related signaling pathway is essential for mediating the antineoplastic activity of erufosine.
abstract: Erufosine is a new antineoplastic agent of the group of alkylphosphocholines, which interferes with signal transduction and induces apoptosis in various leukemic and tumor cell lines. The present study was designed to examine for the first time the mechanism of resistance to erufosine in malignant cells with permanently reduced expression of the retinoblastoma (Rb) protein. Bearing in mind the high number of malignancies with reduced level of this tumor-suppressor, this investigation was deemed important for using erufosine, alone or in combination, in patients with compromised RB1 gene expression. For this purpose, clones of the leukemic T-cell line SKW-3 were used, which had been engineered to constantly express differently low Rb levels. The alkylphosphocholine induced apoptosis, stimulated the expression of the cyclin dependent kinase inhibitor p27Kip1 and inhibited the synthesis of cyclin D3, thereby causing a G2 phase cell cycle arrest and death of cells with wild type Rb expression. In contrast, Rb-deficiency impeded the changes induced by erufosine in the expression of these proteins and abrogated the induction of G2 arrest, which was correlated with reduced antiproliferative and anticlonogenic activities of the compound. In conclusion, analysis of our results showed for the first time that the Rb signaling pathway is essential for mediating the antineoplastic activity of erufosine and its efficacy in patients with malignant diseases may be predicted by determining the Rb status.
authors.affiliation: Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Maya M
authors.initials: MM
authors.lastname: Zaharieva
authors.affiliation: Department of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Milen
authors.initials: M
authors.lastname: Kirilov
authors.affiliation: Department of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Minquang
authors.initials: M
authors.lastname: Chai
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Berger
authors.affiliation: Laboratory for Molecular Pharmacology and Experimental Chemotherapy, Department for Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria.
authors.forename: Spiro
authors.initials: S
authors.lastname: Konstantinov
authors.affiliation: Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Berger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010755:Organophosphates / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C534696:CCND3 protein, human; C436291:CDKN1B protein, human; D056743:Cyclin D3; D010755:Organophosphates; D000644:Quaternary Ammonium Compounds; D016160:Retinoblastoma Protein; C472787:erucylphospho-N,N,N-trimethylpropylammonium; D050760:Cyclin-Dependent Kinase Inhibitor p27