title: Cytostatic/cytotoxic effects of 5-fluorouridine nucleolipids on colon, hepatocellular, and renal carcinoma cells: in vitro identification of a potential cytotoxic multi-anticancer drug.
abstract: The insufficient penetration through the cell membranes is one of the major drawbacks of chemotherapeutics such as 5-fluorouracil (5-FU; 1). To improve the penetration, a useful strategy is the attachment of lipophilic moieties. Thus, we have synthesized a series of nucleolipid derivatives of 5-fluorouridine (5-FUrd; 2a), carrying lipophilic moieties at N(3) and/or at the 2',3'-O position, i.e., 3a, 3b, 4-7, and tested their cytostatic/cytotoxic activities towards three carcinoma cell lines (colon (HT-29), hepatocellular (HepG2), and renal (RENCA)) in comparison with 5-FU (1) and 5-FUrd (2a). After 48 h of incubation, four derivatives, 3a, 3b, 5, and 7, showed inhibitory effects on the survival of HT-29, HepG2, and RENCA cells. Additionally, to differentiate between anticancer and side-effects, we tested the cytotoxicity of the derivatives in human macrophages. Interestingly, the derivatives 4, 5, and 6 did not exhibit any effects on survival of THP-1 macrophages. Furthermore, we investigated the apoptosis induction of compound 1 and 2a, and the above-mentioned derivatives in HT-29 cells. Derivative 5 showed the highest significant (p<0.05; p<0.01) increase of the apoptosis at 80 μM after 2-h or 4-h treatment, as well as after 6-h incubation at 40 μM (p<0.05). Real-time PCR revealed that 40-μM derivative 5 showed a 1.8-fold increase of the pro-apoptotic caspase-3 gene and a twofold significant increase (p<0.01 and p<0.05 vs. control and 1, resp.) of the tumor suppressor TP53 gene, whereas the other compounds did not show any effect. We demonstrated that some 5-FUrd derivatives such as compound 5 are more effective than 5-FU or 5-FUrd concerning a cytotoxic (vs. cytostatic (5-FU, 5-FUrd)) effect on different cancer cell lines, but without cytotoxic side-effects on differentiated macrophages. Thus, compound 5 is suggested as a novel potent cytotoxic multi-anti-cancer drug.
authors.affiliation: Anatomy und Cell Biology, Department of Medical Cell Biology, University of Marburg, Robert-Koch-Strasse 8, D-35032 Marburg.
authors.forename: Anisa
authors.initials: A
authors.lastname: Farhat
authors.forename: Edith
authors.initials: E
authors.lastname: Malecki
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Bonaterra
authors.forename: Doris
authors.initials: D
authors.lastname: Röthlein
authors.forename: Martin
authors.initials: M
authors.lastname: Wolf
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schmitt
authors.forename: Helmut
authors.initials: H
authors.lastname: Rosemeyer
authors.forename: Ralf
authors.initials: R
authors.lastname: Kinscherf
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C001943:5-fluorouridine; D053148:Caspase 3; D014529:Uridine
keywords: 5-Fluorouracil; Anticancer activity; Cytotoxic activity; Nucleolipids