Cytostatic/Cytotoxic Effects of 5-Fluorouridine Nucleolipids on Colon, Hepatocellular, and Renal Carcinoma Cells: in vitro Identification of a Potential Cytotoxic Multi-Anticancer Drug
Autor(en): | Farhat, Anisa Malecki, Edith Bonaterra, Gabriel A. Roethlein, Doris Wolf, Martin Schmitt, Juergen Rosemeyer, Helmut Kinscherf, Ralf |
Stichwörter: | 5-FLUORO-2'-DEOXYURIDINE; 5-Fluorouracil; ADJUVANT THERAPY; Anticancer activity; APOPTOSIS; Biochemistry & Molecular Biology; CANCER; Chemistry; Chemistry, Multidisciplinary; Cytotoxic activity; DIFFERENTIATION; EXPRESSION; LIPOPHILIZATION; MODULATION; Nucleolipids; OLIGONUCLEOTIDES; THYMIDINE | Erscheinungsdatum: | 2014 | Herausgeber: | WILEY-V C H VERLAG GMBH | Journal: | CHEMISTRY & BIODIVERSITY | Volumen: | 11 | Ausgabe: | 3 | Startseite: | 469 | Seitenende: | 482 | Zusammenfassung: | 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 (pp<0.01) increase of the apoptosis at 80 mu M after 2-h or 4-h treatment, as well as after 6-h incubation at 40 mu M (p<0.05). Real-time PCR revealed that 40-mu M derivative 5 showed a 1.8-fold increase of the pro-apoptotic caspase-3 gene and a twofold significant increase (ppvs. 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. |
ISSN: | 16121872 | DOI: | 10.1002/cbdv.201300347 |
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geprüft am 20.05.2024