Potent cytotoxic effects of novel retinamide derivatives in ovarian cancer cells
| Autor: | Hye-Sook Han, Sun-Young Kim, Eun-Joo Kim, Si-Ho Park, Hong-Sig Sin, Tae-Sung Bae, Jong-Sup Park, Soo-Jong Um, Young-Soy Rho, Youn-Ja Kwon |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
medicine.drug_class Retinoic acid Pharmaceutical Science Cell Count Tretinoin Butyrate Pharmacology Biology chemistry.chemical_compound Internal medicine Cell Line Tumor medicine Humans Retinoid Receptor Ovarian Neoplasms Dose-Response Relationship Drug General Medicine Retinoic acid receptor Fenretinide Endocrinology chemistry Apoptosis Tumor promotion Female Cell Division |
| Zdroj: | Biologicalpharmaceutical bulletin. 26(10) |
| ISSN: | 0918-6158 |
| Popis: | 4-(N-Hydroxyphenyl)retinamide (also known as 4-HPR or fenretinide), a synthetic amide of all-trans retinoic acid (RA), has been implicated as a promising anticancer agent associated with reducing the toxicity related to RA. However, the low plasma levels of 4-HPR in patients limited clinical trials, leading to a search for derivatives with better efficacy. In this study, we synthesized a series of 4-HPR derivatives in good yields by introducing acetate (compound 1). propionate (2). pyruvate (3). butyrate (4). or stearate (5). to the 4-hydroxylphenyl moiety of 4-HPR. In our initial proliferation assays, we identified compound 3 as the most cytotoxic of the series against four ovarian cancer cell lines (OVCAR-3, PA-1, 2774, and SKOV-3). Dose-response curves yielded IC(50) values of 3.75-7.75 microM for AtRA, 2.80-5.50 microM for 9-cis RA, 0.65-4.05 microM for 4-HPR, and 0.25-0.75 microM for compound 3, depending on the cell type treated. Nuclear staining with 4',6-diamidino-2-phenylindole (DAPI) and DNA fragmentation assays clearly indicated that the antiproliferative effect of compound 3 was mediated by apoptosis. In contrast to natural retinoids, both 4-HPR and compound 3 activated two (RARbeta and RARgamma) of the three retinoic acid receptor (RAR) subtypes tested, but did not activate any of the three retinoid X receptors (RXRs), as determined by transcription assays in OVCAR-3 cells. However, like natural retinoids, 4-HPR and compound 3 actively suppressed c-Jun transcriptional activity. Thus, compound 3 not only showed more potent antiproliferative activity than any other retinoid derivatives tested, but also effectively inhibited the c-Jun activity that has been implicated in tumor promotion and invasion. These results, together with compound 3's selectivity for RAR subtypes, suggest that compound 3 could be an effective anticancer drug for ovarian cancer, with less toxicity than RA. |
| Databáze: | OpenAIRE |
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