Potent cytotoxic effects of novel retinamide derivatives in ovarian cancer cells.
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.
Um
Soo-Jong
SJ
Department of Bioscience and Biotechnology/Institute of Bioscience, Sejong University, Seoul, Korea. umsj@sejong.ac.kr
Sin
Hong-Sig
HS
Han
Hye-Sook
HS
Kwon
Youn-Ja
YJ
Kim
Eun-Joo
EJ
Park
Si-Ho
SH
Kim
Sun-Young
SY
Bae
Tae-Sung
TS
Park
Jong-Sup
JS
Rho
Young-Soy
YS
D002452:Cell Count / Q000379:methods; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity*
D014212:Tretinoin; C054441:retinamide