PMID- 14519946
OWN - NLM
STAT- MEDLINE
DCOM- 20040217
LR  - 20220321
IS  - 0918-6158 (Print)
IS  - 0918-6158 (Linking)
VI  - 26
IP  - 10
DP  - 2003 Oct
TI  - Potent cytotoxic effects of novel retinamide derivatives in ovarian cancer cells.
PG  - 1412-7
AB  - 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.
FAU - Um, Soo-Jong
AU  - Um SJ
AD  - Department of Bioscience and Biotechnology/Institute of Bioscience, Sejong 
      University, Seoul, Korea. umsj@sejong.ac.kr
FAU - Sin, Hong-Sig
AU  - Sin HS
FAU - Han, Hye-Sook
AU  - Han HS
FAU - Kwon, Youn-Ja
AU  - Kwon YJ
FAU - Kim, Eun-Joo
AU  - Kim EJ
FAU - Park, Si-Ho
AU  - Park SH
FAU - Kim, Sun-Young
AU  - Kim SY
FAU - Bae, Tae-Sung
AU  - Bae TS
FAU - Park, Jong-Sup
AU  - Park JS
FAU - Rho, Young-Soy
AU  - Rho YS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Japan
TA  - Biol Pharm Bull
JT  - Biological & pharmaceutical bulletin
JID - 9311984
RN  - 5688UTC01R (Tretinoin)
RN  - BQC43T81DZ (retinamide)
SB  - IM
MH  - Cell Count/methods
MH  - Cell Division/drug effects/physiology
MH  - Cell Line, Tumor/drug effects/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Humans
MH  - Ovarian Neoplasms/*drug therapy/metabolism
MH  - Tretinoin/*analogs & derivatives/chemistry/*therapeutic use/*toxicity
EDAT- 2003/10/02 05:00
MHDA- 2004/02/18 05:00
CRDT- 2003/10/02 05:00
PHST- 2003/10/02 05:00 [pubmed]
PHST- 2004/02/18 05:00 [medline]
PHST- 2003/10/02 05:00 [entrez]
AID - 10.1248/bpb.26.1412 [doi]
PST - ppublish
SO  - Biol Pharm Bull. 2003 Oct;26(10):1412-7. doi: 10.1248/bpb.26.1412.