In vitro antitumor potential of 4-BPRE, a butyryl aminophenyl ester of retinoic acid: role of the butyryl group.
Retinoic acid (RA) and sodium butyrate (NaB) have been implicated in the regulation of growth and differentiation in various cancer cells. To produce an agent with the properties of both RA and NaB, a butyryl aminophenyl ester of RA (4-BPRE) was synthesized. The agent was compared with an aminophenyl ester devoid of the butyryl group (4-APRE) for antitumor potential in vitro. Like RA, 4-hydroxyphenyl retinamide (4-HPR) and 4-APRE, 4-BPRE was an active ligand for all three subtypes of RAR, but not for RXR, as determined by transcription assays in COS-1 cells. In addition, regardless of the butyryl group, 4-BPRE actively suppressed c-Jun transcriptional activity, which may result in reduced expression of matrix metalloproteinases (MMP-1 and MMP-2), and effectively inhibited HCT116 cell invasion into Matrigel. In these respects, 4-BPRE is similar to 4-APRE, and even to RA and 4-HPR. However, our results showed that in HCT116 colon and A549 lung cancer cells, 4-BPRE was much more cytotoxic than RA and 4-APRE, and was also more cytotoxic than 4-HPR, which is the most cytotoxic retinoid derivative under clinical investigation. Subsequent assays using DAPI staining, DNA fragmentation, and FACS analysis suggested that the cytotoxic effect of 4-BPRE is mediated by apoptosis in HCT116 cells. Moreover, 4-BPRE inhibited histone deacetylase (HDAC) activity to some degree, although inhibition was less than that induced by the known HDAC inhibitors TSA and NaB. These results suggest that 4-BPRE could be a promising antitumor retinoid with both NaB activity and RA function.
Um
Soo-Jong
SJ
Department of Bioscience and Biotechnology, Sejong University, Kwangjin-gu, Seoul 143-747, Korea. umsj@sejong.ac.kr
Han
Hye-Sook
HS
Kwon
Youn-Ja
YJ
Park
Si-Ho
SH
Bae
Tae-Sung
TS
Rho
Young-Soy
YS
Sin
Hong-Sig
HS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D019556:COS Cells; D045744:Cell Line, Tumor; D002469:Cell Separation; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry*; D005434:Flow Cytometry; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D008956:Models, Chemical; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*
C480262:4-amino-2-(butyrylamino)phenyl(2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)-2,4,6,8-nonatetraenoate; D000970:Antineoplastic Agents; D004952:Esters; D006877:Hydroxamic Acids; D012176:Retinoids; C077779:4-(acetylamino)phenylretinoate; C012589:trichostatin A; D014212:Tretinoin; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D006655:Histone Deacetylases