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Potent effect of 5‐HPBR, a butanoate derivative of 4‐HPR, on cell growth and apoptosis in cancer cells
Author(s) -
Han HyeSook,
Kwon YounJa,
Park SiHo,
Kim EunJoo,
Rho YoungSoy,
Sin HongSig,
Um SooJong
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11643
Subject(s) - fenretinide , apoptosis , cytotoxicity , dna fragmentation , sodium butyrate , dapi , cell culture , cancer cell , cell growth , retinoid , chemistry , retinoic acid , microbiology and biotechnology , cancer research , biology , biochemistry , in vitro , pharmacology , programmed cell death , cancer , genetics
Fenretinide, 4‐(N‐hydroxyphenyl) retinamide (4‐HPR), has demonstrated anticancer activity associated with a favorable toxicity profile and is now being investigated in several clinical trials. However, its plasma levels in patients have been far lower than the effective concentration required to induce apoptosis (usually 10 μM). This result has led to the synthesis of derivatives with better efficacy. Sodium butyrate's potential as an anticancer agent prompted us to synthesize a butanoate derivative of 4‐HPR, 5‐hydroxyphenyl butanoate retinamide (5‐HPBR) and compare it to the parent compound for antitumor potential in vitro . The cytotoxicity of 5‐HPBR was 2‐ to 6‐fold greater than that of 4‐HPR against cancer cell lines derived from various tissues. In premalignant bronchial cells (BEAS2B), 5‐HPBR exhibited about a 10‐fold stronger cytotoxicity than did 4‐HPR. Normal CHANG liver cells were unaffected by either 4‐HPR or 5‐HPBR. Subsequent assays using DNA fragmentation, DAPI staining, FACS and Western blotting suggested that the potent inhibitory effect of 5‐HPBR is mediated by apoptosis; the exact mechanism appears to differ among cancer cell types. In transcription assays with COS‐1 cells, 5‐HPBR selectively activated RARβ and RARγ but was a weaker ligand for all 3 subtypes of RAR than either all‐ trans retinoic acid or 4‐HPR. Overall, these data suggest that 4‐BHPR may be a promising retinoid with enhanced antitumor activity and reduced toxicity. © 2003 Wiley‐Liss, Inc.