RRC ID 41383
著者 Komatsu Y, Tomizaki KY, Tsukamoto M, Kato T, Nishino N, Sato S, Yamori T, Tsuruo T, Furumai R, Yoshida M, Horinouchi S, Hayashi H.
タイトル Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity.
ジャーナル Cancer Res
Abstract Cyclic hydroxamic-acid-containing peptide 1 (CHAP1), designed as a hybrid of trichostatin A and trapoxin, is a lead compound for the development of potent inhibitors of histone deacetylase (HDAC). In this study, we synthesized a series of CHAP derivatives and evaluated their biological activities by monitoring the potency of their inhibition of HDAC activity, their ability to augment the expression of MHC class-I molecules in B16/BL6 cells, and their effect on cell proliferation. A structure-activity relationship study using these three assay systems revealed several requirements of their structure for the strong inhibition of HDAC not only in the cell-free situation, but also in cells. When the structures of CHAP derivatives are represented as cyclo(-Asu(NHOH)-AA(2)-AA(3)-Pro or Pip-)(n), where Asu(NHOH) and Pip are zeta-hydroxamide-alpha-aminosuberic acid and pipecolic acid, respectively, (a) the tetrapeptide structure (n = 1) was better than the octapeptide one (n = 2); (b) AA(2) and AA(3) should be hydrophobic; and (c) the combination of amino acid chirality should be LDLD for the strongest inhibition of HDAC in cells (LDLD > LLLD, LDLL > LLDL). cyclo(-L-Asu(NHOH)-D-Tyr(Me)-L-Ile-D-Pro-) or CHAP31 was selected as one of the strongest CHAPs, and its biological activity was characterized further. CHAP31 was much more stable in the presence of cultured cells (t(1/2) > 3000 h) than trichostatin A (t(1/2) = 14.7 h) or trapoxin A (t(1/2) = 2.10 h). CHAP31 exhibited antitumor activity in C57BL x DBA/2 F(1) (BD2F(1)) mice bearing B16/BL6 tumor cells. Furthermore, CHAP31 inhibited the growth in four of five human tumor lines implanted into nude mice. These results suggest CHAP31 to be promising as a novel therapeutic agent for cancer treatment.
巻・号 61(11)
ページ 4459-66
公開日 2001-6-1
PMID 11389076
MeSH Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology* Drug Screening Assays, Antitumor Enzyme Inhibitors / chemistry Enzyme Inhibitors / pharmacology* Histone Deacetylase Inhibitors* Humans Hydroxamic Acids / chemistry Melanoma, Experimental / drug therapy Melanoma, Experimental / enzymology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Inbred DBA Mice, Nude Peptides, Cyclic / chemistry Peptides, Cyclic / pharmacology* Proline / chemistry Stereoisomerism Structure-Activity Relationship Tumor Cells, Cultured Xenograft Model Antitumor Assays
IF 9.727
引用数 165
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 SP2/0-Ag14(RCB0209)