Histone deacetylase as a new target for cancer chemotherapy

Citation
M. Yoshida et al., Histone deacetylase as a new target for cancer chemotherapy, CANC CHEMOT, 48, 2001, pp. S20-S26
Citations number
48
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
03445704 → ACNP
Volume
48
Year of publication
2001
Supplement
1
Pages
S20 - S26
Database
ISI
SICI code
0344-5704(200108)48:<S20:HDAANT>2.0.ZU;2-L
Abstract
Trichostatin A (TSA) and trapoxin (TPX), inhibitors of the eukaryotic cell cycle and inducers of morphological reversion of transformed cells, inhibit histone deacetylase (HDAC) at nanomolar concentrations. Recently, FK228 (a lso known as FR901228 and depsipeptide) and MS-275, antitumor agents struct urally unrelated to TSA, have been shown to be potent HDAC inhibitors. Thes e inhibitors activate the expression of p21Waf1 in a p53-independent manner . Changes in the expression of regulators of the cell cycle, differentiatio n, and apoptosis with increased histone acetylation may be responsible for the cell cycle arrest and antitumor activity of HDAC inhibitors. TSA has be en suggested to block the catalytic reaction by chelating a zinc ion in the active site pocket through its hydroxamic acid group. On the other hand, a n epoxyketone has been suggested to be the functional group of TPX capable of alkylating the enzyme. We synthesized a novel TPX analogue containing a hydroxamic acid instead of the epoxyketone. The hybrid compound, called cyc lic hydroxamic-acid containing peptide I (CHAP1) inhibited HDAC at low nano molar concentrations. The HDAC1 inhibition by CHAP1 was reversible, as is t hat by TSA, in contrast to irreversible inhibition by TPX. Interestingly, H DAC6, but not HDAC1 or HDAC4, was resistant to TPX and CHAP I, while TSA in hibited these HDACs to a similar degree. CHAP31, the strongest HDAC inhibit or obtained from a variety of CHAP derivatives, exhibited antitumor activit y in BDF1 mice bearing B16/BL6 tumor cells. These results suggest that CHAP 31 is promising as a novel therapeutic agent for cancer treatment, and that CHAP may serve as a basis for new HDAC inhibitors and be useful for combin atorial synthesis and high-throughput screening.