title: Curcumin analog GO-Y030 is a novel inhibitor of IKKβ that suppresses NF-κB signaling and induces apoptosis.
abstract: Curcumin is a dietary constituent with tumor-suppressing potential, inhibiting various pathways involved in carcinogenesis. However, because of its low bioavailability, the use of curcumin in in vivo trials has been limited. To overcome this problem, we synthesized more than 50 analogs and identified a monoketone analog, GO-Y030, which has a 30-fold higher potential to suppress tumor cell growth compared with curcumin. We investigated the inhibitory effect of GO-Y030 on NF-κB activation. In thyroid, pancreatic cancers and cholangiocarcinoma cells, in which NF-κB is activated, NF-κB activation was suppressed to 8-62% of the control value following treatment with 1 μM GO-Y030, an effect comparable to that of 10 μM curcumin. Direct inhibition of IKKβ kinase activity and suppression of nuclear translocation of the NF-κB p65 subunit were observed. The 50% growth inhibition concentrations of GO-Y030 ranged from one-11th to one-14th of those of curcumin. GO-Y030 also induced cell death comparable to that induced by curcumin but at a 10-fold lower concentration. In pancreatic and thyroid cancer cells, the growth-inhibitory effect of GO-Y030 was 4- and 15-fold greater, respectively, than that of curcumin. GO-Y030 was a much stronger inducer of apoptosis compared with curcumin. The enhanced potency of GO-Y030 may make it more useful than curcumin, which suffers from low bioavailability. GO-Y030 is a good lead compound for the development of useful compounds for practical cancer chemotherapy.
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Sato
authors.forename: Chieko
authors.initials: C
authors.lastname: Kudo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamakoshi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Uehara
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Ohori
authors.forename: Chikashi
authors.initials: C
authors.lastname: Ishioka
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Iwabuchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shibata
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001555:Benzene Derivatives / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C541015:1,5-bis(3,5-bis(methoxymethoxy)phenyl)penta-1,4-dien-3-one; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D007659:Ketones; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase; D003474:Curcumin