Isoprenoid geranylgeranylacetone inhibits human colon cancer cells through induction of apoptosis and cell cycle arrest.
Geranylgeranylacetone (GGA), an isoprenoid compound, is a widely used antiulcer drug developed in Japan. GGA is structurally similar to plaunotol and geranylgeraniol, another isoprenoid reported to exert strong anticancer effects. In an earlier study, GGA was shown to inhibit ovarian cancer invasion by attenuating not only Rho activation, but also Ras-MAPK activation. In this study, we aimed to test whether GGA could have a therapeutic effect on colon cancer cells. As a result, we found that GGA induced a dose-dependent decrease in the proliferative activity through induction of cell apoptosis and cell cycle arrest in the G1 phase. The induction of apoptosis was mediated by the activation of both caspase-8 and caspase-9 pathways. The induction of G1 arrest was mediated by the increase of p21 and p27, and also the decrease of phosphorylated retinoblastoma protein levels. This study showed the potential anticancer activity of GGA. As this drug is already available in Japan for clinical use as an antiulcer/antigastritis agent, clinical trials will be designed to confirm its potential usefulness for cancer patients.
Yoshikawa
Naoyuki
N
Department of Transfusion Medicine, University of Tokyo, Japan. yoshikawan-blo@h.u-tokyo.ac.jp
Tsuno
Nelson H
NH
Okaji
Yurai
Y
Kawai
Kazushige
K
Shuno
Yasutaka
Y
Nagawa
Hirokazu
H
Oshima
Noriko
N
Takahashi
Koki
K
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004224:Diterpenes; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053181:Caspase 8; D053453:Caspase 9; C031049:geranylgeranylacetone