Low concentrations of the histone deacetylase inhibitor, depsipeptide, enhance the effects of gemcitabine and docetaxel in hormone refractory prostate cancer cells.
Histone deacetylase inhibitors (HDACis) have been developed as a new type of drug for cancer treatment. In this study, we examine the augmentation efficacy of depsipeptide (FK228) in combination with gemcitabine (GEM) or docetaxel (DOC) in vitro and in vivo against hormone refractory prostate cancer (HRPC). The anti-proliferative effects, cell cycle distribution and apoptotic status were assessed in HRPC DU145 cells treated with these agents. The in vivo anti-tumor effects of the combination therapy with FK228 and GEM were further evaluated in the DU145 xenografts. FK228 induced a substantial acetylation of the histone proteins even at a low concentration of IC20 (0.56 ng/ml for 48 h treatment), while no effects on the cell cycle arrest and apoptosis induction were observed at the low concentration level. The pretreatment of cells with the IC20 dose of FK228 enhanced the cytotoxicity of both chemotherapeutic agents although the augmentation was more profoundly observed in GEM than DOC. The effects of the FK228 pretreatment were also observed in the in vivo experiment. The mean tumor doubling-time in the FK228 pretreatment combined with GEM was two times longer than that of the monotherapy with FK228 or GEM (p<0.001). These results show that pretreatment with low-dose FK228 enhances the chemosensitivity of DU145 tumors to GEM in vivo, suggesting the therapeutic potential of a new combination of HDACis and conventional chemotherapeutic agents. Further studies are required in order to assess the efficacy of this combination regimen in HRPCs in general.
Kanzaki
Masatoshi
M
Department of Urology, Akita University School of Medicine, Akita 010-8543, Japan.
Kakinuma
Hideaki
H
Kumazawa
Teruaki
T
Inoue
Takamitsu
T
Saito
Mitsuru
M
Narita
Shintarou
S
Yuasa
Takeshi
T
Tsuchiya
Norihiko
N
Habuchi
Tomonori
T
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D047630:Depsipeptides / Q000627:therapeutic use*; D000077143:Docetaxel; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D043823:Taxoids / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; C087123:romidepsin; D000093542:Gemcitabine