Depsipeptide and roxithromycin induce apoptosis of lymphoma cells by blocking extracellular signal-regulated kinase activation.
Depsipeptide (FK228), a histone deacetylase inhibitor, was recently approved for use in cutaneous T-cell lymphoma. Roxithromycin (RXM) is a macrolide antibiotic that can induce apoptosis of some T-cell lines. In this study, we investigated whether combination of FK228 and RXM had a synergistic inhibitory effect on cell survival of various lymphoma cells and which signaling pathway was affected by the drugs in the presence or absence of chemokines, which were reported to inhibit apoptosis of some tumor cells. FK228 and RXM additively decreased the number of HUT-78, Ki-JK and EL-4 lymphoma cells at doses over 50 nmol/L and 50 μmol/L, respectively. These drugs inhibited phosphorylation of Akt and extracellular signal-regulated kinase (ERK) of EL-4 cells in a dose-dependent manner. Significant association between ERK phosphorylation and cell number or annexin V(+) cells suggested that the ERK pathway may be critical for survival of EL-4 cells. Combination of 10 or 50 nmol/L of FK228 and 10 μmol/L of RXM decreased cell number of HUT78 and EL-4 compared to a single use of each drug. Our in vitro study suggested that combination of FK228 and RXM may be helpful for enhancing tumor killing effects. Although further study is necessary, this combination may be applicable to patients with cutaneous T-cell lymphoma in the future.
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Sohshi
S
Morimura
Makoto
M
Sugaya
Hiromichi
H
Kai
Tomomitsu
T
Miyagaki
Yoshihide
Y
Asano
Yayoi
Y
Tada
Takafumi
T
Kadono
Takashi
T
Murakami
Sinichi
S
Sato
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D051379:Mice; D015575:Roxithromycin / Q000494:pharmacology / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D015575:Roxithromycin; C087123:romidepsin; D048049:Extracellular Signal-Regulated MAP Kinases
CCL11; CCL27; depsipeptide; lymphoma; roxithromycin