Checkpoint kinase 1-mediated phosphorylation of Cdc25C and bad proteins are involved in antitumor effects of loratadine-induced G2/M phase cell-cycle arrest and apoptosis.
In this study, we first demonstrated that loratadine (LOR), a promising world widely used oral anti-histamine, effectively inhibits growth of tumors derived from human colon cancer cells (COLO 205) in an in vivo setting. In vitro study demonstrated that the anti-tumor effects of LOR in COLO 205 cells were mediated by causing G(2)/M phase cell growth cycle arrest and caspase 9-mediated apoptosis. Cell-cycle arrest induced by LOR (75 microM, 24 h) was associated with a significant decrease in protein levels of cyclin B1, cell division cycle (Cdc) 25B, and Cdc25C, leading to accumulation of Tyr-15-phosphorylated Cdc2 (inactive form). Interestingly, LOR (75 microM, for 4 h) treatment also resulted in a rapid and sustained phosphorylation of Cdc25C at Ser-216, leading to its translocation from the nucleus to the cytoplasm because of increased binding with 14-3-3. We further demonstrated that the LOR-induced Cdc25C (Ser-216) phosphorylation was blocked in the presence of checkpoint kinase 1 (Chk1) specific inhibitor (SB-218078). The cells treated with LOR in the presence of Chk1 specific inhibitor (SB-218078) were then released from G(2)/M arrest into apoptosis. These results implied that Chk1-mediated phosphorylation of Cdc25C plays a major role in response to LOR-mediated G(2)/M arrest. Although the Chk1-mediated cell growth arrest in response to DNA damage is well documented, our results presented in this study was the first report to describe the Chk1-mediated G(2)/M cell-cycle arrest by the histamine H1 antagonist, LOR.
Chen
Jinn-Shiun
JS
Department of Surgery, Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan.
Lin
Shyr-Yi
SY
Tso
Wei-Ling
WL
Yeh
Geng-Chang
GC
Lee
Wen-Sen
WS
Tseng
How
H
Chen
Li-Ching
LC
Ho
Yuan-Soon
YS
D000230:Adenocarcinoma; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms; D003600:Cytosol / Q000187:drug effects / Q000502:physiology; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D017336:Loratadine / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000378:metabolism*
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011480:Protease Inhibitors; D017336:Loratadine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases