Induction of apoptosis and cell-cycle arrest in human colon cancer cells by meclizine.
Meclizine (MEC), a histamine H1 antagonist, is used for the treatment of motion sickness and vertigo. In this study, we demonstrate that MEC dose-dependently induced apoptosis in human colon cancer cell lines (COLO 205 and HT 29 cells). Results of a DNA ladder assay revealed that DNA ladders appeared with MEC treatment in COLO 205 cells at dosage of >50 microM. In addition, the total cell number decreased dose-dependently after treatment with MEC in COLO 205 and HT 29 cells. Using flow cytometry, the percentage of COLO 205 cells arrested at G0/G1 phase increased dose-dependently. Analysis of changes in cell-cycle arrest-associated proteins with Western blotting showed that p53 and p21 were upregulated after treatment with MEC. The kinase activities of cyclin-dependent kinase 2 (CDK2) and CDK4 were suppressed in MEC-treated cells. As for apoptosis, MEC may induce upregulation of p53 and downregulation of Bcl-2, thus causing the release of cytochrome C from mitochondria and the translocation of apoptosis-inducing factor (AIF) to the nucleus. This resulted in the activation of caspase 3, 8, and 9. Our results provide the molecular basis of MEC-induced apoptosis and cell-cycle arrest in human colon cancer cells.
Lin
Jiunn-Chang
JC
Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
Ho
Yuan-Soon
YS
Lee
Jie-Jen
JJ
Liu
Chien-Liang
CL
Yang
Tsen-Long
TL
Wu
Chih-Hsiung
CH
D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D019073:HT29 Cells; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D008468:Meclizine / Q000494:pharmacology*
D051033:Apoptosis Inducing Factor; D018797:Cell Cycle Proteins; D006634:Histamine H1 Antagonists; D008468:Meclizine; D045304:Cytochromes c; D018844:Cyclin-Dependent Kinases