The sigma receptor ligand, reduced haloperidol, induces apoptosis and increases intracellular-free calcium levels [Ca2+]i in colon and mammary adenocarcinoma cells.
The sigma receptor ligand reduced haloperidol (50 and 100 microM), potently inhibited cell proliferation, and induced apoptosis in WIDr colon and MCF-7 adenocarcinoma cell lines. Apoptosis was confirmed after drug treatment of the cells by the presence of nuclear fragmentation after staining of the cells with Hoechst 33258 and cellular DNA fragmentation ELISA and by condensation of the heterochromatin using transmission electron microscopy. However, internucleosomal DNA cleavage was not detected using gel electrophoresis. Reduced haloperidol (100 microM) increased the intracellular free calcium levels [Ca2+]i in both cell lines, which was independent of extracellular calcium, suggesting that the rise in [Ca2+]i was from intracellular stores and that an increase in [Ca2+]i may act as a "trigger" for apoptosis in these cell lines.
Brent
P J
PJ
Neuroscience Group, Faculty of Medicine and Health Sciences, University of Newcastle, N.S.W., Australia.
Pang
G
G
Little
G
G
Dosen
P J
PJ
Van Helden
D F
DF
D000230:Adenocarcinoma; D017209:Apoptosis / Q000187:drug effects*; D006690:Bisbenzimidazole; D001943:Breast Neoplasms; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects / Q000648:ultrastructure*; D003110:Colonic Neoplasms; D004273:DNA, Neoplasm / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology*; D006570:Heterochromatin / Q000187:drug effects / Q000648:ultrastructure; D006801:Humans; D008024:Ligands; D008854:Microscopy, Electron; D010084:Oxidation-Reduction; D017480:Receptors, sigma / Q000502:physiology*; D014407:Tumor Cells, Cultured
D002843:Chromatin; D004273:DNA, Neoplasm; D006570:Heterochromatin; D008024:Ligands; D017480:Receptors, sigma; D006220:Haloperidol; D006690:Bisbenzimidazole; D002118:Calcium