Chlorimipramine: a novel anticancer agent with a mitochondrial target.
Mitochondria have been suggested to be a potential intracellular target for cancer chemotherapy. In this report, we demonstrate the ability of the tricyclic antidepressant chlorimipramine to kill human glioma cells in vitro by a molecular mechanism resulting in an increase in caspase 3 activity following inhibition of glioma oxygen consumption. Studies with isolated rat mitochondria showed that chlorimipramine specifically inhibited mitochondrial complex III activity, which causes decreased mitochondrial membrane potential as well as mitochondrial swelling and vacuolation. The use of chlorimipramine in human as an effective, non-toxic cancer therapeutic having a strong selectivity between cancer cells and normal cells on the basis of their mitochondrial function is discussed.
Daley
E
E
Experimental Neuro-oncology Group, Department of Neuropathology, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Wilkie
D
D
Loesch
A
A
Hargreaves
I P
IP
Kendall
D A
DA
Pilkington
G J
GJ
Bates
T E
TE
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019069:Cell Respiration / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002997:Clomipramine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014450:Electron Transport Complex III; D002997:Clomipramine