Experimental results using 3-bromopyruvate in mesothelioma: in vitro and in vivo studies.
Over many years we have taken advantage of the special metabolism of cancer cells involving an increased consumption of glucose associated with lactic acid production even in the presence of oxygen, a phenomenon referred to as the "Warburg effect", to counteract cancer cell growth. We have tested 3-bromopyruvate (3-BrPA), an inhibitor of pyruvate-associated reactions. Firstly, we tested this agent, in vitro, in two mesothelioma cell lines. Cellular response would appear to depend on the mode of administration (immediately or 24 h after seeding). Depending on the line, 3-BrPA induced a cytostatic or cytotoxic effect. This effect was accompanied by cell death induction even in cells highly refractory to cisplatin. Mitochondrial apoptotic death appeared to involve both lines; however, a different death pathway such as necrosis cannot be excluded. Interestingly, 3-BrPA leads to a diminution of the expression of the anti-apotptoic protein Mcl-1. We then tested 3-BrPA in vivo. Survival of nude mice bearing human mesothelioma was significantly prolonged (p < 0.0001). Toxicity and clinical studies should be performed to test 3- BrPA as local therapy for patients suffering from pleural or peritoneal mesothelioma. Association with cisplatin should be particularly considered.
Service de Chirurgie Thoracique, Centre Hospitalier Universitaire de Caen Basse-Normandie, Avenue de la Côte de Nacre, Caen 14000, France. icard-p@chu-caen.fr
Philippe
P
Icard
Icard
I
Philippe
Xiao-Dong
XD
Zhang
Zhang
Z
Xiao-Dong
Edwige
E
Lemoisson
Lemoisson
L
Edwige
Marie-Hélène
MH
Louis
Louis
L
Marie-Hélène
Stéphane
S
Allouche
Allouche
A
Stéphane
Hubert
H
Lincet
Lincet
L
Hubert
Laurent
L
Poulain
Poulain
P
Laurent
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D008654:Mesothelioma / Q000188:drug therapy*; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects*; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*
C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011773:Pyruvates; C017092:bromopyruvate