Caspase-1 as a radio- and chemo-sensitiser in vitro and in vivo.
The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. This observation raises the possibility that factors affecting caspase activation might be important determinants of anticancer drug sensitivity. Ectopic expression of caspase-1 has been shown to trigger apoptosis. However, the role of caspase-1 in apoptosis is now considered as minor compared to other caspases. In patients, high levels of caspase-1 expression may be associated with spontaneous regression in neuroblastomas and with a good clinical response to chemotherapy in acute myeloid leukemia and osteosarcoma. In experimental therapeutics for cancer, caspase-1 has been related to some anticancer activity. These observations led us to examine the effect of over-expression on the response to chemotherapy and radiotherapy in vitro and in vivo. Caspase-1 expression mediated by an adenoviral vector was able to kill directly cells and to sensitise the remaining cells to cisplatin or gamma-radiation in vitro. In HeLa cells stably transfected with caspase-1, sensitisation to cisplatin was due to an amplification of the cisplatin-induced mitochondrial apoptotic pathway activation. Caspase-1 mediated sensitisation to cisplatin and gamma-radiation was also observed in vivo. Altogether, we conclude that caspase-1 can act as a radio- and chemo-sensitiser, in vitro and in vivo.
Martín-Duque
Pilar
P
Cancer Research-UK Molecular Oncology Unit, Bart's and The London School of Medicine and Dentistry, John Vane Science Centre, UK. p.martin@ufv.es
Quintanilla
Miguel
M
McNeish
Iain
I
Lopes
Rita
R
Romero
Jesús
J
Romero
Diana
D
Lemoine
Nick R
NR
Ramón y Cajal
Santiago
S
Vassaux
Georges
G
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000970:Antineoplastic Agents; D020170:Caspase 1; D002945:Cisplatin