The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. This observation raises the possibility that factors affecting caspase activation and activity might be important determinants as anticancer drug sensitivity. Caspase 1 is an initiator caspase that was originally described as a proteolytic activity responsible for the cleavage of prointerleukin-1β into its active counterpart: the pro-inflammatory cytokine interleukin-1β (IL-1β). For this reason, Caspase-1 was also named Interleukin-Converting Enzyme (ICE). Ectopic expression of caspase-1 has been shown to trigger apoptosis. However, the role of ICE in apoptosis has now been revisited and it is now considered as a minor compared to Caspase-3, -6, -7, -8, -9. In experimental therapeutics for cancer, Caspase-1 has been shown to produce some anti-cancer activity on its own or in an immunotherapy protocol. In clinical studies, it has been suggested that ICE may be associated with the spontaneous regression in favourable neuroblastomas in patients and high expression of ICE is correlated with a good clinical response to chemotherapy in myeloid leukemia and osteosarcoma. 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 resistant cells to cisplatin or γ-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 γ-radiation could also be observed in vivo. Altogether, we conclude that caspase-1 can act as a radio- and chemo-sensitiser, in vitro and in vivo. Acknowledgments: Work funded by Cancer Research-UK and Programa Ramón y Cajal del MEC de España.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]