Carcinogenesis Advance Access published online on November 21, 2007
Carcinogenesis, doi:10.1093/carcin/bgm265
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Licofelone, a dual COX/5-LOX inhibitor, induces apoptosis in HCA-7 colon cancer cells through the mitochondrial pathway independently from its ability to affect the arachidonic acid cascade
1 Department of Experimental Evolutionary Biology, University of Bologna, Bologna, Italy
2 Center for Applied Biomedical Research, Sant'Orsola University Hospital, Bologna, Italy
3 Department of Histology, Embryology and Applied Biology, University of Bologna, Bologna, Italy
4 ISOF, Consiglio Nazionale delle Ricerche, Bologna, Italy
5 Pharmaceutical/Medicinal Chemistry Department, Eberhard Karls Universität Tübingen, Germany
* To whom correspondence should be addressed: Department of Experimental Evolutionary Biology, via F. Selmi 3, University of Bologna, 40126, Bologna, Italy, Tel.: +39/ 051-2094253; Fax: +39/ 051-2094286, E-mail address: tiziana.guarnieri{at}unibo.it
Nowadays, no data are available concerning the potential use of dual COX/5-LOX inhibitors as anticancer agents in colon cancer treatment. Here we report, for the first time, that the dual COX/5-LOX inhibitor licofelone triggers apoptosis in a dose- and time-dependent manner in HCA-7 colon cancer cells. Induction of apoptosis was related to the recruitment of the intrinsic mitochondrial apoptotic pathway, as shown by loss in mitochondrial membrane potential, cytochrome c release, caspase-9 and 3 activation and poly-(ADP-ribose)polymerase-1 cleavage. Moreover, licofelone induced the cleavage of the full length p21Bax into p18Bax, a more potent inducer of the apoptotic process than the uncleaved form. Pre-treatment of HCA-7 cells with the pan-caspase inhibitor z-VAD-fmk significantly blocked licofelone-induced apoptosis, confirming that this process occurred primarily in a caspase-dependent pathway. We also present evidences that licofelone was able to affect the arachidonic acid cascade, as it blocked the activity of 5-LOX and COXs enzymes, and it induced, through the phosphorylation of cytoplasmic phospholipase A2, the release of unesterified arachidonic acid from HCA-7 membrane phospholipids. However, apoptosis induction was not related to the ability of licofelone to affect the arachidonic acid cascade, since neither exogenous PGE2 and LTB4 addition, nor pharmacological inhibition of cytoplasmic phospholipase A2, were able to rescue HCA-7 cells from apoptosis. Even if further studies are needed to clarify the mechanism of licofelone-induced apoptosis, this study suggest that this drug, as well as similar dual COX/5-LOX inhibitors, may represent a novel and promising approach in colon cancer treatment.
Key Words: Colon cancer • licofelone • COX/5-LOX inhibition • arachidonic acid • apoptosis
Received July 23, 2007; revised October 26, 2007; accepted November 12, 2007.