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-(ADPribose) 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.

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.

TAVOLARI, SIMONA;BONAFE', MASSIMILIANO;MARINI, MARINA;BARTOLINI, GIOVANNA;BRIGHENTI, ELISA;TOMASI, VITTORIO;GUARNIERI, TIZIANA
2008

Abstract

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-(ADPribose) 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.
CARCINOGENESIS
Tavolari S.; Bonafè M.; Marini M.; Ferreri C.; Bartolini G.; Brighenti E.; Manara S.; Tomasi V.; Laufer S.; Guarnieri T.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/52788
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