Licofelone

Abstract: Licofelone, a competitive inhibitor of 5-lipoxygenase, cyclooxygenase (COX)-1 and COX-2, is currently in clinical development for the treatment of osteoarthritis (OA). Licofelone decreases the production of proinflammatory leukotrienes and prostaglandins-which are involved in the pathophysiology of OA and in gastrointestinal (GI) damage induced by NSAIDs-and has the potential to combine good analgesic and anti-inflammatory effects with excellent GI tolerability. initial endoscopy data in healthy volunteers have demonstrated that licofelone is well tolerated and has a GI safety profile similar to placebo and significantly better than naproxen. These tolerability results were confirmed in patients with OA in two separate randomized studies. Furthermore, a long-term study (52 weeks) has shown that licofelone is at least as effective as naproxen in the treatment of OA. Licofelone also appears to be as effective as the selective COX-2 inhibitor celecoxib in the treatment of the signs and symptoms of OA. Licofelone has a GI safety profile similar to that of celecoxib, but may offer the advantage of fewer incidences or worsening of peripheral oedema. Preliminary data have also shown that licofelone coadministration with low-dose aspirin does not lead to increased GI toxicity. The emerging clinical data for licofelone indicate that it is an effective and well-tolerated therapy that could offer safety advantages over current treatment options, and that it could be suitable for the long-term treatment of a broad spectrum of patients with OA.

Abstract: Nowadays, no data are available concerning the potential use of dual cyclooxygenase (COX)/5-lipoxygenase (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 p21(Bax) into p18(Bax), 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 (AA) cascade, as it blocked the activity of 5-LOX and COX enzymes, and it induced, through the phosphorylation of cytoplasmic phospholipase A(2) (cPLA(2)), the release of unesterified AA from HCA-7 membrane phospholipids. However, apoptosis induction was not related to the ability of licofelone to affect the AA cascade, since neither exogenous prostaglandin E(2) and leukotriene B(4) addition, nor pharmacological inhibition of cPLA(2), was able to rescue HCA-7 cells from apoptosis. Even if further studies are needed to clarify the mechanism of licofelone-induced apoptosis, this study suggests that this drug, as well as similar dual COX/5-LOX inhibitors, may represent a novel and promising approach in colon cancer treatment.