Lung Cancer Chemoprevention with Celecoxib in Former Smokers

Abstract

Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2 selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥45, ≥30 pack-years of smoking, ≥1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI). Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t-test). Participants crossed over to the other study arm at 6 months. Therefore, at 12 months all remaining participants had received 6 months of celecoxib, and their decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in BAL samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in bronchoalveolar lavage (BAL) cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease.

Grape Seed Procyanidin Extract Mediates Antineoplastic Effects against Lung Cancer via Modulations of Prostacyclin and 15-HETE Eicosanoid Pathways

“…GSE dose dependently increased 15-HETE productions by these cells, but GSE did not increase expression of 15-LOX (1 or 2) in A549 cells (data not shown), suggesting that the increase of 15-HETE by GSE is also a result of shunting, as was previously found in a phase IIb clinical trial with celecoxib (11). Taken together, these findings reflect the A and B, GSE dose dependently increases 6-keto PGF1a (A) and 15-HETE (B) productions by human BAL cells ex vivo.…”

“…Overexpression of COX-2 and subsequent overproduction of prostaglandin E 2 (PGE 2 ) are associated with a variety of well-established lung cancer risk factors (5)(6)(7)(8)(9). In two independent phase IIb lung cancer chemoprevention trials involving heavy former and/or active smokers, COX-2 inhibition with celecoxib significantly reduced bronchial Ki67 expressions, a marker of cell proliferation and the primary endpoint for the trials (10,11). Unfortunately, the increase in cardiovascular risks associated with selective, pharmaceutical COX-2 inhibitors prevented further evaluation of celecoxib in phase III trials.…”

Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non–Small-Cell Lung Cancer: ECOG 5597

“…Previous attempts at primary and secondary chemoprevention with ␤-carotene, 5 ␣-tocopherol, 6 and several retinoids 7,8 have largely shown no benefit of these agents. 6,9 Positive outcomes for vitamin B 12 , 10 folic acid, 10 aspirin, 11 and the prostaglandin pathway modulators celecoxib and iloprost [12][13][14] have been achieved. Although smaller phase III trials attempting tertiary prevention of SPT development reported positive outcomes with isotretinoin 15 and retinyl palmitate, 16 larger phase III studies reported negative outcomes with lower doses of retinyl palmitate 17 and 13-cisretinoic acid.…”

Induction but not inhibition of COX-2 confers human lung cancer cell apoptosis by celecoxib

“…Another study suggested celecoxib for prevention of colorectal adenomas ( 3 ). Recent reports indicate celecoxib as treatment and preventive option for lung cancer (4)(5)(6)(7) and to enhance the response to classical chemotherapeutics in early stage non-small cell lung cancer (NSCLC) ( 8 ). These studies have attracted particular interest given that lung cancer is worldwide the most common cancer in terms of both incidence and mortality and that the response and remission rates in NSCLC patients still remains relatively low ( 9 ).…”