The herbal flavonoid quercetin inhibits the growth of various cancer cells, but how it affects human cancer cells, particularly lung cancer cells, is unclear. We investigated the anticancer activity of quercetin and the underlying molecular mechanisms in non-small cell lung cancer (NSCLC) cells. Quercetin strongly inhibited cell proliferation, and increased sub-G1 and apoptotic cell populations regardless of p53 status. Quercetin-induced apoptosis was verified by caspase cleavage, Hoechst staining, trypan blue exclusion, and DNA fragmentation assays. Microarray analysis using H460 cells indicated that quercetin increased the expression of genes associated with death receptor signaling tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAILR), caspase-10, interleukin (IL) 1R DNA fragmentation faotor 45 (DFF45), tumor necrosis factor receptor (TNFR) 1, FAS, inhibitor of kappaBalpha (IκBα)) and cell cycle inhibition growth arrest and DNA-damage inducible 45 (GADD45), p21 Cip1), but decreased the expression of genes involved in nuclear factor (NF)-kappaB activation (NF-κB, IKKα). Further validation assays confirmed that quercetin inhibited growth by suppressing NF-κB and by increasing the expression of death receptors and cell cycle inhibitors. Taken together, these findings suggest that quercetin may be useful in the prevention and therapy of NSCLC.Key words quercetin; lung cancer; apoptosis; death receptor; nuclear factor-kappaB pathway Lung cancer is the leading cause of cancer death in many developed countries because of its poor prognosis. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, of which 70% show advanced-stage disease at the time of diagnosis.1,2) Although various chemical drugs have been developed, 3,4) frequent chemoresistance and side effects in patients with NSCLC require the development of new preventive and therapeutic agents. High intake of flavonoids from fruits and vegetables is associated with a low risk of various cancers, 5-10) including lung cancer. 11,12) Of these polyphenolic flavonoids, quercetin is readily found in fruits, vegetables, green and black tea, and various medical plants such as Euonymus alatus (Thunb.) Sieb. Quercetin can act as either an antioxidant or a prooxidant depending on its concentration (1-40 µm or 40-100 µm, respectively). 13,14) Numerous studies have reported a broad range of pharmacological properties of quercetin, including benefits for inflammation, 15) atherosclerosis, 16) hypertension, 17) and neurodegeneration. 18,19) In addition to these beneficial effects, quercetin plays preventive and therapeutic roles in various types of cancer and cancer cells. [20][21][22][23][24][25] However, the anticancer effect of quercetin in NSCLC cells has been rarely addressed, and the underlying molecular mechanism remains to be determined.Here, we investigated the growth inhibitory role of quercetin in three NSCLC cell lines and found that its effect is p53-independent and triggered by apoptosis. Subsequent microarray analysis usin...

Our data indicate that levobupivacaine-induced contraction of rat aortic smooth muscle is mediated mainly by activation of the lipoxygenase pathway and in part by activation of the cyclooxygenase pathway. In addition, activation of the lipoxygenase pathway seems to facilitate calcium influx via L-type calcium channels. Endothelial nitric oxide attenuates levobupivacaine-induced contraction.

PurposeDexmedetomidine, a full agonist of α2B-adrenoceptors, is used for analgesia and sedation in the intensive care units. Dexmedetomidine produces an initial transient hypertension due to the activation of post-junctional α2B-adrenoceptors on vascular smooth muscle cells (SMCs). The aims of this in vitro study were to identify mitogen-activated protein kinase (MAPK) isoforms that are primarily involved in full, α2B-adrenoceptor agonist, dexmedetomidine-induced contraction of isolated rat aortic SMCs.Materials and MethodsRat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dexmedetomidine (10-9 to 10-6 M) dose-response curves were generated in the presence or absence of extracellular signal-regulated kinase (ERK) inhibitor PD 98059, p38 MAPK inhibitor SB 203580, c-Jun NH2-terminal kinase (JNK) inhibitor SP 600125, L-type calcium channel blocker (verapamil and nifedipine), and α2-adrenoceptor inhibitor atipamezole. Dexmedetomidine-induced phosphorylation of ERK, JNK, and p38 MAPK in rat aortic SMCs was detected using Western blotting.ResultsSP 600125 (10-6 to 10-5 M) attenuated dexmedetomidine-evoked contraction in a concentration-dependent manner, whereas PD 98059 had no effect on dexmedetomidine-induced contraction. SB 203580 (10-5 M) attenuated dexmedetomidine-induced contraction. Dexmedetomidine-evoked contractions were both abolished by atipamezole and attenuated by verapamil and nifedipine. Dexmedetomidine induced phosphorylation of JNK and p38 MAPK in rat aortic SMCs, but did not induce phosphorylation of ERK.ConclusionDexmedetomidine-induced contraction involves a JNK- and p38 MAPK-mediated pathway downstream of α2-adrenoceptor stimulation in rat aortic SMCs. In addition, dexmedetomidine-induced contractions are primarily dependent on calcium influx via L-type calcium channels.

PurposeFentanyl was reported to inhibit the α1-adrenoceptor agonist-induced contraction. The goal of this in vitro study was to identify the α1-adrenoceptor subtype primarily involved in the fentanyl-induced attenuation of phenylephrine-induced contraction in isolated endothelium-denuded rat aorta.Materials and MethodsAortic rings were suspended in order to record isometric tension. Concentration-response curves for phenylephrine (10-9 to 10-5 M) were generated in the presence or absence of one of the following drugs: fentanyl (3×10-7, 10-6, 3×10-6 M), 5-methylurapidil (3×10-8, 10-7, 3×10-7 M), chloroethylclonidine (10-5 M) and BMY 7378 (3×10-9, 10-8, 3×10-8 M). Phenylephrine concentration-response curves were generated in the presence or absence of fentanyl in rings pretreated with either 3×10-9 M prazosin, 10-9 M 5-methylurapidil or 3×10-9 M BMY 7378.ResultsFentanyl (10-6, 3×10-6 M) attenuated phenylephrine-induced contraction in the rat aorta. 5-Methylurapidil and BMY 7378 produced a parallel rightward shift in the phenylephrine concentration-response curve. The pA2 values for 5-methylurapidil and BMY 7378 were estimated to be 7.71 ± 0.15 and 8.99 ± 0.24, respectively. Fentanyl (10-6 M) attenuated phenylephrine-induced contraction in rings pretreated with 10-9 M 5-methylurapidil, but did not alter the rings when pretreated with 3×10-9 M BMY 7378. Pretreatment of the rings with chloroethylclonidine showed a 72.9 ± 2.3% reduction in phenylephrine-induced maximal contraction.ConclusionThe results suggest that fentanyl attenuates phenylephrine-induced contraction by inhibiting the pathway involved in the α1D-adrenoceptor-mediated contraction of the rat aorta.

A supraclinical dose of alfentanil attenuates the phenylephrine-induced contraction via an inhibitory effect on calcium influx by blocking the l-type calcium channels in the rat aortic vascular smooth muscle.