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Abstract. Background Antimitotic drugs are widely used to treat numerous types of cancers (1, 2). These compounds inhibit mitosis by targeting microtubules and preventing their polymerization or depolymerization (1-4). However, patients develop resistance to these drugs (5). Thus, to improve the efficacy of treatment, research has been focused on increasing antimitotic drug-associated apoptosis.Cyclooxygenase-2 (COX-2) is an enzyme whose expression increases in response to inflammation and mitotic stimuli (6-8). COX-2 expression is also positively correlated with cancer cell proliferation and growth (9). Increased COX-2 expression is also observed in P-glycoprotein (P-gp)-mediated drug resistance (10, 11). There are reports that the COX-2 inhibitors NS398 and celecoxib can suppress cancer by COX-2-dependent and COX-2-independent mechanisms (12, 13). In addition, co-treatment with COX-2 inhibitors showed increased sensitization to anti-cancer drugs in various models (14-17). Adverse effects, such as cardiovascular events, have been reported in clinical trials involving celecoxib-treated cancer patients (18,19). Better understanding of the mechanism governing the sensitization effect of COX-2 inhibitors in cancer patients could facilitate their safe therapeutic use.In the present study, we compared the sensitization efficacy of two well-known COX-2 inhibitors, NS398 and celecoxib, in antimitotic drug-resistant KBV20C cancer cells. We also tested whether co-treatment with COX-2 inhibitors increases sensitization in antimitotic drug-treated KBV20C resistant cancer cells. Since we have already demonstrated their strong inhibitory effects in drug-resistant cancer, the current study supports the use of COX-2 inhibitors in combinatorial treatment of antimitotic drug-resistant patients. Materials and MethodsReagents. Paclitaxcel (PAC) and verapamil (VER) were purchased from Sigma-Aldrich (St.Louis, MO, USA). Vinblastine (VIB) and vincristine (VIC) were purchased from Enzo Life Sciences (Farmingdale, NY, USA). Celecoxib and rhodamine123 (rhodamine) was purchased from Santa Cruz Biotechnology (Dallas, TX, USA). 5063

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Tyrosinase is a key player in ultraviolet-induced melanogenesis. Because excessive melanin accumulation in the skin can induce hyperpigmentation, the development of tyrosinase inhibitors has attracted attention in cosmetic-related fields. However, side effects including toxicity and low selectivity have limited the use of many tyrosinase inhibitors in cosmetics. We synthesized 12 novel 2-(substituted benzylidene)malononitrile derivatives and investigated their anti-melanogenic activities. Of these 12 compounds, 2-(3, 4-dihydroxy benzylidene)malononitrile (BMN11) exhibited the strongest inhibitory activity against tyrosinase (IC 50 = 17.05 μM). In parallel with this, BMN11 treatment notably decreased alpha-melanocytestimulating hormone-induced melanin accumulation in B16F10, cells without toxicity and also decreased melanin accumulation in a human skin model. As a mechanism underlying the BMN11-mediated anti-melanogenic effect, docking simulation showed that BMN11 can directly bind to tyrosinase by forming two hydrogen bonds with GLY281 and ASN260 residues, and via three hydrophobic interactions with VAL283, PHE264, and ALA286 residues in the tyrosinase binding pocket, and this likely contributes to its inhibitory effect on tyrosinase. Consistently, Lineweaver-Burk and Cornish-Bowden plots showed that BMN11 is a competitive inhibitor of tyrosinase. We concluded that BMN11 may be a novel tyrosinase inhibitor that could be used in cosmetics.

The five-driving test mode is vehicle driving cycles made by the Environment Protection Association (EPA) in the United States of America (U.S.A.) to fully reflect actual driving environments. Recently, fuel consumption value calculated from the adjusted fuel consumption formula has been more effective in reducing the difference from that experienced in real-world driving conditions, than the official fuel efficiency equation used in the past that only considered the driving environment included in FTP and HWFET cycles. There are many factors that bring about divergence between official fuel consumption and that experienced by drivers, such as driving pattern behavior, accumulated mileage, driving environment, and traffic conditions. In this study, we focused on the factor of causing change of fuel efficiency value, calculated according to how many environmental conditions that appear on the real-road are considered, in producing the fuel consumption formula, and that of the vehicle’s accumulated mileage in a 2.0 L gasoline-fueled vehicle. So, the goals of this research are divided into four major areas to investigate divergence in fuel efficiency obtained from different equations, and what factors and how much CO2 and CO emissions that are closely correlated to fuel efficiency change, depending on the cumulative mileage of the vehicle. First, the fuel consumption value calculated from the non-adjusted formula, was compared with that calculated from the corrected fuel consumption formula. Also, how much CO2 concentration levels change as measured during each of the three driving cycles was analyzed as the vehicle ages. In addition, since the US06 driving cycle is divided into city mode and highway mode, how much CO2 and CO production levels change as the engine ages during acceleration periods in each mode was investigated. Finally, the empirical formula was constructed using fuel economy values obtained when the test vehicle reached 6500 km, 15,000 km, and 30,000 km cumulative mileage, to predict how much fuel consumption of city and highway would worsen, when mileage of the vehicle is increased further. When cumulative mileage values set in this study were reached, experiments were performed by placing the vehicle on a chassis dynamometer, in compliance with the carbon balance method. A key result of this study is that fuel economy is affected by various fuel consumption formula, as well as by aging of the engine. In particular, with aging aspects, the effect of an aging engine on fuel efficiency is insignificant, depending on the load and driving situation.