GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD ؉ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD ؉ turnover, which makes NAD ؉ modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD ؉ and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD ؉ repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.

Introduction Stress has been found to be a significant risk factor for cigarette smoking. Stress affects males and females differently, as does the use of smoking for stress reduction. Few studies have examined gender differences with the interrelation of perceived stress and smoking behaviors and nicotine related symptomatology. Our study investigates this association, as well as the influence of sociodemographic variables. Methods This is a retrospective analysis of 62 smokers (41 males, 21 females) enrolled in a smoking cessation study. At the screening visit sociodemographic information, smoking behaviors and survey measures were completed. These included the Perceived Stress Scale (PSS), Minnesota Nicotine Withdrawal Scale (MNWS), and others. Analyses were conducted using multiple linear regression models. Results PSS score was found to have a negative association with number of cigarettes smoked in males (slope -0.29 +/- 0.08; p = 0.0009) and females (slope -0.20 +/- 0.18; p = 0.26) with no difference in effect between genders (p =0.64). Linear regression of MNWS on PSS revealed a positive association for both males (slope 0.41 +/- 0.068; p < 0.0001) and females (slope 0.73 +/- 0.14; p < 0.0001). There was a significant difference in effect between genders (p = 0.04). Conclusions A strong positive association was observed between perceived stress and nicotine withdrawal symptomatology in smokers of both sexes, with a larger effect seen in women. These findings emphasize the importance of stress reduction in smokers, which may lead to fewer withdrawal symptoms and more effective smoking cessation.

Tumor cells often exhibit an altered metabolic phenotype. However, it is unclear as to when this switch takes place in ovarian cancer, and the potential for these changes to serve as therapeutic targets in clinical prevention and intervention trials. We used our recently developed and characterized mouse ovarian surface epithelial (MOSE) cancer progression model to study metabolic changes in distinct disease stages. As ovarian cancer progresses, complete oxidation of glucose and fatty acids were significantly decreased, concurrent with increases in lactate excretion and 3H-deoxyglucose uptake by the late-stage cancer cells, shifting the cells towards a more glycolytic phenotype. These changes were accompanied by decreases in TCA flux but an increase in citrate synthase activity, providing substrates for de novo fatty acid and cholesterol synthesis. Also, uncoupled maximal respiration rates in mitochondria decreased as cancer progressed. Treatment of the MOSE cells with 1.5μM sphingosine, a bioactive sphingolipid metabolite, decreased citrate synthase activity, increased TCA flux, decreased cholesterol synthesis and glycolysis. Together, our data confirm metabolic changes during ovarian cancer progression, indicate a stage specificity of these changes, and suggest that multiple events in cellular metabolism are targeted by exogenous sphingosine which may be critical for future prevention trials.

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