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Increased telomerase activity is associated with malignancy and poor prognosis in human cancer, but the development of targeted agents has not yet provided clinical benefit. Here we report that, instead of targeting the telomerase enzyme directly, small molecules that bind to the G-hairpin of the hTERT G-quadruplex-forming sequence kill selectively malignant cells without altering the function of normal cells. RG260 targets the hTERT G-quadruplex stem-loop folding but not tetrad DNAs, leading to downregulation of hTERT expression. To improve physicochemical and pharmacokinetic properties, we derived a small-molecule analog, RG1603, from the parent compound. RG1603 induces mitochondrial defects including PGC1α and NRF2 inhibition and increases oxidative stress, followed by DNA damage and apoptosis. RG1603 injected as a single agent has tolerable toxicity while achieving strong anticancer efficacy in a tumor xenograft mouse model. These results demonstrate a unique approach to inhibiting the hTERT that functions by impairing mitochondrial activity, inducing cell death., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Several studies suggested that women may be more susceptible to oxidative damage induced by cigarette smoking, but the role of smoking status and antioxidant capacity in gender difference in susceptibility to oxidative damage has not been well studied., Methods: We conducted a cross-sectional analysis of the baseline data from 146 current and former heavy smokers enrolled in a chemoprevention trial to determine the gender difference in oxidative damage and antioxidant capacity. Oxidative DNA and lipid damage were assessed by urinary 8-hydroxy-2'-deoxyguanosine (8OHdG) and 8-isoprostaglandin F(2α) (8-iso-PGF(2α)), respectively. The erythrocyte antioxidant enzymes and serum fat-soluble antioxidants were measured to assess antioxidant capacity., Results: Female smokers had significantly greater levels of 8OHdG and 8-iso-PGF(2α) than males but the gender difference was only significant in current smokers. No gender difference was noted in erythrocyte antioxidant enzymes, although female current smokers had significantly lower or a trend for lower antioxidant enzymes. Female smokers had higher serum β-carotene than males. Biomarkers of oxidative damage did not correlate significantly with the antioxidant enzymes. Urinary 8OHdG did not correlate significantly with fat-soluble antioxidants. Inverse correlations were observed between urinary 8-iso-PGF(2α) and several serum carotenoids., Conclusion: Female current smokers have a greater extent of oxidative damage despite having higher serum levels of fat-soluble antioxidants. Lower erythrocyte antioxidant enzymes in female current smokers may contribute to the greater extent of oxidative damage., Impact: The study may help identify appropriate high-risk populations for interventions that attenuate oxidative damage and appropriate biomarkers for clinical studies in smokers.

Imexon, a novel pro-oxidant, thiol-binding agent, is currently in phase I/II clinical trials in patients with advanced solid tumors. The aim of this study was to characterize the preclinical pharmacology of imexon in vivo. We investigated the anticancer activity of imexon in several cancer cell lines grown as xenografts in severe combined immunodeficient mice. Imexon was active against both hematologic and solid tumor types. The maximally tolerated dose, at the selected dosing schedule, was 150 mg/kg. Using the maximally tolerated dose of imexon, we sought to identify a potential pharmacodynamic biomarker to monitor the mechanistic effect systemically. As imexon binds cellular thiols in vitro, thiol depletion by imexon in vivo was evaluated as a potential biomarker. Following a single 150 mg/kg dose of imexon by intraperitoneal injection, glutathione levels decreased by 40% at 3 h in mouse erythrocytes. In mouse plasma, imexon treatment led to a significant decrease in cystine levels 2-4 h after drug administration. Notably, by this time, free imexon plasma levels were nondetectable. By investigating the pharmacokinetics of imexon, we also found that imexon undergoes rapid clearance from plasma in a dose-independent fashion with a half-life of 12-15 min. In summary, imexon is active against several cancer types in vivo. Imexon also decreases circulating thiols and exhibits dose-independent pharmacokinetics in mice. Plasma cystine levels may represent a biomarker of imexon activity in vivo.