Ascorbate, or vitamin C, is usually thought of as an antioxidant. The body tightly controls blood levels of orally ingested ascorbate, capping them at 0.2 mM.However, Qi Chen et al. show that injection can circumvent this limit, allowing pharmacological concentrations up to 30 mM, which exert an oxidative effect and slow tumor growth. A previous study suggested that ascorbate might be effective against terminal cancer, but a subsequent trial appeared to show that ascorbate had no effect. Later research revealed the tight constraints on orally ingested ascorbate and provided the rationale for the present work. The authors first tested a range of tumor and normal cell lines, showing that the ascorbate EC50 for most tumor lines was <10 mM, whereas normal cells easily tolerate >20 mM. The authors then demonstrated ascorbate's protective effects in a mouse tumor model, showing that ascorbate slowed tumor growth by 43–51% in three types of aggressive tumors. Because clinical investigation revealed that plasma levels of ascorbate reached in human patients are similar to those achieved in the mice, the authors suggest that ascorbate may prove to be a useful component of an anticancer regimen. — K.M.
Proposed mechanism for tumoricidal action of ascorbate (AA).
“Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice” by Qi Chen, Michael Graham Espey, Andrew Y. Sun, Chaya Pooput, Kenneth L. Kirk, Murali C. Krishna, Deena Beneda Khosh, Jeanne Drisko, and Mark Levine (see pages 11105–11109)
Transmitted by mosquitoes, the West Nile virus is now endemic to regions of North America and causes hundreds of deaths annually in humans. No vaccine exists for the virus, which can result in a fatal encephalitis in elderly and immunocompromised individuals. Erin McCandless et al. developed a treatment that spurs the immune system to clear West Nile from the central nervous system. The authors continuously infused infected mice with AMD3100, also known as Plerixafor, which was initially developed to treat HIV infection. The molecule works by blocking the chemokine receptor CXCR4. Typically, this receptor binds the CXCL12 chemokine on immune cells, and the interaction sequesters the cells into perivascular spaces, preventing them from crossing the blood–brain barrier. By blocking CXCR4 in infected mice, the authors freed T cells from breaching the blood–brain barrier, which allowed the cells to clear the viral infection from the central nervous system. Treated animals recovered 8 days after infection, whereas untreated mice continued to sicken and died. The authors suggest that their results may point to a method for treating West Nile infection and other forms of viral encephalitis. — F.A.
AMD3100 enhances T cells (red) to clear West Nile virus infection (green).
“CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis” by Erin E. McCandless, Bo Zhang, Michael S. Diamond, and Robyn S. Klein (see pages 11270–11275)
South Africa has one of the world's highest burdens of tuberculosis (TB), including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. The gold standard for TB diagnosis is growth of the bacillus in culture, but estimates show that this test is applied to only ≈5% of new cases. David Dowdy et al. developed a quantitative model to investigate the benefits of expanding culture and drug susceptibility testing to a larger fraction of South Africa's TB patients over a 10-year period. The authors found substantial benefit from the expanded testing, at a reasonable cost, provided the new regime is initiated immediately. They considered eight scenarios, each with variations in the proportion of patients tested and the time of program onset. Their model showed that if culture and drug susceptibility tests are applied to 37% of new patients and to 85% of patients whose first round of treatment was unsuccessful, then ≈48,000 lives will be saved and 60,000 TB cases averted—including 7,700 MDR cases—of the estimated 2 million TB cases that are likely to develop in South Africa over the next 10 years. However, this strategy will not reduce the incidence of XDR-TB unless transmission is also inhibited, the authors say. — K.M.
“Impact of enhanced tuberculosis diagnosis in South Africa: A mathematical model of expanded culture and drug susceptibility testing” by David W. Dowdy, Richard E. Chaisson, Gary Maartens, Elizabeth L. Corbett, and Susan E. Dorman (see pages 11293–11298)
José Jiménez et al. report the complete set of genes required for aerobic nicotinic acid (vitamin B3) degradation. Their findings reveal details of an important metabolic pathway for the detoxification and biotransformation of many N-heterocyclic aromatic compounds, including pyridine cofactors such as NAD and NADP, toxic hydroxypyridines, and alkaloids such as nicotine and anabasine. The authors found that some of the proteins used by Pseudomonas putida to degrade nicotinic acid have unique structures and mechanisms. For example, the first step in degradation involves the hydroxylation of nicotinic acid to 6-hydroxynicotinic acid, which is catalyzed by a two-component hydroxylase, NicAB, which represents a unique class of xanthine dehydrogenases. An iron-dependent dioxygenase called NicX then converts 2,5-dihydroxypyridine to N-formylmaleamic acid. The authors say NicX is the founding member of a previously unreported family of extradiol ring-cleavage dioxygenases that evolved from metalloproteases, with no relationship to other dioxygenase enzymes. Further conversions catalyzed by NicD—the first α/β hydrolase with deformylase activity—yield NicE and NicF proteins that ultimately produce ammonium ion, formic acid, and fumaric acid. The authors suggest that similar genes in other saprophytic bacteria and pathogens may play a role in virulence. — P.D.
Structure of NicX, the first member of a newly identified family of dioxygenases.
“Deciphering the genetic determinants for aerobic nicotinic acid degradation: The nic cluster from Pseudomonas putida KT2440” by José I. Jiménez, Ángeles Canales, Jesús Jiménez-Barbero, Krzysztof Ginalski, Leszek Rychlewski, José L. García, and Eduardo Díaz (see pages 11329–11334)
