Spotlight pubs.acs.org/crt
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TRICLOSAN PROMOTES LIVER TUMOR DEVELOPMENT The antimicrobial craze prevalent in modern culture has led to an explosion of products containing the antibacterial compound triclosan. For people using large amounts of antimicrobial personal care products, the potential for exposure is very high; triclosan has been found to accumulate in human serum and urine at concentrations up to 12 nM and 13 μM, respectively, depending on the subjects’ level of product use and ability to metabolically detoxify the molecule. Individuals with low ability to metabolize triclosan may experience accumulation in the body, causing a team of researchers led by Robert H. Tukey and Bruce D. Hammock to question the potential carcinogenicity of triclosan upon long-term exposure in vivo ((2014) PNAS, 111, 17200−17205). After the team fed mice with triclosan-supplemented chow for 8 months, they found that triclosan induced enhanced hepatocyte proliferation, fibrosis, and high levels of superoxide in the liver as well as upregulation of genes associated with these processes. Because these processes are associated with carcinogenesis, the team measured the ability of triclosan to promote tumor formation in mice treated with the mutagenic initiator diethylnitrosamine. Indeed, mice supplemented with triclosan grew tumors at higher incidence and in greater size and numbers than did untreated control mice. The authors conclude that the triclosan-induced tumor promotion in mice warrants further investigation of the effects of triclosan in human hepatocellular carcinoma development. Heidi A. Dahlmann
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ANTICANCER/ANTIVIRAL AGENT WREAKS HAVOC IN MITOCHONDRIA
AKTIV’s anticancer and antiviral activities likely stem from its extreme effects on the structure and function of mitochondria. Heidi A. Dahlmann
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ANTITUMOR THERANOSTIC PRODRUG: ONE MOLECULE, MANY FUNCTIONS
Reprinted from Meinig, J. M, and Peterson, B. R. (2014) ACS Chem. Biol., DOI: 10.1021/cb500856c. Copyright 2014 American Chemical Society.
The cationic benzimidazole Akt inhibitor-IV (AKTIV) exhibits anticancer and broad-spectrum antiviral activity at low micromolar concentrations. Although AKTIV was named for its ability to suppress the phosphorylation of serine-threonine kinase AKt in U205 human osteosarcoma cells, further investigations showed that it did not block any known kinases in the P13K/Akt pathway. In fact, AKTIV was later found to actually increase phosphorylation of AKt in a different cell line, baby hamster kidney fibroblasts. Adding to the uncertainty of how AKTIV mediates its cytotoxicity, the mechanistic basis for AKTIV’s antiviral activity was equally murky. During prior structure−activity studies with AKTIV, Blake R. Peterson and co-workers noticed that solutions of the compound appeared to fluoresce under UV light. So recently, Peterson and J. Matthew Meinig decided to capitalize on the molecules’ intrinsic fluorescence to elucidate its mode of action ((2014) ACS Chem. Biol., DOI: 10.1021/cb500856c). When they imaged HeLa cells and Jurkat lymphocytes treated with AKTIV (1−5 μM) by confocal laser scanning microscopy, they found that AKTIV accumulated in high micromolar to millimolar concentrations in mitochondria. The AKTIVloaded mitochondria underwent depolarization and showed diminished respiration, release of reactive oxygen species, swelling, and disintegration. The authors concluded that © 2015 American Chemical Society
Adapted from Kumar et al. (2014) J. Am. Chem. Soc., DOI: 10.1021/ja510421q. Copyright 2014 American Chemical Society.
Theranostic molecules are multicomponent agents designed to selectively deliver therapeutic drugs to tumors while simultaneously enabling the monitoring of drug release and cancer progression. A team of researchers led by Jong-Hoon Kim and Jong Sueng Kim recently synthesized a theranoistic containing a tumor-targeting biotin moiety that allowed it to be more efficiently internalized into biotin-receptor-positive human lung cancer cells (A549 cells) than into biotin-receptor-negative human lung fibroblasts ((2014) J. Am. Chem. Soc., DOI: 10.1021/ja510421q). Once internalized, the theranostic was oxidatively cleaved by endogenous H2O2 to release 5′-deoxy-5fluorouridine (5′-DFUR). In turn, 5′-DFUR was converted into cytotoxic 5-fluorouracil (5′-FU) by thymidine phosphorylase, an enzyme present in high concentrations in carcinoma cells. The theranostic was also oxidatively cleaved to release ethidium, which produces a strong fluorescent signal upon intercalation into DNA. Published: January 20, 2015 2
dx.doi.org/10.1021/tx500523j | Chem. Res. Toxicol. 2015, 28, 2−3
Chemical Research in Toxicology
Spotlight
To the research team’s surprise, the fluorescence signal in cells treated with their theranostic was strongly localized to the mitochondria, hinting that the cytoxicity of the theranosticderived 5′FU was at least partially attributable to a mode of action other than the expected inhibition of nuclear DNA synthesis and repair. Sure enough, the team found that their theranositic-induced upregulation of mitochondria-mediated apoptotic genes and cell surface death receptors. Furthermore, the theranostic fluorescently labeled and significantly shrunk tumors in A549-inoculated xenograft mice, supporting the potential for theranostics to be applied in the early diagnosis and targeted treatment of cancer in humans. Heidi A. Dahlmann
The human genome contains over 3 billion base pairs divided among 23 paired chromosomes per cell. To confine a lot of DNA into a little bit of space, the negatively charged DNA condenses into chromatin with the assistance of positively charged histone proteins. Histone proteins H2A, H2B, H3, and H4 form octameric cores around which 145−147 base pairs wrap 1.6−1.7 times. The close electrostatic attraction between DNA and histone proteins is modulated by enzymatic alkylation or acetylation of the lysine-rich tails of histone proteins that protrude out of the nucleosome core particles. The nucleophilic residues in histone protein tails also interact with DNA abasic sites induced by antitumor therapeutics and other DNA damaging agents, catalyzing DNA strand cleavage. Previously described studies of DNA cleavage by histones with mutated nucleophilic tail residues indicated that five lysines and a single histidine in H4 all played a role in mediating DNA cleavage, but the relative contribution of each residue could not be determined. However, a new method developed by Marc M. Greenberg and co-workers has helped the research team to further quantify the extent to which these residues catalyze DNA cleavage ((2014) ACS Chem. Biol., DOI: 10.1021/cb500737y). The team prepared nucleosome core particles with DNA substrates containing phenylselenidemodified thymidine derivatives at specific sites. Upon oxidation under mild conditions, the thymidine derivatives are transformed into electrophilic species that form cross-links with nucleophilic histone residues. Kinetic analysis of the crosslinking reaction revealed the relative orders of reactivity for the nucleophilic histidine and lysine amino acids in the histone H4 tail. The authors anticipate that the cross-linking nucleoside probe will be useful in future investigations of DNA−protein interactions. Heidi A. Dahlmann
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DUAL METHOD FOR PREDICTING IMMUNOGENIC TUMOUR MUTATIONS On the surface of almost every cell in the body are major histocompatibility complex class 1 (MHC1) molecules which present fragments of cytosolic proteins from within the cell to cytotoxic T-cells (CD8+ cells) scanning the body for foreign antigens. CD8+ cells express T-cell receptors (TCRs) that recognize specific antigens; when a TCR finds its match, the CD8+ cell kills the cell bearing the target antigen. The human body uses this system to destroy not only damaged or virus-infected cells but certain cancer cells as well, setting the foundation for a type of cancer treatment called immunotherapy. A research team led by Jennie R. Lill and Léila Delamarre hypothesized that when CD8+ cells attack tumors, the immune cells are most likely responding to antigens derived from mutant tumor-specific proteins. The sheer volume of potential tumorspecific antigens precludes comprehensive experimental identification, so the team developed a two-pronged approach instead for predicting immunogenic tumor mutations ((2014) Nature, 515, 572−576). Focusing on two common murine tumor models, the research team sequenced the entire protein-coding portion of the tumor cell lines to identify tumor-specific point mutations and then used predictive software to determine whether the mutant protein products would produce epitopes capable of being presented by MHC1 molecules. Meanwhile, the team also used mass spectrometry to characterize tumor-cell-derived MHC1presented peptides and found that several peptides corresponded to those identified by exome-sequencing and epitope prediction. Ultimately, the team hypothesized that certain MHC1recognizable proteins bearing solvent-exposed mutations would act as antigens; indeed, vaccination of mice with their predicted antigens produced strong antitumor immunogenic responses. Heidi A. Dahlmann
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CROSS-LINKING REVEALS HOW HISTONE TAILS INTERACT WITH NUCLEOSOMAL DNA
Reprinted from Weng et al. (2014) ACS Chem. Biol., DOI: 10.1021/cb500737y. Copyright 2014 American Chemical Society. 3
dx.doi.org/10.1021/tx500523j | Chem. Res. Toxicol. 2015, 28, 2−3
