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CARBON NANOTUBE TOXICITY: A CAUTIONARY TALE The silicate-based, fire-resistant insulator asbestos has become notorious for its ability to induce malignant lung cancers such as mesothelioma following prolonged inhalation of the material’s submicrometer scale fibers. Over 100 years since asbestos use boomed in manufacturing and building industries, certain asbestos-containing products are closely regulated or banned outright in some countries. Today, researchers are taking care to ensure that history does not repeat itself by evaluating the toxicity of a different class of nanoscale fibers: carbon nanotubes (CNTs), which are currently used in electronics and medicine, among other applications. Like asbestos fibers, CNTs (which may be single-walled (SW) or multiwalled (WT)) have a high aspect ratio. They also pose a similar occupational risk as an inhalation hazard and induce mesothelioma in animal models. Researchers led by Yon Rojanasakul recently investigated the underlying mechanisms of CNT-induced mesothelioma by studying the impact of CNTs on proliferation, migration (movement of cells from one location to another), and invasion (penetration of cells through an extracellular matrix, one of the hallmarks of malignancy) of human lung cells exposed to noncytotoxic concentrations of CNTs over a four-month period ((2013) ACS Nano, 7, 7711−7723). They observed that after 16 weeks, the growth rate of cells treated with SWCNTs, MWCNTs, or asbestos was significantly higher than that of control cells. Furthermore, the treated cells were more migratory and invasive than control cells, the latter property resulting from increased expression of the extracellular matrixdegrading enzyme MMP2. Therefore, the authors urge that prevention strategies and exposure controls be implemented for people handling CNTs. Heidi A. Dahlmann
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ALDOSE REDUCTASE DETOXIFIES CARNOSINE-ACROLEIN CONJUGATES
Aldehydes are generated in cells as products of unsaturated fatty acid peroxidation, protein glycation, and amino acid oxidation. Generally, aldehyde moieties are subject to attack by cellular nucleophiles, particularly amines (histidine, lysine, arginine residues in proteins, and guanosine residues in DNA) and thiols (such as glutathione). Furthermore, α,β-unsaturated aldehydes can undergo Michael addition to generate β-substituted aldehydes that are susceptible to further alkylation, potentially resulting in harmful protein and DNA cross-links. Alternatively, aldehyde Michael addition products can be detoxified via reduction by the enzyme aldose reductase (AR), which produces unreactive primary alcohols. One α,β-unsaturated aldehyde of particular concern is acrolein, which is both produced in cells (by the pathways listed above) and present in cooked foods, tobacco smoke, and car exhaust. Acrolein was previously known to undergo Michael addition with carnosine (histidyl-β-alanine), an endogenous dipeptide that appears to protect against heart tissue injury, neurodegenerative diseases, and aging. However, until recently, the metabolic fate of the carnosine− acrolein conjugates (i.e., carnosine-propanal) was unclear. Therefore, in their recent work Aruni Bhatnagar and co-workers ((2013) J. Biol. Chem., 288, 28163−28179) used LC-MS/MS to track the reduction of carnosine-propanal by AR to form carnosine-propanol in isolated enzyme systems, in tissue homogenates, and in mice. The observation that AR-null mice had higher levels of proteins bound to carnosine than did wild-type mice prompted the researchers to conclude that AR is a critical regulator of protein carnosinylation and that the enzyme can prevent tissue injury caused by protein modification by carnosine-propanals. Heidi A. Dahlmann © 2013 American Chemical Society
HYDROPHOBICITY DRIVES DUOCARMYCIN BINDING AND CYTOTOXICITY
Adapted from Wolfe et al. (2013) J. Med. Chem., 56, 6845− 6857. Copyright 2013 American Chemical Society. The Streptomyces-derived natural product duocarmycin SA and its synthetic derivates display antitumor activity derived from their ability to alkylate DNA and thus create cytotoxic DNA lesions. In solution, duocarmycins are unreactive, but upon selectively associating with the minor groove in AT-rich regions of DNA, the compounds undergo a conformational change that activates their cyclopropane group for attack by the nucleophilic N3-position of adenine. Notably, seco-phenol synthetic precursors to duocarmycin possess identical bioactivity to their natural-product counterparts, indicating that they readily undergo spirocyclization to generate the cyclopropane group prior to binding to and alkylating DNA. Recently, researchers led by Dale L. Boger ((2013) J. Med. Chem., 56, 6845−6857) attempted to improve the water solubility of the seco-phenol duocarmycin SA precursor by incorporating polyethylene glycol (PEG) chains at the 5-, 6-, and 7-postions of the molecule’s trimethoxyindole subunit. As the water solubility of the precursors increased with progressive addition Published: November 18, 2013 1600
dx.doi.org/10.1021/tx4003897 | Chem. Res. Toxicol. 2013, 26, 1600−1601
Chemical Research in Toxicology
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of PEG units, their cytoxicity and DNA-alkylation efficiency (AE) decreased such that remarkably linear correlations between cLogP vs −log IC50 and −log AE were observed. The authors rationalize these findings by noting that duocarmycin association with duplex DNA is driven by hydrophobic interactions that stabilize the noncovalent complexes prior to alkylation. Heidi A. Dahlmann
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Every day, cellular DNA is exposed to reactive oxygen and nitrogen species (RONS) derived from inflammatory responses or even simply from normal cellular respiration. Deoxyguanosine (dG) residues are particularly susceptible to oxidation by RONS, which transforms the nucleoside into 8-oxo-dG as well as the further oxidized lesions guanidinohydantoin (Gh) and spiroiminodihydantion (Sp) lesions. These lesions induce G-toC and G-to-T transversion mutations, but fortunately, they can be repaired via cellular DNA damage responses. In one such pathway, base excision repair (BER), DNA glycosylases extrude and excise damaged nucleobases; in another pathway, nucleotide excision repair (NER), protein complexes bind to DNA lesions and excise short oligonucleotides containing the lesion. Traditionally, it was believed that BER repaired subtle DNA alkylation adducts, while NER repaired bulky and helixdestabilizing lesions. For example, Gh and Sp lesions are both substrates for several BER glycosylases. However, hydantoin derivatives can occur via reaction with nucleophilic amino acids to form DNA−protein cross-links, and the susceptibility of these hydantoin adducts to be repaired was unknown. New research by Sheila S. David and co-workers shows that hydantoin adducts (specifically Sp conjugated with lysine, glucosamine, and tetramer or hexamer peptide fragments) are indeed recognized and repaired by both NER and BER enzymes ((2013) J. Am. Chem. Soc., 135, 13851−13861). As expected, the efficiency of NER-mediated repair increased with increasing size of the lesion. Surprisingly, the BER glycosylase NEIL1 readily excised the lesions regardless of their size. The authors note that due to the mutagenicity and toxicity of hydantoin and hydantoin-peptide lesions, it is important that overlapping mechanisms are available for their repair. Heidi A. Dahlmann
OSMIUM COMPLEXES: DIFFERENT LIGANDS, DIFFERENT TARGETS
Adapted from Suntharalingam et al. (2013) J. Am. Chem. Soc., 135, 14060−14063. Copyright 2013 American Chemical Society.
The administration of DNA-damaging drugs that cause cytotoxic DNA lesions is a tried-and-true approach for treating cancer. Among the frontline DNA-damaging agents are transition metalbased compounds such as cisplatin, carboplatin, and oxaliplatin. Aside from these platinum-based drugs, ruthenium- and titaniumbased compounds have also been studied and evaluated in clinical trials. However, osmium-based compounds have traditionally been overlooked in drug development due to the inherent toxicity of the metal. However, the occasional failure of platinum-based drugs due to resistance, dangerous side effects, or tumor recurrence has prompted the consideration of osmium compounds as an alternative. The bioactivity of a series of osmium(VI) nitride complexes bearing bidentate ligands has recently been studied by Stephen J. Lippard and co-workers ((2013) J. Am. Chem. Soc., 135, 14060− 14063). Of the compounds tested, those bearing either the 1,10phenanthroline or the bulkier 4,7-diphenyl-1,10-phenanthroline ligand were the most cytotoxic toward cisplatin-sensitive and cisplatinresistant ovarian tumor cells. Surprisingly, the two compounds displayed completely different modes of action; whereas the smaller 1,10-phenanthroline-bearing complex partitioned equally in the nucleus and cytoplasm and induced apoptosis triggered by DNA damage, the larger 4,7-diphenyl-1,10-phenanthroline-bearing complex localized predominantly in the cytoplasm and induced endoplasmic reticulum (ER) stress, which activated the unfolded protein response(UPR) and ultimately led to apoptosis. The authors note that the latter mode of action is unprecedented among previously reported osmium agents, most of which induce cell death by damaging DNA. Heidi A. Dahlmann
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HYDANTOIN LESIONS REPAIRED BY MULTIPLE MECHANISMS
Adapted from McKibbin et al. (2013) J. Am. Chem. Soc., 135, 13851−13861. Copyright 2013 American Chemical Society. 1601
dx.doi.org/10.1021/tx4003897 | Chem. Res. Toxicol. 2013, 26, 1600−1601
