Accumulating evidence indicates that carbon nanotubes (CNTs) are biopersistent and can cause lung damage. With similar fibrous morphology and mode of exposure to asbestos, a known human carcinogen, growing concern has arisen for elevated risk of CNT-induced lung carcinogenesis; however, relatively little is known about the long-term carcinogenic effect of CNT. Neoplastic transformation is a key early event leading to carcinogenesis. We studied the ability of single- and multi-walled CNTs to induce neoplastic transformation of human lung epithelial cells compared to asbestos. Long-term (6-month) exposure of the cells to occupationally relevant concentrations of CNT in culture caused a neoplastic-like transformation phenotype as demonstrated by increased cell proliferation, anchorage-independent growth, invasion and angiogenesis. Whole-genome expression signature and protein expression analyses showed that single- and multi-walled CNTs shared similar signaling signatures which were distinct from asbestos. These results provide novel toxicogenomic information and suggest distinct particle-associated mechanisms of neoplasia promotion induced by CNTs and asbestos.

A growing body of evidence indicates that digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of digitoxin or synthetic analogs is still subject to study while concerns about digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.

Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or derivate analogs induce their cytotoxic effect below therapeutically relevant concentrations will help in designing and developing novel, safer and more effective anti-cancer drugs. In this study, NCI-H460 cells were treated with digitoxin and a synthetic analog D6-MA to determine their anti-cancer activity. Different concentrations of digitoxin and D6-MA were used and the subsequent changes in cell morphology, viability, cell cycle, and protein expressions were determined. Digitoxin and D6-MA induced dose-dependent apoptotic morphologic changes in NCI-H460 cells via caspase-9 cleavage, with D6-MA possessing 5-fold greater potentcy than digitoxin. In comparison, non-tumorigenic immortalized bronchial and small airway epithelial cells displayed significantly less apoptotic sensitivity compared to NCI-H460 cells suggesting that both digitoxin and D6-MA were selective for NSCLC. Furthermore, NCI-H460 cells arrested in G(2)/M phase following digitoxin and D6-MA treatment. Post-treatment evaluation of key G2/M checkpoint regulatory proteins identified down-regulation of cyclin B1/cdc2 complex and survivin. Additionally, Chk1/2 and p53 related proteins experienced down-regulation suggesting a p53-independent cell cycle arrest mechanism. In summary, digitoxin and D6-MA exert anti-cancer effects on NCI-H460 cells through apoptosis or cell cycle arrest, with D6-MA showing at least 5-fold greater potency relative to digitoxin.

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A stereochemically diverse array of monosaccharide analogues of the trisaccharide based cardiac glycoside natural product digitoxin has been synthesized using a de novo asymmetric approach. The analogues were tested for cytotoxicity against the NCI panel of 60 human cancer cell lines and in more detail against non-small cell human lung cancer cells (NCI-H460). The results were compared with digitoxin and its aglycone digitoxigenin. Three novel digitoxin monosaccharide analogues with β-d-digitoxose, α-l-rhamnose, and α-l-amicetose sugar moieties showed excellent selectivity and activity. Further investigation revealed that digitoxin α-l-rhamnose and α-l-amicetose analogues displayed similar anti-proliferation effects, but with at least 5-fold greater potency in apoptosis induction than digitoxin against NCI-H460. This study demonstrates the ability to improve the digitoxin anti-cancer activity by modification of the stereochemistry and substitution of the carbohydrate moiety of this known cardiac drug.

Given their extremely small size and light weight, carbon nanotubes (CNTs) can be readily inhaled by human lungs resulting in increased rates of pulmonary disorders, particularly fibrosis. Although the fibrogenic potential of CNTs is well established, there is a lack of consensus regarding the contribution of physicochemical attributes of CNTs on the underlying fibrotic outcome. We designed an experimentally validated in vitro fibroblast culture model aimed at investigating the effect of fiber length on single-walled CNT (SWCNT)-induced pulmonary fibrosis. The fibrogenic response to short and long SWCNTs was assessed via oxidative stress generation, collagen expression and transforming growth factor-beta (TGF-β) production as potential fibrosis biomarkers. Long SWCNTs were significantly more potent than short SWCNTs in terms of reactive oxygen species (ROS) response, collagen production and TGF-β release. Furthermore, our finding on the length-dependent in vitro fibrogenic response was validated by the in vivo lung fibrosis outcome, thus supporting the predictive value of the in vitro model. Our results also demonstrated the key role of ROS in SWCNT-induced collagen expression and TGF-β activation, indicating the potential mechanisms of length-dependent SWCNT-induced fibrosis. Together, our study provides new evidence for the role of fiber length in SWCNT-induced lung fibrosis and offers a rapid cell-based assay for fibrogenicity testing of nanomaterials with the ability to predict pulmonary fibrogenic response in vivo.

Recruitment is a key factor in benthic population dynamics, and spatial and temporal processes that affect settlement may determine recruitment; however, temporal processes are not well understood. We tested whether the date that recruits settle is a random sample within the settlement season by measuring daily settlement of the barnacle Semibalanus balanoides throughout the entire settlement season. A total of 2721 barnacle larvae settled during 89 d on 12 quadrats. Individual settlers were tracked to reproductive age (11 mo after settlement); only 8 survived to reproduction. Survivors settled within a narrow 21 d recruitment window, a period shorter than expected by chance. The concept of a recruitment window has broad implications in studying benthic recruitment and population dynamics. Focus on the recruitment window when it is narrow could simplify the study of recruitment, since fewer factors would have to be considered. KEY WORDS: Recruitment · Settlement · Intertidal ecology · BarnacleResale or republication not permitted without written consent of the publisher

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