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The current options for treating human cancer are limited to excision surgery, general chemotherapy, radiation therapy and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. Although there has been considerable improvement in the treatment of cancer, the overall prognosis remains not good. Therefore, investigators continue to search for new therapeutic strategies. One approach, as pursued in our study, seeks to identify medicinal agents capable of retarding the cell cycle and/or activating the cellular apoptotic response in the cancerous cells.Recently, we have shown that a number of antifungal agents exert antiproliferative and/or apoptotic activities in various malignant cells in vitro and in vivo. For instance, our previous studies showed that ketoconazole (Nizoral) induced cell cycle arrest at the G0/G1 phase of the cell cycle and the occurrence of apoptosis in hepatoma and colon cancer cells, 1,2 whereas griseofulvin (Grifulvin) induced apoptosis and cell cycle arrest at the G2/M phase through abnormal microtubule polymerization. 3 We also showed that combined treatment of griseofulvin and nocodazole (ND) significantly enhanced the therapeutic efficacy in the treatment of cancerous cells in athymic mice bearing COLO 205 tumor xenografts. 3 In the present study, we examined the antitumoral activity of terbinafine (TB) (Lamisil).TB is a newly synthesized oral antimycotic drug in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. 4 It shows a good safety profile and relatively few drug interactions. 5 The cream form and oral tablet of TB have been approved for clinical uses in the United States. 6 The oral formulation has been on the market in various countries for more than 8 years, and as of 1997, more than 7.5 million individuals had been treated with this drug. 7 Here, we showed that TB inhibited the proliferation of tumor cells in vitro and in vivo. The experimental findings reported below highlight the molecular mechanisms of TB-induced antitumoral activity. MATERIAL AND METHODS Cell lines and cell cultureThe HT 29 (p53 mutant) 8 and COLO 205 (p53 wild) 9 cell lines were isolated from human colon adenocarcinoma (American Type

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths globally. Due to the lack of successful chemopreventive agents for lung cancer, there is an emerging need to evaluate new and effective agents for lung cancer prevention. Pterostilbene, a naturally occurring analogue of resveratrol, has been reported to be an effective chemopreventive agent against many cancers. The aim of this study is to investigate the chemopreventive effects of pterostilbene in urethane-induced murine lung tumors. Pretreatment with pterostilbene at 50 or 250 mg/kg significantly reduced tumor multiplicity by 26 and 49%, respectively. Pterostilbene also significantly inhibited tumor volume by 25 and 34% and decreased the tumor burden per mouse by 45 and 63%, respectively. The mechanisms by which pterostilbene suppresses lung tumorigenesis have been investigated in lung tissues and homogenates. The results indicate that the pterostilbene-mediated chemopreventive effects in vivo were a result of the inhibition of epidermal growth factor receptor (EGFR) and its downstream pathways, leading to retarded cell cycle progression, and of the induction of apoptosis and autophagy during urethane-induced lung tumorigenesis.

Cellular senescence is characterized by permanent cell cycle arrest, triggered by a variety of stresses, such as telomerase inhibition, and it is recognized as a tumor-suppressor mechanism. In recent years, telomerase has become an important therapeutic target in several cancers; inhibition of telomerase can induce senescence via the DNA damage response (DDR). Pterostilbene (PT), a dimethyl ether analog of resveratrol, possesses a variety of biological functions, including anticancer effects; however, the molecular mechanisms underlying these effects are not fully understood. In this study, we investigated the possible mechanisms of PT-induced senescence through telomerase inhibition in human non-small cell lung cancer cells and delineated the role of p53 in senescence. The results indicated that PT-induced senescence is characterized by a flattened morphology, positive staining for senescence-associated-β galactosidase activity, and the formation of senescence-associated heterochromatic foci. Telomerase activity and protein expression was significantly decreased in H460 (p53 wild type) cells compared with H1299 (p53 null) cells and p53 knockdown H460 cells (H460-p53-). A more detailed mechanistic study revealed that PT-induced senescence partially occurred via a p53-dependent mechanism, triggering inhibition of telomerase activity and protein expression, and leading to the DDR, S phase arrest and, finally, cellular senescence. This study is the first to explore the novel anticancer mechanism of PT senescence induction via the inhibition of telomerase in lung cancer cells.

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Inflammatory skin diseases are the most common problem in dermatology. The induction of skin inflammation by environmental stressors such as ultraviolet radiation (UVR), hexavalent chromium (Cr(VI)) and TiO2/ZnO/Ag nanoparticles (NPs) has been demonstrated previously. Recent studies have indicated that the inflammasome is often wrongly activated by these environmental irritants, thus inducing massive inflammation and resulting in the development of inflammatory diseases. The regulation of the inflammasome with respect to skin inflammation is complex and is still not completely understood. Autophagy, an intracellular degradation system that is associated with the maintenance of cellular homeostasis, plays a key role in inflammasome inactivation. As a housekeeping pathway, cells utilize autophagy to maintain the homeostasis of the organ structure and function when exposed to environmental stressors. However, only a few studies have examined the effect of autophagy and/or the inflammasome on skin pathogenesis. Here we review recent findings regarding the involvement of autophagy and inflammasome activation during skin inflammation. We posit that autophagy induction is a novel mechanism inter-modulating environmental stressor-induced skin inflammation. We also attempt to highlight the role of the inflammasome and the possible underlying mechanisms and pathways reflecting the pathogenesis of skin inflammation induced by UVR, Cr(VI) and TiO2/ZnO/Ag NPs. A more profound understanding about the crosstalk between autophagy and the inflammasome will contribute to the development of prevention and intervention strategies against human skin disease.

Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.