Understanding arsenic carcinogenicity by the use of animal models

Although numerous epidemiological studies have indicated that human arsenic exposure is associated with increased incidences of bladder, liver, skin, and lung cancers, limited attempts have been made to understand mechanisms of carcinogenicity using animal models. Dimethylarsinic acid (DMA), an organic arsenic compound, is a major metabolite of ingested inorganic arsenics in mammals. Recent in vitro studies have proven DMA to be a potent clastogenic agent, capable of inducing DNA damage including double strand breaks and cross-link formation. In our attempts to clarify DMA carcinogenicity, we have recently shown carcinogenic effects of DMA and its related metabolites using various experimental protocols in rats and mice: (1) a multi-organ promotion bioassay in rats; (2) a two-stage promotion bioassay by DMA of rat urinary bladder and liver carcinogenesis; (3) a 2-year carcinogenicity test of DMA in rats; (4) studies on the effects of DMA on lung carcinogenesis in rats; (5) promotion of skin carcinogenesis by DMA in keratin (K6)/ornithine decarboxylase (ODC) transgenic mice; (6) carcinogenicity of DMA in p53(+/-) knockout and Mmh/8-OXOG-DNA glycolase (OGG1) mutant mice; (7) promoting effects of DMA and related organic arsenicals in rat liver; (8) promoting effects of DMA and related organic arsenicals in a rat multi-organ carcinogenesis test; and (9) 2-year carcinogenicity tests of monomethylarsonic acid (MMA) and trimethylarsine oxide (TMAO) in rats. The results revealed that the adverse effects of arsenic occurred either by promoting and initiating carcinogenesis. These data, as covered in the present review, suggest that several mechanisms may be involved in arsenic carcinogenesis.     

A comparison of thyroxine- and polyamine-mediated enhancement of rat facial nerve regeneration

Thyroid hormones and spermidine, a motor neuron trophic polyamine (PA), have been shown to enhance peripheral motor nerve regeneration; however, the mechanism by which these treatment modalities exert their effect is unknown. Similarities in treatment outcome suggest that these molecules may be working via a common mechanism. Such an explanation is plausible since thyroid hormone is a potent inducer of ornithine decarboxylase (ODC), which is the rate-limiting enzyme involved in polyamine synthesis. This study was designed to morphologically evaluate the effects of exogenous thyroxine and spermidine on the regeneration of the rat facial nerve. Myelinated fiber density, axonal size, and degree of myelination were assayed by light and electron microscopy 21 days following facial nerve crush. Strikingly, the two treatment modalities had identical effects on all parameters tested. Each significantly enhanced the density of myelinated axons in regenerating nerves relative to the vehicle control. In addition, relative to the control treatment, both thyroxine and spermidine significantly increased the cross-sectional area of regenerating axons (P < 0.05). Interestingly, neither of the drug treatments had any effect on remyelination at the position where this parameter was analyzed. The concurrent administration of both thyroxine and spermidine did not synergistically enhance motor neuron regeneration. These data support the hypothesis that thyroxine and spermidine enhance neural regeneration by a common mechanism.     

Structure-activity relations of s-adenosylmethionine decarboxylase inhibitors on the growth of MCF-7 breast cancer cells

Summary SAMDC is a key enzyme in the biosynthesis of spermidine and spermine, 2 polyamines that are essential for cell proliferation. Inhibition of polyamine biosynthesis is often targeted as a therapeutic strategy to suppress cancer cell growth as these cells contain elevated levels of polyamines. We examined the effect of a new group of SAMDC inhibitors, CGP33829, CGP35753, CGP36958, CGP39937, and CGP48664, (obtained from CibaGeigy, Basel, Switzerland), and their parent compound, MGBG, on the proliferation of MCF-7 breast cancer cells. MGBG had minimal effects on the proliferation of MCF-7 cells up to 6 µM concentration. In contrast, CGP48664 and CGP39937, containing 2 aromatic rings that delocalize the electron system of the backbone of MGBG, were potent inhibitors with 50% growth inhibition at 0.5 µM concentration. Other CGP compounds were less effective in inhibiting cell growth. The ability of CGP48664 to inhibit MCF-7 cell proliferation was related to its ability to inhibit SAMDC and to consequently deplete spermidine and spermine levels in the cell. Exogenous spermidine and spermine could reverse the growth inhibitory effects of this compound. CGP compounds also increased the activity of ODC, another enzyme involved in polyamine biosynthesis. Northern blot analysis of mRNA from MCF-7 cells progressing in cell cycle after G1 synchronization did not show an increase in ODC mRNA level by CGP48664. These data demonstrate structure-activity relationships of a series of MGBG derivatives on cell growth, enzyme activities, and polyamine biosynthesis in a hormoneresponsive breast cancer cell line and suggest potential application of SAMDC inhibitors as therapeutic agents.     

鸟氨酸脱羧酶与食管鳞癌血管生成相关性的研究

目的 研究ODc mRNA和MVD在食管鳞癌中的表达及相关关系,探讨ODC在食管鳞癌血管生成中的可能作用及其与肿瘤浸润和转移的关系。方法 研究对象为41例经手术和病理证实的食管鳞癌患者,用RT-PCR方法测定癌组织和相应癌旁正常组织的ODC mRNA表达,以β-actin做内参照求得各自T/N值;用免疫组化方法测定癌组织和癌旁正常组织的MVD的T/N值。结果 在41例中,39例ODc mRNA的T/N值>1.0,占95.1％;40例MVD的T/N值>1.0,占97.6％。ODC mRNA和MVD与食管鳞癌的肿瘤大小、浸润深度和淋巴结转移有关,ODC mRNA与肿瘤分化程度有关。ODC mRNA的T/N值与MVD的T/N值正相关。结论 ODC与食管鳞癌血管生成和肿瘤浸润转移密切相关。ODC可能是通过影响血管生成而促进食管鳞癌的浸润和转移。     

Relationship between ornithine decarboxylase-inducing activity and configuration at C-4 in phorbol ester derivatives

Summary Measurements were made of induction of ornithine decarboxylase activity after painting mouse skin with 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate and its two epimeric 4-deoxy-analogs, 12-O-hexadecanoyl-4-deoxy-16-hydroxyphorbol-13-acetate and 12-O-hexadecanoyl-4-deoxy-4-16-hydroxyphorbol-13-acetate. The inductive activities of HHPA and 4-deoxy-HHPA were similar, but 4-deoxy-4-HHPA had no inductive activity. These findings on natural phorbol esters confirm that both the 4-hydrogen and the 4-hydroxyl in phorbol esters are essential for ODC-inducing activity. The interactions of 4-deoxy-HHPA and 4-deoxy-4-HHPA with a possible receptor are discussed.Abbreviations ODC ornithine decarboxylase - TPA 12-O-tetradecanoylphorbol-13-acetate - PDD phorbol-12,13-didecanoate - HHPA 12-O-hexandecanoyl-16-hydroxyphorbol-13-acetate - 4-deoxy-HHPA 12-O-hexadecanoyl-4-deoxy-16-hydroxyphorbol-13-acetate - 4-deoxy-4-HHPA 12-O-hexadecanoyl-4-deoxy-4-16-hydroxyphorbol-13-acetate This work was supported by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare and the Ministry of Education, Science, and Culture of Japan     

Therapeutic targets for neuroblastomas

Introduction: Neuroblastoma (NB) is the most common and deadly solid tumor in children. Despite recent improvements, the long-term outlook for high-risk NB is still < 50%. Further, there is considerable short- and long-term toxicity. More effective, less toxic therapy is needed, and the development of targeted therapies offers great promise.

Areas covered: Relevant literature was reviewed to identify current and future therapeutic targets that are critical to malignant transformation and progression of NB. The potential or actual NB therapeutic targets are classified into four categories: i) genes activated by amplification, mutation, translocation or autocrine overexpression; ii) genes inactivated by deletion, mutation or epigenetic silencing; iii) membrane-associated genes expressed on most NBs but few other tissues; or iv) common target genes relevant to NB as well as other tumors.

Expert opinion: Therapeutic approaches have been developed to some of these targets, but many remain untargeted at the present time. It is unlikely that single targeted agents will be sufficient for long-term cure, at least for high-risk NBs. The challenge will be how to integrate targeted agents with each other and with conventional therapy to enhance their efficacy, while simultaneously reducing systemic toxicity.     

党参、黄芪化学组份对IEC-6细胞增殖、ODC及hephaestin表达的影响

目的:研究党参提取物D8、黄芪注射液和黄芪甲苷对IEC-6细胞增殖、ODC及hephaestin蛋白表达的影响,探讨益气健脾中药对小肠隐窝细胞的药理作用.方法:培养大鼠小肠隐窝细胞IEC-6,药物刺激24 h,3H-TdR法检测药物对细胞增殖的影响;药物刺激12 h,用ELISA法检测细胞ODC、hephaestin蛋白的表达.结果:党参D8与黄芪注射液、黄芪甲苷能部分促进细胞的增殖及ODC和hephaestin蛋白的表达.结论:党参与黄芪化学组份对IEC-6细胞具有明显的药理作用.     

Radiofrequency radiation does not significantly affect ornithine decarboxylase activity,proliferation, or caspase-3 activity of fibroblasts in different physiological conditions

Purpose: The aim of this study was to test the hypothesis that variations in the physiological state of cells explain inconsistent results from in vitro studies on biological effects of radiofrequency (RF) radiation.

Materials and methods: Murine L929 fibroblasts stimulated with fresh medium, stressed with serum deprivation or not subjected to stimulation or stress were exposed in a waveguide exposure chamber to 872 MHz continuous wave or pulse modulated (217 pulses per second) RF radiation at specific absorption rate of 5 W/kg. Ornithine decarboxylase (ODC) activity after 1-and 24-h exposures, proliferation during 48 h after 24 h exposure, and caspase-3 activity (a measure of apoptosis) after 1 h exposure were measured.

Results: The cells responded to fresh medium and serum deprivation, but no consistent effects of RF radiation were found. One statistically significant (p = 0.03) RF radiation-related difference was observed in ODC activity, but this is most likely a chance finding, as many statistical comparisons were performed, and the finding was not supported by any other data.

Conclusions: The results did not support effects on the endpoints studied. Furthermore, stressed and stimulated cells were not more sensitive than normal cells to possible RF radiation-induced effects.     

The genus Commiphora: a review of its traditional uses, phytochemistry and pharmacology

Ethnopharmacological relevance

The resinous exudates of the Commiphora species, known as ‘myrrh’, are used in traditional Chinese medicine for the treatment of trauma, arthritis, fractures and diseases caused by blood stagnation. Myrrh has also been used in the Ayurvedic medical system because of its therapeutic effects against inflammatory diseases, coronary artery diseases, gynecological disease, obesity, etc.

Aim of the review

Based on a comprehensive review of traditional uses, phytochemistry, pharmacological and toxicological data on the genus Commiphora, opportunities for the future research and development as well as the genus’ therapeutic potential are analyzed.

Methods

Information on the Commiphora species was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar and Web of Science) and a library search for articles published in peer-reviewed journals. Furthermore, information also was obtained from some local books on ethnopharmacology. This paper covers the literature, primarily pharmacological, from 2000 to the end of December 2011.

Results

The resinous exudates from the bark of plants of the genus Commiphora are important indigenous medicines, and have a long medicinal application for arthritis, hyperlipidemia, pain, wounds, fractures, blood stagnation, in Ayurvedic medicine, traditional Chinese medicine and other indigenous medical systems. Phytochemical investigation of this genus has resulted in identification of more than 300 secondary metabolites. The isolated metabolites and crude extract have exhibited a wide of in vitro and in vivo pharmacological effects, including antiproliferative, antioxidant, anti-inflammatory and antimicrobial. The bioactive steroids guggulsterones have attracted most attention for their potent hypolipidemic effect targeting farnesoid X receptor, as well as their potent inhibitory effects on tumor cells and anti-inflammatory efficiency.

Conclusions

The resins of Commiphora species have emerged as a good source of the traditional medicines for the treatment of inflammation, arthritis, obesity, microbial infection, wound, pain, fractures, tumor and gastrointestinal diseases. The resin of C. mukul in India and that of C. molmol in Egypt have been developed as anti-hyperlipidemia and antischistosomal agents. Pharmacological results have validated the use of this genus in the traditional medicines. Some bioassays are difficult to reproduce because the plant materials used have not been well identified, therefore analytical protocol and standardization of extracts should be established prior to biological evaluation. Stem, bark and leaf of this genus should receive more attention. Expansion of research materials would provide more opportunities for the discovery of new bioactive principles from the genus Commiphora.