Effects of chemopreventive natural products on non-homologous end-joining DNA double-strand break repair.

Double-strand breaks (DSBs) may result from endogenous (e.g., reactive oxygen species, variable (diversity) joining, meiotic exchanges, collapsed replication forks, nucleases) or exogenous (e.g., ionizing radiation, chemotherapeutic agents, radiomimetic compounds) events. DSBs disrupt the integrity of DNA and failed or improper DSBs repair may lead to genomic instability and, eventually, mutations, cancer, or cell death. Non-homologous end-joining (NHEJ) is the major pathway used by higher eukaryotic cells to repair these lesions. Given the complexity of NHEJ and the number of proteins and cofactors involved, secondary metabolites from medicinal or food plants might interfere with the process, activating or inhibiting repair. Twelve natural products, arbutin, curcumin, indole-3-carbinol, and nine flavonoids (apigenin, baicalein, chalcone, epicatechin, genistein, myricetin, naringenin, quercetin, sakuranetin) were chosen for their postulated roles in cancer chemoprevention and/or treatment. The effects of these compounds on NHEJ were investigated with an in vitro protocol based on plasmid substrates. Plasmids were linearized by a restriction enzyme, generating cohesive ends, or by a combination of enzymes, generating incompatible ends; plasmids were then incubated with a nuclear extract prepared from normal human small-intestinal cells (FHS 74 Int), either treated with these natural products or untreated (controls). The NHEJ repair complex from nuclear extracts ligates linearized plasmids, resulting in plasmid oligomers that can be separated and quantified by on-chip microelectrophoresis. Some compounds (chalcone, epicatechin, myricetin, sakuranetin and arbutin) clearly activated NHEJ, whereas others (apigenin, baicalein and curcumin) significantly reduced the repair rate of both types of plasmid substrates. Although this in vitro protocol is only partly representative of the in vivo situation, the natural products appear to interfere with NHEJ repair and warrant further investigation.

Methods applied to the in vitro primary toxicology testing of natural products: state of the art, strengths, and limits.

The present review attempts to build up a comprehensive picture of the major primary techniques used to screen and assess the cytotoxicity of plant complex mixtures. These can be based on metabolic activity, on membrane integrity, on morphological features, on cell growth; the type of cell death can also be established from more or less specific events (e.g., apoptosis, autophagy, DNA damage detection, reactive oxygen species involvement). This review will discuss the benefits, the difficulties, and the challenges that may occur along cytotoxicity testing of raw extracts and isolated natural compounds.

Potential genotoxicity of traditional chinese medicinal plants and phytochemicals: an overview.

In the last decades, cases of poisoning due to herbal medicines have occurred in many countries; Chinese herbal medicines (CHMs) are occasionally involved. The experience gained from traditional use is efficient to detect immediate or near-immediate relationship between administration and toxic effects but is quite unlikely to detect medium- to long-term toxicities; thorough investigations of herbal medicines (toxicity assessments, active pharmacovigilance) appear then essential for their safe use. Genotoxicity is an especially insidious toxicity that may result in carcinoma development years after exposure; it can arise from multiple compounds, with or without metabolic activation. The present work reviews traditional CHMs and phytochemicals that have been shown to present a genotoxic hazard.

Synthesis and plasma pharmacokinetics in CD-1 mice of a 18ß-glycyrrhetinic acid derivative displaying anti-cancer activity.

OBJECTIVES: The plasma pharmacokinetic profile in CD-1 mice of a novel 18ß-glycyrrhetinic acid (GA) derivative, which displays in vitro anti-cancer activity, was assessed. METHODS: This study involved an original one-step synthesis of N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide, (2) a compound that displays marked anti-proteasome and anti-kinase activity. The bioselectivity profile of 2 on human normal NHDF fibroblasts vs human U373 glioblastoma cells was assessed. Maximal tolerated dose (MTD) profiling of 2 was carried out in CD1 mice, and its serum pharmacokinetics were profiled using an acute intravenous administration of 40 mg/kg body weight. KEY FINDINGS: Compound 2 displayed IC(50) in vitro growth inhibitory concentrations of 29 and 8 µm on NHDF fibroblasts and U373 glioblastoma cells, respectively, thus a bioselectivity index of ∼4. The intravenous pharmacokinetic parameters revealed that 2 was rapidly distributed (t(1/2dist) of ∼3 min) but slowly eliminated (t(1/2elim) = ∼77 min). CONCLUSIONS: This study describes an original and reliable nanoemulsion of a GA derivative with both anti-proteasome and anti-kinase properties and that should be further tested in vivo using various human xenograft or murine syngeneic tumour models with both single and chronic intravenous administration.

Arsenic levels in tube-wells water, food, residents' urine and the prevalence of skin lesions in Yatenga province, Burkina Faso.

The aim of the present study was to evaluate the levels of arsenic in tube-well water, food and residents' urines samples in Yatenga province, Burkina Faso. The prevalence of skin lesions was evaluated as well. The study was cross-sectional in design. It was conducted during April 2009. Permanent residents of 20 villages were included in the study. Water samples were collected from 31 tube-wells located in the selected villages. Tomatoes, cabbages, and potatoes produced in the selected village were randomly sampled. Arsenic content in water, food, and residents' urine was determined by atomic absorption spectrophotometry using hydride generation method. Finally, 240 people were examined by a medical doctor for skin lesions. Arsenic concentrations from the tube-well water ranged from 1 to 124 µg/l. Arsenic concentrations of more than one-half (52%) of the water samples exceeded the WHO guideline value (10 µg/l). No trace of arsenic was found in the samples of tomatoes, cabbages, and potatoes. Variation in arsenic concentrations in the urines was correlated to arsenic concentrations in tube-well water. Clinical examinations revealed that melanosis and keratosis were respectively identified in 29.26% and 46.34% of the population. Both conditions were observed in 24.39% of the population. The frequency of skin lesions was positively associated with the arsenic concentration in tube-well water. A great majority (89.53%) of those who had skin lesions were at least 18 years old. In conclusion, chronic arsenic poisoning remains a major public health problem in the province of Yatenga (Burkina Faso).

An overview of cancer chemopreventive potential and safety of proanthocyanidins.

Cancer is a major public health problem worldwide. Over two-thirds of cancer-related deaths could most probably be prevented through lifestyle modification, particularly through dietary means. Proanthocyanidins (PAs), the most abundant polyphenolic substances after lignin in the plant kingdom, have been widely investigated for their chemopreventive potential. The PAs literature has, however, been mostly concerned with positive cardiovascular activities, and recent reviews about cancer chemoprevention are scarce. The present review highlights a series of in vitro and in vivo studies indicating ( 1 ) that PAs can act as anticarcinogenic agents through their antioxidant, apoptosis-inducing, immuno-modulating, and/or enzyme modulating properties, effects on epigenetics; and ( 2 ) that PAs could be particularly safe dietary compounds. These convergent data encourage further research to better understand the many aspects of cancer chemoprevention by PAs.

In vitro cytotoxicity study of oxaziridines generated after chlordiazepoxide, demoxepam, and desmethylchlordiazepoxide UV irradiation.

The cytotoxicity of oxaziridines photogenerated after irradiation of chlordiazepoxide (CDZ) and its metabolites was investigated in vitro by a MTT assay on P388 leukemia and B16 melanoma cell lines and compared with that of the anticancer drug, melphalan. For the longer time-exposure experiment, oxaziridines had the same cytotoxicity as melphalan and this toxicity was higher when oxaziridines were photogenerated in the presence of cells. In conclusion, oxaziridines generated after CDZ, demoxepam, and desmethylchlordiazepoxide ultraviolet irradiation exhibited cytotoxicity activity against cancer cell lines. A possibility of CDZ use within the context of photodynamic therapy as a treatment for small, superficial tumors should not be excluded, because oxaziridines can be generated locally by skin-tumor local irradiation after CDZ topical administration.