Characterisation of cytotoxicity and DNA damage induced by the topoisomerase II-directed bisdioxopiperazine anti-cancer agent ICRF-187 (dexrazoxane) in yeast and mammalian cells

BACKGROUND: Bisdioxopiperazine anti-cancer agents are inhibitors of eukaryotic DNA topoisomerase II, sequestering this protein as a non-covalent protein clamp on DNA. It has been suggested that such complexes on DNA represents a novel form of DNA damage to cells. In this report, we characterise the cytotoxicity and DNA damage induced by the bisdioxopiperazine ICRF-187 by a combination of genetic and molecular approaches. In addition, the well-established topoisomerase II poison m-AMSA is used for comparison. RESULTS: By utilizing a panel of Saccharomyces cerevisiae single-gene deletion strains, homologous recombination was identified as the most important DNA repair pathway determining the sensitivity towards ICRF-187. However, sensitivity towards m-AMSA depended much more on this pathway. In contrast, disrupting the post replication repair pathway only affected sensitivity towards m-AMSA. Homologous recombination (HR) defective irs1SF chinese hamster ovary (CHO) cells showed increased sensitivity towards ICRF-187, while their sensitivity towards m-AMSA was increased even more. Furthermore, complementation of the XRCC3 deficiency in irs1SF cells fully abrogated hypersensitivity towards both drugs. DNA-PK(cs )deficient V3-3 CHO cells having reduced levels of non-homologous end joining (NHEJ) showed slightly increased sensitivity to both drugs. While exposure of human small cell lung cancer (SCLC) OC-NYH cells to m-AMSA strongly induced γH2AX, exposure to ICRF-187 resulted in much less induction, showing that ICRF-187 generates fewer DNA double strand breaks than m-AMSA. Accordingly, when yeast cells were exposed to equitoxic concentrations of ICRF-187 and m-AMSA, the expression of DNA damage-inducible genes showed higher levels of induction after exposure to m-AMSA as compared to ICRF-187. Most importantly, ICRF-187 stimulated homologous recombination in SPD8 hamster lung fibroblast cells to lower levels than m-AMSA at all cytotoxicity levels tested, showing that the mechanism of action of bisdioxopiperazines differs from that of classical topoisomerase II poisons in mammalian cells. CONCLUSION: Our results point to important differences in the mechanism of cytotoxicity induced by bisdioxopiperazines and topoisomerase II poisons, and suggest that bisdioxopiperazines kill cells by a combination of DNA break-related and DNA break-unrelated mechanisms

Field emissions of N2O during biomass production may affect the sustainability of agro-biofuels

Field emissions of N2O during cultivation of bioenergy crops may counterbalance a considerable part of the avoided fossil CO2 emissions that are achieved by fossil fuel displacemen

Effective interactions and large-scale diagonalization for quantum dots

The widely used large-scale diagonalization method using harmonic oscillator basis functions (an instance of the Rayleigh-Ritz method, also called a spectral method, configuration-interaction method, or ``exact diagonalization'' method) is systematically analyzed using results for the convergence of Hermite function series. We apply this theory to a Hamiltonian for a one-dimensional model of a quantum dot. The method is shown to converge slowly, and the non-smooth character of the interaction potential is identified as the main problem with the chosen basis, while on the other hand its important advantages are pointed out. An effective interaction obtained by a similarity transformation is proposed for improving the convergence of the diagonalization scheme, and numerical experiments are performed to demonstrate the improvement. Generalizations to more particles and dimensions are discussed.Comment: 7 figures, submitted to Physical Review B Single reference error fixe

Combination of ensiling and fungal delignification as effective wheat straw pretreatment

BACKGROUND: Utilization of lignocellulosic feedstocks for bioenergy production in developing countries demands competitive but low-tech conversion routes. White-rot fungi (WRF) inoculation and ensiling are two methods previously investigated for low-tech pretreatment of biomasses such as wheat straw (WS). This study was undertaken to assess whether a combination of forced ensiling with Lactobacillus buchneri and WRF treatment using a low cellulase fungus, Ceriporiopsissubvermispora, could produce a relevant pretreatment effect on WS for bioethanol and biogas production. RESULTS: A combination of the ensiling and WRF treatment induced efficient pretreatment of WS by reducing lignin content and increasing enzymatic sugar release, thereby enabling an ethanol yield of 66 % of the theoretical max on the WS glucan, i.e. a yield comparable to yields obtained with high-tech, large-scale pretreatment methods. The pretreatment effect was reached with only a minor total solids loss of 5 % by weight mainly caused by the fungal metabolism. The combination of the biopretreatments did not improve the methane potential of the WS, but improved the initial biogas production rate significantly. CONCLUSION: The combination of the L. buchneri ensiling and C. subvermispora WRF treatment provided a significant improvement in the pretreatment effect on WS. This combined biopretreatment produced particularly promising results for ethanol production. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13068-016-0437-x) contains supplementary material, which is available to authorized users