Sequence-dependent formation of alkyl DNA adducts: A review of methods, results, and biological correlates

Understanding the influence of the DNA sequence on chemical-DNA interactions may provide insight into the processes of chemical carcinogenesis and mutagenesis. This article provides a brief overview of studies and methods devoted to examining the distribution of DNA adducts produced by alkylating agents. Particular emphasis is placed on discussion of DNA adducts generated by simple alkylating agents and the role that their distribution may play in the generation of mutational hotspots.     

In vitro effect of fungal cyclodepsipeptides on leukemic cells: study of destruxins A, B and E.

The activities of three mycotoxins isolated from the hyphomycete Metarhizium anisopliae: destruxin A, B, and E (DA, DB and DE) are described and compared in vitro on leukemic cells. Their antitumor effect was investigated by flow cytometry on growth, cell viability and cell cycle perturbation 48 h after destruxin exposure. Against P388 leukemic cells, DE displayed greater antiproliferative activity than DA and DB. The minimum concentration required to inhibit 50% of cell proliferation is 0.33 microgram/ml for DE, 11.7 micrograms/ml for DA and 9.4 micrograms/ml for DB. Cell cycle modifications were only observed with DE at 50 and 10 micrograms/ml and consisted in an accumulation of the cells in G0/1 phase. DA and DB did not modify the number of cells in G0/1 of the cell cycle. Nevertheless a decrease in the number of cells in G2+M phase was induced by the three destruxins.     

Design,synthesis, and biological evaluation of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-Indole-2-Carbohydrazide derivatives: the methuosis inducer 12A as a Novel and selective anticancer agent

This study describes the synthesis and vacuole-inducing activity of 5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)-1H-indole-2-carbohydrazide derivatives, including five potent derivatives 12c, 12 g, 12i, 12n, and 12A that exhibit excellent vacuole-inducing activity. Remarkably, 12A effectively induces methuosis in tested cancer cells but not human normal cells. In addition, 12A exhibits high pan-cytotoxicity against different cancer cell lines but is hardly toxic to normal cells. It is found that the 12A-induced vacuoles are derived from macropinosomes but not autophagosomes. The 12A-induced cytoplasmic vacuoles may originate from the endoplasmic reticulum (ER) and be accompanied by ER stress. The MAPK/JNK signalling pathway is involved in the 12A-induced methuotic cell death. Moreover, 12A exhibits significant inhibition of tumour growth in the MDA-MB-231 xenograft mouse model. The excellent potency and selectivity of 12A prompt us to select it as a good lead compound for further development of methuosis inducers and investigation of the molecular and cellular mechanisms underlying methuosis.