title: Pleiotropic effects of spongean alkaloids on mechanisms of cell death, cell cycle progression and DNA damage response (DDR) of acute myeloid leukemia (AML) cells.
abstract: We investigated cytotoxic mechanisms evoked by the spongean alkaloids aaptamine (Aa) and aeroplysinin-1 (Ap), applied alone and in combination with daunorubicin, employing acute myeloid leukemia (AML) cells. Aa and Ap reduced the viability of AML cells in a dose dependent manner with IC50 of 10-20 µM. Ap triggered apoptotic cell death more efficiently than Aa. Both alkaloids increased the protein level of S139-phosphorylated H2AX (γH2AX), which however was independent of the induction of DNA damage. Expression of the senescence markers p21 and p16 was increased, while the phosphorylation level of p-Chk-2 was reduced following Aa treatment. As a function of dose, Aa and Ap protected or sensitized AML cells against daunorubicin. Protection by Aa was paralleled by reduced formation of ROS and lower level of DNA damage. Both Aa and Ap attenuated daunorubicin-stimulated activation of the DNA damage response (DDR) as reflected on the levels of γH2AX, p-Kap-1 and p-Chk-1. Specifically Ap restored the decrease in S10 phosphorylation of histone H3 resulting from daunorubicin treatment. The cytoprotective effects of Aa and Ap were independent of daunorubicin import/export. Both Aa and Ap abrogated daunorubicin-induced accumulation of cells in S-phase. Inhibition of DNA synthesis was specific for Ap. The data show that Aa and Ap have both congruent and agent-specific pleiotropic effects that are preferential for anticancer drugs. Since Ap showed a broader spectrum of anticancer activities, this compound is suggested as novel lead compound for forthcoming in vivo studies elucidating the usefulness of spongean alkaloids in AML therapy.
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany; Institute of Molecular Medicine I, Heinrich Heine University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Stuhldreier
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf Universitätsstrasse 1, Düsseldorf 40225, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kassel
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Schumacher
authors.affiliation: Institute of Molecular Medicine I, Heinrich Heine University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.affiliation: Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf Universitätsstrasse 1, Düsseldorf 40225, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Proksch
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, Düsseldorf 40225, Germany. Electronic address: fritz@uni-duesseldorf.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000097:Acetonitriles / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D053138:Cyclohexenes / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D003630:Daunorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D009287:Naphthyridines / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000097:Acetonitriles; D000903:Antibiotics, Antineoplastic; D053138:Cyclohexenes; D009287:Naphthyridines; D017382:Reactive Oxygen Species; C042151:aeroplysinin I; C043986:aaptamine; D003630:Daunorubicin
keywords: Acute myeloid leukemia; Anthrayclines; Cell death; DNA damage response; Natural compounds; Spongean alkaloids