title: Study of Bioreductive Anticancer Agent RH-1-Induced Signals Leading the Wild-Type p53-Bearing Lung Cancer A549 Cells to Apoptosis.
abstract: Aziridinylquinone RH-1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-cyclohexa-2,5-diene-1,4-dione) is a potential anticancer agent. RH-1 action is associated with
  quinone oxidoreductase (NQO1) which reduces this diaziridinylbenzoquinone into DNA-alkylating hydroquinone and is overexpressed in many tumors. Another suggested mechanism of RH-1 toxicity is the formation of reactive oxygen species (ROS) arising from its redox cycling. In order to improve anticancer action of this and similar antitumor quinones, we investigated the involvement of different signaling molecules in cytotoxicity induced by RH-1 by using wild-type tumor suppressor p53 bearing nonsmall cell lung carcinoma A549 cells as a model. Gradual and prolonged increase of mitogen-activated protein kinases (MAPK) ERK, P38, and JNK phosphorylation was observed during 24-h RH-1 treatment. In parallel, activation of DNA damage-sensing ATM kinase, upregulation, and phosphorylation of TP53 (human p53) took place. Inhibition studies revealed that RH-1-induced A549 apoptosis involved the NQO1-ATM-p53 signaling pathway and ROS generation. TP53 participated in ROS- and DNA damage-induced cell death differently. Moreover, MAP kinase JNK was another TP53 activator and death inducer in A549 cells. At the same time, rapid and prolonged activation of AKT kinase during RH-1 treatment was found, and it proved to be antiapoptotic kinase in our model system. Therefore, we identified that different and opposite cell death regulating signaling pathways, which may counteract one another, are induced in cancer cells during chemotherapeutic RH-1 treatment.
authors.affiliation: Vilnius University Institute of Biochemistry , Mokslininku st. 12, LT-08662 Vilnius, Lithuania.
authors.forename: Aurimas
authors.initials: A
authors.lastname: Stulpinas
authors.affiliation: Vilnius University Institute of Biochemistry , Mokslininku st. 12, LT-08662 Vilnius, Lithuania.
authors.forename: Aušra
authors.initials: A
authors.lastname: Imbrasaitė
authors.affiliation: Vilnius University Institute of Biochemistry , Mokslininku st. 12, LT-08662 Vilnius, Lithuania.
authors.forename: Natalija
authors.initials: N
authors.lastname: Krestnikova
authors.affiliation: Vilnius University Institute of Biochemistry , Mokslininku st. 12, LT-08662 Vilnius, Lithuania.
authors.forename: Jonas
authors.initials: J
authors.lastname: Šarlauskas
authors.affiliation: Vilnius University Institute of Biochemistry , Mokslininku st. 12, LT-08662 Vilnius, Lithuania.
authors.forename: Narimantas
authors.initials: N
authors.lastname: Čėnas
authors.affiliation: Vilnius University Institute of Biochemistry , Mokslininku st. 12, LT-08662 Vilnius, Lithuania.
authors.forename: Audronė Valerija
authors.initials: AV
authors.lastname: Kalvelytė
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001388:Aziridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053138:Cyclohexenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C000612301:2,5-diaziridinyl-3-hydroxymethyl-6-methyl-cyclohexa-2,5-diene-1,4-dione; D000970:Antineoplastic Agents; D001388:Aziridines; D053138:Cyclohexenes; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt