title: Azidothymidine hinders arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells by induction of p21 and attenuation of G2/M arrest.
abstract: To enhance anticancer efficacy of the arsenic trioxide (ATO), the combination of ATO and azidothymidine (AZT), with convergence anti-telomerase activity, were examined on acute promyelocytic leukemia (APL) cell line, NB4. In spite of an induction of apoptosis by both drugs separately and a synergistic effect of them on hTERT down-regulation and telomerase inhibition, the ATO-induced cytotoxicity was reduced when it was used in combination with AZT. AZT attenuated the ATO effects on viability, metabolic activity, DNA synthesis, and apoptosis. These observations, despite the deflection from the main goal of this study, dedicate an especial opportunity to elucidate the importance of some of the mechanisms that have been suggested by which ATO induces apoptosis. Cell cycle distribution, ROS level, and caspase-3 activation analyses suggest that AZT reduced the ATO-induced cytotoxic effect possibly via relative induction and diminution of cells accumulated in (G1, S) and (G2/M) phase, respectively, as well as through attenuation of ROS generation and subsequent caspase-3 inhibition. QRT-PCR assay revealed that induction of p21expression by the combined AZT/ATO compared to ATO alone could be a reason for the relative decline of cells accumulation in G2/M and the increase of cells in G1 and S phases. Therefore, the G2/M arrest and ROS generation are likely principle mediators for the ATO-induced apoptosis and can be used as a guide to design rational combinatorial strategies involving ATO and agents with G2/M arrest or ROS generation capacity to intensify ATO-induced apoptosis.
authors: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
authors: Saeed
authors: S
authors: Hassani
authors: Seyed H
authors: SH
authors: Ghaffari
authors: Farhad
authors: F
authors: Zaker
authors: Rohellah
authors: R
authors: Mirzaee
authors: Hajar
authors: H
authors: Mardani
authors: Davood
authors: D
authors: Bashash
authors: Ali
authors: A
authors: Zekri
authors: Meysam
authors: M
authors: Yousefi
authors: Azam
authors: A
authors: Zaghal
authors: Kamran
authors: K
authors: Alimoghaddam
authors: Ardeshir
authors: A
authors: Ghavamzadeh
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000502:physiology; D010087:Oxides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015215:Zidovudine / Q000627:therapeutic use*
chemical_list: D001152:Arsenicals; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010087:Oxides; D015215:Zidovudine; D000077237:Arsenic Trioxide