Abstract
Imidazoacridinone 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor inhibitor of topoisomerase II and FMS-like tyrosine kinase 3 receptor. In this study, we describe the unique sequence of cellular responses to C-1311 in human non-small cell lung cancer (NSCLC) cell lines, A549 and H460. In A549 cells, C-1311 (IC80 = 0.08 µM) induced G1 and G2/M arrests, whereas H460 cells (IC80 = 0.051 µM) accumulated predominantly in the G1 phase. In both cell lines, cell cycle arrest was initiated by overexpression of p53 but was sustained for an extended time by elevated levels of p21. Despite prolonged drug exposure (up to 192 hours), no apoptotic response was detected in either cell line. Instead, cells developed a senescent phenotype and did not resume proliferation even after 2 weeks of post-treatment, indicating that C-1311–triggered senescence was permanent. When cell cycle arrest was evident but there were no signs of senescence, C-1311 significantly induced autophagic cells. Pharmacological inhibition of autophagy by 3-methyladenine profoundly reduced the senescent phenotype and slightly sensitized cancer cells to C-1311 by increasing cell death, suggesting a link between both autophagy and senescence. However, a small interfering RNA–mediated knockdown of the autophagy-associated Beclin 1 and ATG5 genes attenuated but failed to block development of senescence. Taken together, our studies suggest that in NSCLC, a C-1311–induced senescence program is preceded and corroborated but not exclusively determined by the induction of autophagy.
Footnotes
- Received February 8, 2013.
- Accepted July 2, 2013.
J.P. and A.S. contributed equally to this work.
This work was supported by the Polish State Committee for Scientific Research [Grant N401 202039]; and the European Union European Social Fund [Framework of the InnoDoktorant Scholarship for Ph.D. students, I edition (to J.P.)].
Parts of this work were previously presented and published in the following abstracts: Koprowska J, Augustin E, Nowak-Ziatyk D, Konopa J (2008) Antitumor imidazoacridinone derivative C-1311 induces cell cycle arrest and cellular senescence-like phenotypic changes in human non-small lung A549 cancer cells. Acta Biochim Polonica 55 (Suppl 1):135; Koprowska J, Skwarska A, Augustin E, Konopa J (2010) Imidazoacridinone C-1311 induces both autophagy and senescence in human lung cancer A549 cells. Acta Biochim Polonica 57 (Suppl 1):63; and Polewska J, Skwarska A, Augustin E, Konopa J (2011) Autophagy mediates imidazoacridinone C-1311-induced senescence in human non-small lung cancer cells. FEBS J 278 (Suppl 1):228–229.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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