Antiproliferative effects of phenylaminonaphthoquinones are increased by ascorbate and associated with the appearance of a senescent phenotype in human bladder cancer cells

Bettega Felipe, Karina;Benites, Julio;Glorieux, Christophe;Sid, Brice;Buc Calderon, Pedro;et.al.
(2013) Biochemical and Biophysical Research Communications — Vol. 433, n° 4, p. 573-578 (2013)

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Authors
  • Bettega Felipe, Karina
    Author
  • Benites, Julio
    Author
  • Glorieux, ChristopheUCLouvain
    Author
  • Sid, BriceUCLouvain
    Author
  • Valenzuela Valderrama, Manuel AlejandroUCLouvain
    Author
  • Levêque, PhilippeUCLouvain
    Author
  • Gallez, Bernardorcid-logoUCLouvain
    Author
  • Verrax, JulienUCLouvain
    Author
  • Buc Calderon, PedroUCLouvain
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Abstract
Quinone-containing molecules have been developed against cancer mainly for their redox cycling ability leading to reactive oxygen species (ROS) formation. We have previously shown that donor-acceptor phenylaminonaphthoquinones are biologically active against a panel of cancer cells. In this report, we explored the mechanisms involved in cancer cell growth inhibition caused by two phenylaminonaphthoquinones, namely Q7 and Q9, with or without ascorbate (ASC). The results show that Q7 and Q9 are both redox cyclers able to form ROS, which strongly inhibit the proliferation of T24 cells. Q9 was a better redox cycler than Q7 because of marked stabilization of the semiquinone radical species arising from its reduction by ascorbate. Indeed, ASC dramatically enhances the inhibitory effect of Q9 on cell proliferation. Q9 plus ASC impairs the cell cycle, causing a decrease in the number of cells in the G2/M phase without involving other cell cycle regulating key proteins. Moreover, Q9 plus ASC influences the MAPK signaling pathways, provoking the appearance of a senescent cancer cell phenotype and ultimately leading to necrotic-like cell death. Because cellular senescence limits the replicative capacity of cells, our results suggest that induction of senescence may be exploited as a basis for new approaches to cancer therapy. © 2013 Elsevier Inc.
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Bettega Felipe, K., Benites, J., Glorieux, C., Sid, B., Valenzuela Valderrama, M. A., Kviecinski, M. R., Pedrosa, R. C., Valderrama, J. A., Levêque, P., Gallez, B., Verrax, J., & Buc Calderon, P. (2013). Antiproliferative effects of phenylaminonaphthoquinones are increased by ascorbate and associated with the appearance of a senescent phenotype in human bladder cancer cells. Biochemical and Biophysical Research Communications, 433(4), 573-578. https://doi.org/10.1016/j.bbrc.2013.03.028 (Original work published 2013)