Open Access

Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: Clinical and occupational implications

  • Authors:
    • Monica Lamberti
    • Stefania Porto
    • Silvia Zappavigna
    • Paola Stiuso
    • Virginia Tirino
    • Vincenzo Desiderio
    • Luigi Mele
    • Michele Caraglia
  • View Affiliations

  • Published online on: February 24, 2015     https://doi.org/10.3892/ijo.2015.2904
  • Pages: 1893-1900
  • Copyright: © Lamberti et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

5-Fluorouracil (5-FU), often used in combination with levofolene (LF), can induce, as an important side effect, the hand-foot syndrome (HFS) due to toxicity on keratinocytes. This can also damage workers involved in its handling. In the present study, we investigated the mechanisms of the toxicity induced by 5-FU alone or together with LF on human keratinocytes in culture. We found that the two drugs, as expected, had potentiating activity on keratinocyte growth inhibition and that this effect was mediated by induction of apoptosis. In our experimental model, an increased autophagic vacuole accumulation was observed in keratinocytes treated with 5-FU as a significant increase of the monodansylcadaverine (MDC) labeling (marker of late autophagy vacuoles) was recorded. However, the synergism of 5-FU with LF on apoptotic occurrence was not paralleled by a similar increase in autophagic vacuoles at 72 h suggesting an antagonistic effect of LF on autophagy elicited by 5-FU. Differential effects on reactive oxygen species (ROS) elevation in cells treated with 5-FU alone or the combination between 5-FU and LF were also observed. 5-FU induced a time-dependent increase of both O2- and lipid peroxidation while the combination of 5-FU and LF caused a stronger intracellular O2- increase only at 24 h while at 48 and 72 h its effect was lower when compared with that one of 5-FU alone. On the other hand, the addition of LF to 5-FU caused a stronger increase of lipid peroxidation at 48 and 72 h, but its effects were significantly lower at 24 h. These results suggest for the first time that LF potentiates the cytotoxicity of 5-FU on keratinocytes likely through the antagonism on autophagy escape pathway and consequent apoptosis potentiation.
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May-2015
Volume 46 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Lamberti M, Porto S, Zappavigna S, Stiuso P, Tirino V, Desiderio V, Mele L and Caraglia M: Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: Clinical and occupational implications. Int J Oncol 46: 1893-1900, 2015
APA
Lamberti, M., Porto, S., Zappavigna, S., Stiuso, P., Tirino, V., Desiderio, V. ... Caraglia, M. (2015). Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: Clinical and occupational implications. International Journal of Oncology, 46, 1893-1900. https://doi.org/10.3892/ijo.2015.2904
MLA
Lamberti, M., Porto, S., Zappavigna, S., Stiuso, P., Tirino, V., Desiderio, V., Mele, L., Caraglia, M."Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: Clinical and occupational implications". International Journal of Oncology 46.5 (2015): 1893-1900.
Chicago
Lamberti, M., Porto, S., Zappavigna, S., Stiuso, P., Tirino, V., Desiderio, V., Mele, L., Caraglia, M."Levofolene modulates apoptosis induced by 5-fluorouracil through autophagy inhibition: Clinical and occupational implications". International Journal of Oncology 46, no. 5 (2015): 1893-1900. https://doi.org/10.3892/ijo.2015.2904