Open Access

Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells

  • Authors:
    • Federica Fratangelo
    • Rosa Camerlingo
    • Maria Vincenza Carriero
    • Giuseppe Pirozzi
    • Giuseppe Palmieri
    • Giusy Gentilcore
    • Concetta Ragone
    • Michele Minopoli
    • Paolo Antonio Ascierto
    • Maria Letizia Motti
  • View Affiliations

  • Published online on: June 27, 2018     https://doi.org/10.3892/ijo.2018.4457
  • Pages: 1149-1159
  • Copyright: © Fratangelo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Melanoma is a molecularly heterogeneous disease with many genetic mutations and altered signaling pathways. Activating mutations in the BRAF oncogene are observed in approximately 50% of cutaneous melanomas and the use of BRAF inhibitor (BRAFi) compounds has been reported to improve the outcome of patients with BRAF-mutated metastatic melanoma. However, the majority of these patients develop resistance within 6-8 months following the initiation of BRAFi treatment. In this study, we examined the possible use of the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, ABT-888 (veliparib), as a novel molecule that may be successfully employed in the treatment of BRAFi-resistant melanoma cells. Sensitive and resistant to BRAFi dabrafenib A375 cells were exposed to increasing concentrations of ABT-888. Cell viability and apoptosis were assessed by MTT assay and Annexin V-FITC analysis, respectively. The cell migratory and invasive ability was investigated using the xCELLigence technology and Boyden chamber assays, respectively. ABT-888 was found to reduce cell viability and exhibited pro-apoptotic activity in melanoma cell lines, independently from the BRAF/NRAS mutation status, in a dose-dependent manner, with the maximal effect being reached in the 25-50 µM concentration range. Moreover, ABT-888 promoted apoptosis in both the sensitive and resistant A375 cells, suggesting that ABT-888 may be useful in the treatment of BRAFi-resistant subsets of melanoma cells. Finally, in accordance with the involvement of PARP1 in actin cytoskeletal machinery, we found that the cytoskeletal organization, motility and invasive capability of both the A375 and A375R cells decreased upon exposure to 5 µM ABT-888 for 24 h. On the whole, the findings of this study highlight the pivotal role of PARP1 in the migration and invasion of melanoma cells, suggesting that ABT-888 may indeed be effective, not only as a pro-apoptotic drug for use in the treatment of BRAFi-resistant melanoma cells, but also in suppressing their migratory and invasive activities.
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September-2018
Volume 53 Issue 3

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

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Spandidos Publications style
Fratangelo F, Camerlingo R, Carriero M, Pirozzi G, Palmieri G, Gentilcore G, Ragone C, Minopoli M, Ascierto P, Motti M, Motti M, et al: Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells. Int J Oncol 53: 1149-1159, 2018
APA
Fratangelo, F., Camerlingo, R., Carriero, M., Pirozzi, G., Palmieri, G., Gentilcore, G. ... Motti, M. (2018). Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells. International Journal of Oncology, 53, 1149-1159. https://doi.org/10.3892/ijo.2018.4457
MLA
Fratangelo, F., Camerlingo, R., Carriero, M., Pirozzi, G., Palmieri, G., Gentilcore, G., Ragone, C., Minopoli, M., Ascierto, P., Motti, M."Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells". International Journal of Oncology 53.3 (2018): 1149-1159.
Chicago
Fratangelo, F., Camerlingo, R., Carriero, M., Pirozzi, G., Palmieri, G., Gentilcore, G., Ragone, C., Minopoli, M., Ascierto, P., Motti, M."Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells". International Journal of Oncology 53, no. 3 (2018): 1149-1159. https://doi.org/10.3892/ijo.2018.4457