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

Federica Fratangelo, Rosa Camerlingo, Maria Vincenza Carriero, Giuseppe Pirozzi, Giuseppe Palmieri, Giusy Gentilcore, Concetta Ragone, Michele Minopoli, Paolo Antonio Ascierto, Maria Letizia Motti

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1149-1159
Number of pages11
JournalInternational Journal of Oncology
Volume53
Issue number3
DOIs
Publication statusPublished - 1 Sep 2018

Fingerprint

Melanoma
Apoptosis
Mutation
Cell Survival
veliparib
Fluorescein-5-isothiocyanate
Annexin A5
Prodrugs
Oncogenes
Actins
Therapeutics
Technology
Cell Line
Skin
Poly (ADP-Ribose) Polymerase-1

Keywords

  • ABT-888
  • BRAF inhibitor resistance
  • Melanoma
  • Poly(Adenosine diphosphate-ribose) polymerase 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fratangelo, F., Camerlingo, R., Carriero, M. V., Pirozzi, G., Palmieri, G., Gentilcore, G., ... Motti, M. L. (2018). Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells. International Journal of Oncology, 53(3), 1149-1159. https://doi.org/10.3892/ijo.2018.4457

Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells. / Fratangelo, Federica; Camerlingo, Rosa; Carriero, Maria Vincenza; Pirozzi, Giuseppe; Palmieri, Giuseppe; Gentilcore, Giusy; Ragone, Concetta; Minopoli, Michele; Ascierto, Paolo Antonio; Motti, Maria Letizia.

In: International Journal of Oncology, Vol. 53, No. 3, 01.09.2018, p. 1149-1159.

Research output: Contribution to journalArticle

Fratangelo, F, Camerlingo, R, Carriero, MV, Pirozzi, G, Palmieri, G, Gentilcore, G, Ragone, C, Minopoli, M, Ascierto, PA & Motti, ML 2018, 'Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells', International Journal of Oncology, vol. 53, no. 3, pp. 1149-1159. https://doi.org/10.3892/ijo.2018.4457
Fratangelo, Federica ; Camerlingo, Rosa ; Carriero, Maria Vincenza ; Pirozzi, Giuseppe ; Palmieri, Giuseppe ; Gentilcore, Giusy ; Ragone, Concetta ; Minopoli, Michele ; Ascierto, Paolo Antonio ; Motti, Maria Letizia. / Effect of ABT-888 on the apoptosis, motility and invasiveness of BRAFi-resistant melanoma cells. In: International Journal of Oncology. 2018 ; Vol. 53, No. 3. pp. 1149-1159.
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