Therapeutic potential of nvp-bkm120 in human osteosarcomas cells

Alberto Bavelloni, Enrico Focaccia, Manuela Piazzi, Arianna Orsini, Giulia Ramazzotti, Lucio Cocco, William Blalock, Irene Faenza

Research output: Contribution to journalArticle

Abstract

Osteosarcoma (OS) is the most common pediatric malignant neoplasia of the skeletal system. It is characterized by a high degree of malignancy and a severe tendency to metastasize. In the past decade, many studies have provided evidence that the phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer, and has a critical role in driving tumor initiation and progression. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120, which has recently entered clinical Phase II for treatment of PI3K-dependent cancers on three OS cell lines. We observed a concentration- and time-dependent decrease of Ser473 p-Akt as well as reduced levels of Thr37/46 p-4E-BP1, an indicator of the mammalian target of rapamycin complex 1 activity. All OS cell lines used in this study responded to BKM120 treatment with an arrest of cell proliferation, an increase in cell mortality, and an increase in caspase-3 activity. MG-63 cells were the most responsive cell line, demonstrating a significant increase in sub-G1 cells, and a rapid induction of cell death. Furthermore, we demonstrate that BKM120 is more effective when used in combination with other standard chemotherapeutic drugs. Combining BKM120 with vincristine demonstrated a more synergistic effect than BKM120 with doxorubicin in all the lines. Hence, we suggest that BKM120 may be a novel therapy for the treatment of OS presenting with anomalous upregulation of the PI3K signaling pathway.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalJournal of Cellular Physiology
DOIs
Publication statusE-pub ahead of print - Dec 7 2018

Keywords

  • Akt
  • BKM120
  • cell death
  • hemotherapeutic drugs
  • Osteosarcomas

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