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The combination of RAF265, SB590885, ZSTK474 on thyroid cancer cell lines deeply impact on proliferation and MAPK and PI3K/Akt signaling pathways.

Abstract
Papillary thyroid cancer (PTC) is the most frequent thyroid cancer entity, accounting for 88 % of cases. It may metastasize and loose iodine uptake capability, preventing any radioiodine or surgical treatment. The main gene altered in PTC is BRAF, which is found altered in over 50 % of cases. Moreover MAPK and PI3K/Akt pathways are greatly implicated in PTC development. Many target therapies for PTC are currently under investigation, unfortunately without the expected results. Aim of this study was to characterized the preclinical effectiveness of novel promising drugs, RAF265, SB590885 and ZSTK474 in 3 thyroid cancer cell lines (BCPAP, K1, 8505C). RAF265 and SB590885 target differentially BRAF, while ZSTK474 acts on PI3K. IC50 demonstrated high drug activities ranging from 0.1 to 6.2 μM, depending on drugs and cell type, while combination index revealed an interesting synergistic effect of combination regimen (RAF265 + ZSTK474 and SB590885 + ZSTK474) in almost all cell lines. Moreover this synergistic effect was particularly evident by Western blot, whereas dual MAPK and PI3K/Akt inhibition was detected. In addition, treating cells with SB590885 induced marked morphological changes, leading to massive vacuolization. This suggests an activation of apoptotic process, as underlined by Annexin V flow cytometry analysis. Also cell cycle was altered in treated cells, without evidence of a common pattern, but rather with a more specific effect relying on single drug or combination regimen used. Since beneficial effects of in vitro combination regimen (RAF265 + ZSTK474 and SB590885 + ZSTK474), it is recommended additional investigation. These data suggest the potential use of combination regimen in in vivo experiment or afterwards in human PTC.
AuthorsSusi Barollo, Loris Bertazza, Enke Baldini, Salvatore Ulisse, Elisabetta Cavedon, Marco Boscaro, Raffaele Pezzani, Caterina Mian
JournalInvestigational new drugs (Invest New Drugs) Vol. 32 Issue 4 Pg. 626-35 (Aug 2014) ISSN: 1573-0646 [Electronic] United States
PMID24821574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Triazines
  • ZSTK474
  • RAF265
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
Topics
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Drug Synergism
  • Humans
  • Imidazoles (administration & dosage)
  • Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf (metabolism)
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
  • Pyridines (administration & dosage)
  • Signal Transduction (drug effects)
  • Thyroid Neoplasms (drug therapy, metabolism)
  • Triazines (administration & dosage)

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