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

Summary 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 case...

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Bibliographic Details
Published in:Investigational new drugs 2014-08, Vol.32 (4), p.626-635
Main Authors: Barollo, Susi, Bertazza, Loris, Baldini, Enke, Ulisse, Salvatore, Cavedon, Elisabetta, Boscaro, Marco, Pezzani, Raffaele, Mian, Caterina
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis - drug effects
Biological and medical sciences
Cancer therapies
Cell culture
Cell cycle
Cell Cycle - drug effects
Cell division
Cell Line, Tumor
Cell Proliferation - drug effects
Cloning
Drug dosages
Drug Synergism
Drug therapy
Drugs
Endocrinopathies
Humans
Imidazoles - administration & dosage
Inhibitor drugs
Iodine
Kinases
Malignant tumors
Medical research
Medical sciences
Medicine
Medicine & Public Health
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - metabolism
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Mutation
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Oncology
Penicillin
Pharmacology. Drug treatments
Pharmacology/Toxicology
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Preclinical Studies
Proto-Oncogene Proteins B-raf - metabolism
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Proto-Oncogene Proteins c-akt - metabolism
Pyridines - administration & dosage
Regression analysis
Signal Transduction - drug effects
Thyroid cancer
Thyroid Neoplasms - drug therapy
Thyroid Neoplasms - metabolism
Thyroid. Thyroid axis (diseases)
Triazines - administration & dosage
Tumors
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Summary:Summary 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.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-014-0108-3