CLM29 and CLM24, pyrazolopyrimidine derivatives, have antitumoral activity in vitro in anaplastic thyroid cancer, with or without BRAF mutation.
We have studied the antitumor activity of two new "pyrazolo[3,4-d]pyrimidine" compounds (CLM29 and CLM24) that inhibit several targets (including the RET tyrosine kinase, epidermal growth factor receptor, vascular endothelial growth factor receptor, with an antiangiogenic effect) in primary anaplastic thyroid cancer (ATC) cell cultures and in the human cell line 8305C (undifferentiated thyroid cancer). The antitumor effect of CLM29 and CLM24 was tested in: nine primary ATC cultures obtained from patients at the time of surgery at the concentrations of 1, 5, 10, 30, 50 µM; in 8305C cells at 1, 5, 10, 30, 50 µM for CLM29, and 0.001, 0.01, 0.1, 1, 10, 100 µM for CLM24. CLM29, and CLM24 significantly inhibited the proliferation of 8305C cells. A significant reduction of proliferation with CLM29 and CLM24 in ATC cells (P < 0.01, for both, ANOVA) was shown. CLM29 and CLM24 increased the percentage of apoptotic ATC cells dose-dependently (P < 0.001, ANOVA). The (V600E) BRAF mutation was observed in three ATCs; the results about the inhibition of proliferation by CLM29 and CLM24, obtained in ATC from tumors with (V600E) BRAF mutation were similar to those from tumors without BRAF mutation. CLM29 inhibited migration and invasion (P < 0.01) of primary ATC cells, while CLM24 had no significant effect. The antitumor activity of two new "pyrazolo[3,4-d]pyrimidine" compounds (CLM24, CLM29) in vitro in ATC, independent from BRAF mutation, has been shown, allowing a future clinical evaluation.
Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126, Pisa, Italy.
Poupak
P
Fallahi
Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126, Pisa, Italy.
Silvia Martina
SM
Ferrari
Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, Pisa, Italy.
Concettina
C
La Motta
Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi 10, Pisa, Italy.
Gabriele
G
Materazzi
Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126, Pisa, Italy.|Istituto Toscano Tumori, Via Alderotti 27/n, Florence, Italy.
Guido
G
Bocci
Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, Pisa, Italy.
Federico
F
Da Settimo
Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Savi 10, Pisa, Italy.
Paolo
P
Miccoli
Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126, Pisa, Italy. alessandro.antonelli@med.unipi.it.
Alessandro
A
Antonelli
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D000970:Antineoplastic Agents; C556684:CLM29 compound; D011720:Pyrazoles; D011743:Pyrimidines; D048493:Proto-Oncogene Proteins B-raf
Anaplastic thyroid cancer; CLM24; CLM29; Tyrosine kinases inhibitors; V600E BRAF mutation