Inhibition of cell survival and invasive potential of colorectal carcinoma cells by the tyrosine kinase inhibitor STI571.
Inhibiting tyrosine kinases has recently emerged as a therapeutic modality in several forms of neoplasia. The tyrosine kinase inhibitor STI571 (IMATINIB MESYLATE; GLEEVEC; GLIVEC) is a case in point as it has shown promise in the treatment of malignancies expressing the BCR/ABL fusion protein. In addition to BCR/ABL, STI571 inhibits the tyrosine kinase moieties of several cell surface receptors including the platelet-derived growth factor (PDGF) receptors and c-Kit. Previous work demonstrated that c-Kit activation supports migration, invasion and, survival of certain colorectal carcinoma cells including DLD-1. Here we describe that blocking c-Kit with STI571 inhibits these malignant traits not only in DLD-1 cells but also in two early passage colorectal carcinoma cell strains. Specifically, STI571 inhibited anchorage-independent colony formation and cell scattering in semi-solid medium. Furthermore, it enhanced apoptosis susceptibility and abrogated invasion of DLD-1 cells through Matrigel. In addition, STI571 treatment affected the balance of the Bcl-2 family of apoptosis regulators on favor of a pro-apoptotic phenotype. Specifically, STI571 treatment of DLD-1 cells was associated with lower levels of Bcl-2 expression accompanied by de novo expression of Bcl-xS. Finally, STI571 acted as a chemosensitizing agent in DLD-1 cells when used in combination with 5-fluorouracil.
Bellone
Graziella
G
Department of Clinical Physiopathology, University of Torino, Torino, Italy. graziella.bellone@unito.it
Ferrero
Dario
D
Carbone
Anna
A
De Quadros
Marlene R
MR
Gramigni
Claudia
C
Prati
Adriana
A
Davidson
William
W
Mioli
Pierroberto
P
Dughera
Luca
L
Emanuelli
Giorgio
G
Rodeck
Ulrich
U
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002277:Carcinoma / Q000473:pathology*; D002450:Cell Communication; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D010879:Piperazines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001549:Benzamides; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases