A celecoxib derivative inhibits focal adhesion signaling and induces caspase-8-dependent apoptosis in human acute myeloid leukemia cells.
Most acute myeloid leukemias (AMLs), including those with c-Kit or FLT3 mutations, show enhanced anchorage independent growth associated with constitutive activation of focal adhesion proteins. Moreover, these alterations increase cell survival, inhibit apoptosis and are associated with poor prognosis and resistance to chemotherapy. Therefore, the induction of apoptosis by selective inhibition of focal adhesion signaling may represent a novel anti-AML therapy. Here, we have evaluated the antitumor effect and the mechanism of action of celecoxib and E7123, a non-Cox-2 inhibitor derivative, in a panel of human AML cell lines and bone marrow mononuclear cells from AML patients. Both compounds induce cell death by inhibiting focal adhesion signaling through p130Cas, FAK and c-Src, leading to caspase-8 dependent apoptosis. This mechanism of action differs from that of classical cytotoxic drugs or of other targeted therapies, and is amenable to rational drug development. Therefore, both drugs could be developed as AML therapeutics; nevertheless, E7123 shows more activity than celecoxib against AML cells, and may not present its Cox-2 dependent cardiovascular toxicity. Finally, our results support the evaluation of celecoxib in AML patients, and the preclinical evaluation of E7123, before its possible clinical testing.
Casanova
Isolda
I
Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
Bosch
Rosa
R
Lasa
Adriana
A
Parreño
Matilde
M
Céspedes
María Virtudes
MV
Brunet
Salut
S
Nomdedéu
Josep F
JF
Mangues
María Antònia
MA
Sierra
Jorge
J
Mangues
Ramon
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism*; D000068579:Celecoxib; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D022001:Focal Adhesions / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D000970:Antineoplastic Agents; D053181:Caspase 8; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; C529090:4-(5-(2,5-dimethylphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides