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A celecoxib derivative inhibits focal adhesion signaling and induces caspase‐8‐dependent apoptosis in human acute myeloid leukemia cells
Author(s) -
Casanova Isolda,
Bosch Rosa,
Lasa Adriana,
Parreño Matilde,
Céspedes María Virtudes,
Brunet Salut,
Nomdedéu Josep F.,
Mangues María Antònia,
Sierra Jorge,
Mangues Ramon
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23516
Subject(s) - myeloid leukemia , apoptosis , cancer research , medicine , focal adhesion , leukemia , cell adhesion , programmed cell death , pharmacology , cytotoxic t cell , signal transduction , immunology , cell , chemistry , biology , microbiology and biotechnology , in vitro , biochemistry
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. © 2008 Wiley‐Liss, Inc.