Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of β-catenin and mTORC1/2.
CML is effectively treated with tyrosine kinase inhibitors (TKIs). However, the efficacy of these drugs is confined to the chronic phase of the disease and development of resistance to TKIs remains a pressing issue. The anti-inflammatory COX2 inhibitor celecoxib has been utilized as anti-tumour drug due to its anti-proliferative activity. However, its effects in hematological malignancies, in particular CML, have not been investigated yet. Thus, we tested biological effects and mechanisms of action of celecoxib in Philadelphia-positive (Ph+) CML and ALL cells.We show here that celecoxib suppresses the growth of Ph+ cell lines by increasing G1-phase and apoptotic cells and reducing S- and G2-phase cells. These effects were independent of COX2 inhibition but required the rapid activation of AMP-activated protein kinase (AMPK) and the consequent inhibition mTORC1 and 2. Treatment with celecoxib also restored GSK3β function and led to down-regulation of β-catenin activity through transcriptional and post-translational mechanisms, two effects likely to contribute to Ph+ cell growth suppression by celecoxib.Celecoxib inhibited colony formation of TKI-resistant Ph+ cell lines including those with the T315I BCR-ABL mutation and acted synergistically with imatinib in suppressing colony formation of TKI-sensitive Ph+ cell lines. Finally, it suppressed colony formation of CD34+ cells from CML patients, while sparing most CD34+ progenitors from healthy donors, and induced apoptosis of primary Ph+ ALL cells.Together, these findings indicate that celecoxib may serve as a COX2-independent lead compound to simultaneously target the mTOR and β-catenin pathways, key players in the resistance of CML stem cells to TKIs.
Department of Pharmacological Sciences, Università del Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
Beatrice
B
Riva
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia 19107, PA, USA.
Marco
M
De Dominici
Department of Pharmacological Sciences, Università del Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
Ilaria
I
Gnemmi
MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Samanta A
SA
Mariani
Department of Pharmacological Sciences, Università del Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
Alberto
A
Minassi
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia 19107, PA, USA.
Valentina
V
Minieri
Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6BT, UK.
Paolo
P
Salomoni
Department of Pharmacological Sciences, Università del Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
Pier Luigi
PL
Canonico
Department of Pharmacological Sciences, Università del Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
Armando A
AA
Genazzani
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia 19107, PA, USA.
Bruno
B
Calabretta
Department of Pharmacological Sciences, Università del Piemonte Orientale "A. Avogadro", 28100 Novara, Italy.
Fabrizio
F
Condorelli
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; C581634:BCR-ABL1 fusion protein, human; C495270:CTNNB1 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D051176:beta Catenin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D055372:AMP-Activated Protein Kinases; D000068579:Celecoxib
AMP-activated kinase; beta-catenin; celecoxib; chronic myelogenous leukemia; cyclooxygenase-2