2,5-Dimethyl-celecoxib inhibits cell cycle progression and induces apoptosis in human leukemia cells.
Cyclooxygenase-2 (COX-2) is an essential regulator of cancer promotion and progression. Extensive efforts to target this enzyme have been developed to reduce growth of cancer cells for chemopreventive and therapeutic reasons. In this context, cyclooxygenase-2 inhibitors present interesting antitumor effects. However, inhibition of COX-2 by anti-COX-2 compounds such as celecoxib was recently associated with detrimental cardiovascular side effects limiting their clinical use. As many anticancer effects of celecoxib are COX-2 independent, analogs such as 2,5-dimethyl-celecoxib (DMC), which lacks COX-2-inhibitory activity, represent a promising alternative strategy. In this study, we investigated the effect of this molecule on growth of hematologic cancer cell lines (U937, Jurkat, Hel, Raji, and K562). We found that this molecule is able to reduce the growth and induces apoptosis more efficiently than celecoxib in all the leukemic cell lines tested. Cell death was associated with downregulation of Mcl-1 protein expression. We also found that DMC induces endoplasmic reticulum stress, which is associated with a decreased of GRP78 protein expression and an alteration of cell cycle progression at the G1/S transition in U937 cells. Accordingly, typical downregulation of c-Myc and cyclin D1 and an upregulation of p27 were observed. Interestingly, for shorter time points, an alteration of mitotic progression, associated with the downregulation of survivin protein expression was observed. Altogether, our data provide new evidence about the mode of action of this compound on hematologic malignancies.
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Cyril
C
Sobolewski
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Jiyun
J
Rhim
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Noémie
N
Legrand
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Florian
F
Muller
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Claudia
C
Cerella
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Fabienne
F
Mack
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Sébastien
S
Chateauvieux
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Jeoung-Gyun
JG
Kim
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Ah-Young
AY
Yoon
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Kyu-Won
KW
Kim
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.).
Mario
M
Dicato
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg, Luxembourg (C.S., N.L., F.Mu. C.C., F.Ma., S.C., M.Dic.); Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea (J.R., S.C., M.Die.); and SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea (J.G.K., A.Y.Y., K.W.K.) marcdiederich@snu.ac.kr.
Marc
http://orcid.org/0000-0003-0115-4725
M
Diederich
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D000068579:Celecoxib / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007938:Leukemia; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000633:toxicity; D013449:Sulfonamides / Q000494:pharmacology* / Q000633:toxicity; D015027:Zebrafish
C506698:2,5-dimethylcelecoxib; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C579095:MCL1 protein, human; C489427:MYC protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016271:Proto-Oncogene Proteins c-myc; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D002118:Calcium