PT  - JOURNAL ARTICLE
AU  - Cyril Sobolewski
AU  - Jiyun Rhim
AU  - Noémie Legrand
AU  - Florian Muller
AU  - Claudia Cerella
AU  - Fabienne Mack
AU  - Sébastien Chateauvieux
AU  - Jeoung-Gyun Kim
AU  - Ah-Young Yoon
AU  - Kyu-Won Kim
AU  - Mario Dicato
AU  - Marc Diederich
TI  - 2,5-Dimethyl-Celecoxib Inhibits Cell Cycle Progression and Induces Apoptosis in Human Leukemia Cells
AID  - 10.1124/jpet.115.225011
DP  - 2015 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 308--328
VI  - 355
IP  - 2
4099  - http://jpet.aspetjournals.org/content/355/2/308.short
4100  - http://jpet.aspetjournals.org/content/355/2/308.full
SO  - J Pharmacol Exp Ther2015 Nov 01; 355
AB  - 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.