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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.

Despite recent advances in the treatment of chronic myelogenous leukemia (CML), the development of drug resistance and minimal residual disease remain major challenges for the treatment of CML patients, thus highlighting the need to develop innovative new approaches to improve therapeutic outcome. Myrtucommulone A (MCA) is a nonprenylated acylphloroglucinol isolated from the leaves of myrtle, a plant traditionally used in folk medicine. To date, studies addressing bioactivities of myrtle and its specific components are rare. Here, we investigated the biological effects of MCA, focusing on its anti-leukemic activity. As evidenced by fragmented nuclei after Hoechst/propidium iodide staining and poly (ADP-ribose) polymerase cleavage, MCA induces apoptosis in CML cells through down-regulation of anti-apoptotic proteins. Interestingly, we showed that chronic treatment with MCA at low doses induced senescence in CML cells. Taken together, this study highlights the chemotherapeutical potential of this natural product in human leukemia.