[en] 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.
Akgul C (2009) Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci 66:1326-1336.
Antman EM, DeMets D, and Loscalzo J (2005) Cyclooxygenase inhibition and cardiovascular risk. Circulation 112:759-770.
Arunasree KM, Roy KR, Anilkumar K, Aparna A, Reddy GV, and Reddanna P (2008) Imatinib-resistant K562 cells are more sensitive to celecoxib, a selective COX-2 inhibitor: role of COX-2 and MDR-1. Leuk Res 32:855-864.
Backhus LM, Petasis NA, Uddin J, Schönthal AH, Bart RD, Lin Y, Starnes VA, and Bremner RM (2005) Dimethyl celecoxib as a novel non-cyclooxygenase 2 therapy in the treatment of non-small cell lung cancer. J Thorac Cardiovasc Surg 130:1406-1412.
Bertrand J, Tennoune N, Marion-Letellier R, Goichon A, Chan P, Mbodji K, Vaudry D, Déchelotte P, and Coëffier M (2013) Evaluation of ubiquitinated proteins by proteomics reveals the role of the ubiquitin proteasome system in the regulation of Grp75 and Grp78 chaperone proteins during intestinal inflammation. Proteomics 13:3284-3292.
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248-254.
Burlacu A (2003) Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med 7:249-257.
Candé C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N, and Kroemer G (2002) Apoptosis-inducing factor (AIF): A novel caspase-independent death effector released from mitochondria. Biochimie 84:215-222.
Cao Y and Prescott SM (2002) Many actions of cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 190:279-286.
Carmena M, Wheelock M, Funabiki H, and Earnshaw WC (2012) The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol 13:789-803.
Cerella C, Cordisco S, Albertini MC, Accorsi A, Diederich M, and Ghibelli L (2011a) Magnetic fields promote a pro-survival non-capacitative Ca21 entry via phospholipase C signaling. Int J Biochem Cell Biol 43:393-400.
Cerella C, Sobolewski C, Chateauvieux S, Henry E, Schnekenburger M, Ghelfi J, Dicato M, and Diederich M (2011b) COX-2 inhibitors block chemotherapeutic agent-induced apoptosis prior to commitment in hematopoietic cancer cells. Biochem Pharmacol 82:1277-1290.
Chandrasekharan NV and Simmons DL (2004) The cyclooxygenases. Genome Biol 5:241.
Cobrinik D (2005) Pocket proteins and cell cycle control. Oncogene 24:2796-2809.
Coca R, Soler F, Cortés-Castell E, Gil-Guillén V, and Fernández-Belda F (2014) Inhibition mechanism of the intracellular transporter Ca21-pump from sarcoendoplasmic reticulum by the antitumor agent dimethyl-celecoxib. PLoS One 9:e102083.
Dai RY, Chen SK, Yan DM, Chen R, Lui YP, Duan CY, Li J, He T, and Li H (2010) PI3K/Akt promotes GRP78 accumulation and inhibits endoplasmic reticulum stress-induced apoptosis in HEK293 cells. Folia Biol (Praha) 56:37-46.
Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, Lemaire C, and Brenner C (2008) Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27:285-299.
Dent P, Yacoub A, and Grant S (2005) DMC: novel celecoxib derivatives to rap cancer. Cancer Biol Ther 4:583-584.
Fan X, Takahashi-Yanaga F, Morimoto S, Zhan DY, Igawa K, Tomooka K, and Sasaguri T (2011) Celecoxib and 2, 5-dimethyl-celecoxib prevent cardiac remodeling inhibiting Akt-mediated signal transduction in an inherited dilated cardiomyopathy mouse model. J Pharmacol Exp Ther 338:2-11.
Fenaux P (2005) Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol 2 (Suppl 1):S36-S44.
Ferrario A, Lim S, Xu F, Luna M, Gaffney KJ, Petasis NA, Schönthal AH, and Gomer CJ (2011) Enhancement of photodynamic therapy by 2, 5-dimethyl celecoxib, a noncyclooxygenase- 2 inhibitor analog of celecoxib. Cancer Lett 304:33-40.
Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, and González- Barón M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193-204.
Gao M, Yeh PY, Lu YS, Hsu CH, Chen KF, Lee WC, Feng WC, Chen CS, Kuo ML, and Cheng AL (2008) OSU-03012, a novel celecoxib derivative, induces reactive oxygen species-related autophagy in hepatocellular carcinoma. Cancer Res 68:9348-9357.
Geyer HL and Mesa RA (2014) Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood 124:3529-3537.
Han C, Jin L, Mei Y, and Wu M (2013) Endoplasmic reticulum stress inhibits cell cycle progression via induction of p27 in melanoma cells. Cell Signal 25:144-149.
Howe LR (2007) Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. Breast Cancer Res 9:210.
Hudson M, Rahme E, Richard H, and Pilote L (2007) Risk of congestive heart failure with nonsteroidal antiinflammatory drugs and selective Cyclooxygenase 2 inhibitors: A class effect? Arthritis Rheum 57:516-523.
Ishikawa T (2014) Novel therapeutic strategies using hypomethylating agents in the treatment of myelodysplastic syndrome. Int J Clin Oncol 19:10-15.
Jacquemin G, Granci V, Gallouet AS, Lalaoui N, Morlé A, Iessi E, Morizot A, Garrido C, Guillaudeux T, and Micheau O (2012) Quercetin-mediated Mcl-1 and survivin downregulation restores TRAIL-induced apoptosis in non-Hodgkin's lymphoma B cells. Haematologica 97:38-46.
Jendrossek V, Handrick R, and Belka C (2003) Celecoxib activates a novel mitochondrial apoptosis signaling pathway. FASEB J 17:1547-1549.
Johnson AJ, Hsu AL, Lin HP, Song X, and Chen CS (2002) The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca21-ATPases: A plausible link with its anti-tumour effect and cardiovascular risks. Biochem J 366:831-837.
Johnson AJ, Smith LL, Zhu J, Heerema NA, Jefferson S, Mone A, Grever M, Chen CS, and Byrd JC (2005) A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma cell line via a caspase- And Bcl-2-independent mechanism. Blood 105:2504-2509.
Juncker T, Cerella C, Teiten MH, Morceau F, Schumacher M, Ghelfi J, Gaascht F, Schnekenburger M, Henry E, and Dicato M, et al. (2011) UNBS1450, a steroid cardiac glycoside inducing apoptotic cell death in human leukemia cells. Biochem Pharmacol 81:13-23.
Kardosh A, Golden EB, Pyrko P, Uddin J, Hofman FM, Chen TC, Louie SG, Petasis NA, and Schönthal AH (2008) Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2, 5-dimethyl-celecoxib. Cancer Res 68:843-851.
Kardosh A, Wang W, Uddin J, Petasis NA, Hofman FM, Chen TC, and Schönthal AH (2005) Dimethyl-celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-inhibitory function, potently mimics the anti-tumor effects of celecoxib on Burkitt's lymphoma in vitro and in vivo. Cancer Biol Ther 4:571-582.
Kelly RJ, Lopez-Chavez A, Citrin D, Janik JE, and Morris JC (2011) Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin. Mol Cancer 10:35.
Kim SH, Ricci MS, and El-Deiry WS (2008) Mcl-1: A gateway to TRAIL sensitization. Cancer Res 68:2062-2064.
Kuijlen JM, Bremer E, Mooij JJ, den Dunnen WF, and Helfrich W (2010) Review: on TRAIL for malignant glioma therapy? Neuropathol Appl Neurobiol 36:168-182.
Lamers F, van der Ploeg I, Schild L, Ebus ME, Koster J, Hansen BR, Koch T, Versteeg R, Caron HN, and Molenaar JJ (2011) Knockdown of survivin (BIRC5) causes apoptosis in neuroblastoma via mitotic catastrophe. Endocr Relat Cancer 18:657-668.
Lau LM, Wolter JK, Lau JT, Cheng LS, Smith KM, Hansford LM, Zhang L, Baruchel S, Robinson F, and Irwin MS (2009) Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma. Oncogene 28:2024-2033.
Lee AS (2014) Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer 14:263-276.
Lee J and Ozcan U (2014) Unfolded protein response signaling and metabolic diseases. J Biol Chem 289:1203-1211.
Lee TX, Packer MD, Huang J, Akhmametyeva EM, Kulp SK, Chen CS, Giovannini M, Jacob A, Welling DB, and Chang LS (2009) Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. Eur J Cancer 45:1709-1720.
Lin Y, Wang Z, Liu L, and Chen L (2011) Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells. Lung Cancer 71:291-297.
Liu B, Shi ZL, Feng J, and Tao HM (2008) Celecoxib, a cyclooxygenase-2 inhibitor, induces apoptosis in human osteosarcoma cell line MG-63 via down-regulation of PI3K/Akt. Cell Biol Int 32:494-501.
Liu J, Qin CK, Lv W, Zhao Q, and Qin CY (2013) OSU-03012, a non-Cox inhibiting celecoxib derivative, induces apoptosis of human esophageal carcinoma cells through a p53/Bax/cytochrome c/caspase-9-dependent pathway. Anticancer Drugs 24:690-698.
McCubrey JA, Lahair MM, and Franklin RA (2006) OSU-03012 in the treatment of glioblastoma. Mol Pharmacol 70:437-439.
Mita AC, Mita MM, Nawrocki ST, and Giles FJ (2008) Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res 14:5000-5005.
Mutter R, Lu B, Carbone DP, Csiki I, Moretti L, Johnson DH, Morrow JD, Sandler AB, Shyr Y, and Ye F, et al. (2009) A phase II study of celecoxib in combination with paclitaxel, carboplatin, and radiotherapy for patients with inoperable stage IIIA/B non-small cell lung cancer. Clin Cancer Res 15:2158-2165.
Nigg EA and Stearns T (2011) The centrosome cycle: Centriole biogenesis, duplication and inherent asymmetries. Nat Cell Biol 13:1154-1160.
Norberg E, Orrenius S, and Zhivotovsky B (2010) Mitochondrial regulation of cell death: processing of apoptosis-inducing factor (AIF). Biochem Biophys Res Commun 396:95-100.
Orrenius S, Gogvadze V, and Zhivotovsky B (2015) Calcium and mitochondria in the regulation of cell death. Biochem Biophys Res Commun 460:72-81.
Ortiz E (2004) Market withdrawal of Vioxx: is it time to rethink the use of COX-2 inhibitors? J Manag Care Pharm 10:551-554.
Park SW, Kim HS, Hah JW, Jeong WJ, Kim KH, and Sung MW (2010) Celecoxib inhibits cell proliferation through the activation of ERK and p38 MAPK in head and neck squamous cell carcinoma cell lines. Anticancer Drugs 21:823-830.
Pi L, Li X, Song Q, Shen Y, Lu X, and Di B (2014) Knockdown of glucose-regulated protein 78 abrogates chemoresistance of hypopharyngeal carcinoma cells to cisplatin induced by unfolded protein in response to severe hypoxia. Oncol Lett 7:685-692.
Pyrko P, Kardosh A, Liu YT, Soriano N, Xiong W, Chow RH, Uddin J, Petasis NA, Mircheff AK, and Farley RA, et al. (2007) Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2, 5-dimethylcelecoxib, a non-coxib analogue of celecoxib. Mol Cancer Ther 6:1262-1275.
Pyrko P, Soriano N, Kardosh A, Liu YT, Uddin J, Petasis NA, Hofman FM, Chen CS, Chen TC, and Schönthal AH (2006) Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2- inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo. Mol Cancer 5:19.
Raldúa D and Piña B (2014) In vivo zebrafish assays for analyzing drug toxicity. Expert Opin Drug Metab Toxicol 10:685-697.
Ristimaki A (2004) Cyclooxygenase 2: from inflammation to carcinogenesis. Novartis Found Symp 256:215-221; discussion 221-216, 259-269.
Roboz GJ (2012) Current treatment of acute myeloid leukemia. Curr Opin Oncol 24: 711-719.
Ryan EP, Bushnell TP, Friedman AE, Rahman I, and Phipps RP (2008) Cyclooxygenase-2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells. Cancer Immunol Immunother 57:347-358.
Sánchez-Alcázar JA, Ault JG, Khodjakov A, and Schneider E (2000) Increased mitochondrial cytochrome c levels and mitochondrial hyperpolarization precede camptothecin-induced apoptosis in Jurkat cells. Cell Death Differ 7:1090-1100.
Schönthal AH (2006) Antitumor properties of dimethyl-celecoxib, a derivative of celecoxib that does not inhibit cyclooxygenase-2: implications for glioma therapy. Neurosurg Focus 20:E21.
Schönthal AH (2007) Induction of apoptosis by celecoxib in cell culture: An uncertain role for cyclooxygenase-2. Cancer Res 67:5575-5576, author reply 5576.
Secchiero P, Barbarotto E, Gonelli A, Tiribelli M, Zerbinati C, Celeghini C, Agostinelli C, Pileri SA, and Zauli G (2005) Potential pathogenetic implications of cyclooxygenase-2 overexpression in B chronic lymphoid leukemia cells. Am J Pathol 167:1599-1607.
Shi Y, Porter K, Parameswaran N, Bae HK, and Pestka JJ (2009) Role of GRP78/BiP degradation and ER stress in deoxynivalenol-induced interleukin-6 upregulation in the macrophage. Toxicol Sci 109:247-255.
Sobolewski C, Cerella C, Dicato M, and Diederich M (2011) Cox-2 inhibitors induce early c-Myc downregulation and lead to expression of differentiation markers in leukemia cells. Cell Cycle 10:2978-2993.
Sobolewski C, Cerella C, Dicato M, Ghibelli L, and Diederich M (2010) The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol 2010:215158.
Stankovic T and Marston E (2008) Molecular mechanisms involved in chemoresistance in paediatric acute lymphoblastic leukaemia. Srp Arh Celok Lek 136: 187-192.
Sudhindra A and Smith CC (2014) FLT3 inhibitors in AML: Are we there yet? Curr Hematol Malig Rep 9:174-185.
Teske BF, Wek SA, Bunpo P, Cundiff JK, McClintick JN, Anthony TG, and Wek RC (2011) The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Mol Biol Cell 22: 4390-4405.
Trivigno D, Bornes L, Huber SM, and Rudner J (2013) Regulation of protein translation initiation in response to ionizing radiation. Radiat Oncol 8:35.
Vesci L, Bernasconi E, Milazzo FM, De Santis R, Gaudio E, Kwee I, Rinaldi A, Pace S, Carollo V, and Giannini G, et al. (2015) Preclinical antitumor activity of ST7612AA1: A new oral thiol-based histone deacetylase (HDAC) inhibitor. Oncotarget 6:5735-5748.
Virrey JJ, Liu Z, Cho HY, Kardosh A, Golden EB, Louie SG, Gaffney KJ, Petasis NA, Schönthal AH, and Chen TC, et al. (2010) Antiangiogenic activities of 2, 5-dimethylcelecoxib on the tumor vasculature. Mol Cancer Ther 9:631-641.
Wang M, Wey S, Zhang Y, Ye R, and Lee AS (2009) Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid Redox Signal 11:2307-2316.
Wang W, Bergh A, and Damber JE (2005) Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer. Clin Cancer Res 11:3250-3256.
Wang YC, Kulp SK, Wang D, Yang CC, Sargeant AM, Hung JH, Kashida Y, Yamaguchi M, Chang GD, and Chen CS (2008) Targeting endoplasmic reticulum stress and Akt with OSU-03012 and gefitinib or erlotinib to overcome resistance to epidermal growth factor receptor inhibitors. Cancer Res 68:2820-2830.
Whitaker M (1997) Calcium and mitosis. Prog Cell Cycle Res 3:261-269.
Wun T, McKnight H, and Tuscano JM (2004) Increased cyclooxygenase-2 (COX-2): A potential role in the pathogenesis of lymphoma. Leuk Res 28:179-190.
Zhang LH and Zhang X (2010) Roles of GRP78 in physiology and cancer. J Cell Biochem 110:1299-1305.
Zhang S, Suvannasankha A, Crean CD, White VL, Johnson A, Chen CS, and Farag SS (2007) OSU-03012, a novel celecoxib derivative, is cytotoxic to myeloma cells and acts through multiple mechanisms. Clin Cancer Res 13:4750-4758.