Imatinib and its combination with 2,5-dimethyl-celecoxib induces apoptosis of human HT-29 colorectal cancer cells
Abstract
Mono-targeting by imatinib as a main antitumor agent does not always accomplish complete cancer suppression. 2,5-dimethyl-celecoxib (DMC) is a close structural analog of the selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, that lacks COX-2 inhibitory function. In this study, we aimed to show the apoptotic effects of imatinib in combination with DMC in human HT-29 colorectal cancer (CRC) cells. HT-29 CRC cells were treated with IC50 dose of imatinib (6.60 µM), DMC (23.45 µM), and their combination (half dose of IC50) for 24 h. The caspase-3 activity was estimated with colorimetric kit. The caspase-3 gene expression was evaluated by real-time PCR method. There was a significant up-regulation in caspase-3 enzyme activity and caspase-3 expression by imatinib and its half dose combination with DMC as compared to control. As a summary, the results of this study strongly suggest that half dose combination of imatinib with DMC induced apoptosis as potent as full dose imatinib in human HT-29 CRC cells, while minimizing undesired side effects related to imatinib mono-therapy. This study also pointed towards possible caspase-dependent actions of imatinib and DMC.
Keywords
Full Text:
PDFReferences
Danese S, Mantovani A. Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene. 2010;29(23):3313-3323.
Twelves C, Wong A, Nowacki MP, Abt M, Burris H, Carrato A, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-2704.
Nita ME, Nagawa H, Tominaga O, Tsuno N, Fujii S, Sasaki S, et al. 5-Fluorouracil induces apoptosis in human colon cancer cell lines with modulation of Bcl-2 family proteins. Br J Cancer. 1998;78(8):986-992.
Fuchs C, Mitchell EP, Hoff PM. Irinotecan in the treatment of colorectal cancer. Cancer Treat Rev. 2006;32(7):491-503.
Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27(19):3109-3116.
Kundu P, Genander M, Straat K, Classon J, Ridgway RA, Tan EH, et al. An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth. Sci Transl Med. 2015;7(281):281ra44.
Abdel-Aziz AK, Azab SS, Youssef SS, El-Sayed AM, El-Demerdash E, Shouman S. Modulation of imatinib cytotoxicity by selenite in HCT116 colorectal cancer cells. Basic Clin Pharmacol Toxicol. 2015;116(1):37-46.
Attoub S, Rivat C, Rodrigues S, Van Bocxlaer S, Bedin M, Bruyneel E, et al. The c-kit tyrosine kinase inhibitor STI571 for colorectal cancer therapy. Cancer Res. 2002;62(17):4879-4883.
Stahtea XN, Roussidis AE, Kanakis I, Tzanakakis GN, Chalkiadakis G, Mavroudis D, et al. Imatinib inhibits colorectal cancer cell growth and suppresses stromal-induced growth stimulation, MT1-MMP expression and pro-MMP2 activation. Int J Cancer. 2007;121(12):2808-2814.
Tamascar I, Ramanarayanan J. Targeted treatment of chronic myeloid leukemia: role of imatinib. Onco Targets Ther. 2009;2:63-71.
Kelley RK, Hwang J, Magbanua MJ, Watt L, Beumer JH, Christner SM, et al. A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer. Br J Cancer. 2013;109(7):1725-1734.
Sabharwal A, Kerr D. Chemotherapy for colorectal cancer in the metastatic and adjuvant setting: past, present and future. Expert Rev Anticancer Ther. 2007;7(4):477-487.
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352(11):1092-1102.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005;352(11):1081-1091.
Sadeghi-Aliabadi H, Aliasgharluo M, Fattahi A, Mirian M, Ghanadian M. In vitro cytotoxic evaluation of some synthesized COX-2 inhibitor derivatives against a panel of human cancer cell lines. Res Pharm Sci. 2013;8(4):298-303.
Backhus LM, Petasis NA, Uddin J, Schonthal AH, Bart RD, Lin Y, et al. Dimethyl celecoxib as a novel non-cyclooxygenase 2 therapy in the treatment of non-small cell lung cancer. J Thorac Cardiovasc Surg. 2005;130(5):1406-1412.
Virrey JJ, Liu Z, Cho HY, Kardosh A, Golden EB, Louie SG, et al. Antiangiogenic activities of 2,5-dimethyl-celecoxib on the tumor vasculature. Mol Cancer Ther. 2010;9(3):631-641.
Fan X, Takahashi-Yanaga F, Morimoto S, Zhan DY, Igawa K, Tomooka K, et al. 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. 2011;338(1):2-11.
Pyrko P, Soriano N, Kardosh A, Liu YT, Uddin J, Petasis NA, et al. 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. 2006;5:19.
Nikanfar S, Atari-hajipirloo S, Heydari A, Kheradmand F. Combination of imatinib and celecoxib, synergistically inhibit cell prolifration in colon cancer cells. Poster No. 68. 5th International congress on cell membranes and oxidative stress: focus on calcium signaling and TRP channels. 2014;6(1):361.
Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72(1-2):248-254.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402-408.
Kardosh A, Soriano N, Liu YT, Uddin J, Petasis NA, Hofman FM, et al. Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib. Blood. 2005;106(13):4330-4338.
Shi DX, Ma LM, Lu YJ, Bai B. [Apoptosis-inducing effect of tetrandrine and imatinib on K562/G01 cells and its related mechanism]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014;22(3):723-728.
Baran Y, Oztekin C, Bassoy EY. Combination of fludarabine and imatinib induces apoptosis synergistically through loss of mitochondrial membrane potential and increases in caspase-3 enzyme activity in human K562 chronic myleloid leukemia cells. Cancer Invest. 2010;28(6):623-628.
Hsieh YY, Yen CC, Yeh CN, Tzen CY, Liu JH, Lee HJ, et al. Effective salvage therapy of imatinib-resistant gastrointestinal stromal tumor with combination of imatinib and pegylated liposomal doxorubicin. J Chin Med Assoc. 2011;74(6): 272-274.
Schoffski P, Reichardt P, Blay JY, Dumez H, Morgan JA, Ray-Coquard I, et al. A phase I-II study of everolimus (RAD001) in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors. Ann Oncol. 2010;21(10):1990-1998.
Gajiwala KS, Wu JC, Christensen J, Deshmukh GD, Diehl W, DiNitto JP, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proc Natl Acad Sci U S A. 2009;106(5):1542-1547.
Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24(29):4764-4774.
Gross DJ, Munter G, Bitan M, Siegal T, Gabizon A, Weitzen R, et al. The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer. 2006;13(2):535-540.
Atari-Hajipirloo S, Nikanfar S, Heydari A, Noori F, Kheradmand F. The effect of celecoxib and its combination with imatinib on human HT-29 colorectal cancer cells: involvement of COX-2, caspase-3, VEGF and NF-kappaB genes expression. Cell Mol Biol(Noisy-le-grand). 2016;62(2
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.