Celecoxib enhances the sensitivity of non-small-cell lung cancer cells to radiation-induced apoptosis through downregulation of the Akt/mTOR signaling pathway and COX-2 expression


Autoři: Pan Zhang aff001;  Dan He aff002;  Erqun Song aff001;  Mingdong Jiang aff003;  Yang Song aff001
Působiště autorů: Key Laboratory of Luminescence and Real-Time Analytical Chemistry, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, P. R. China aff001;  Department of Oncology, Nuclear Industry Hospital, Chengdu, Sichuan, P. R. China aff002;  Department of Radiation Oncology, The Ninth People's Hospital of Chongqing, Chongqing, P. R. China aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223760

Souhrn

The current study aimed to identify the radiosensitizing effect of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in combination with radiotherapy in non-small-cell lung cancer (NSCLC) cells. The combination of celecoxib potentiated radiation-induced apoptosis; however, no changes in cell cycle distribution and number of phosphorylated histone H2AX foci were detected, indicating a DNA damage-independent mechanism. In an in vivo mouse model, the tumor size was significantly decreased in the group combining celecoxib with radiation compared with the radiation only group. Phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), as well as expression of COX-2 were significantly downregulated in cells treated with the combination of celecoxib and radiation compared with the radiation only group. The result indicated that celecoxib exhibits radiosensitizing effects through COX-2 and Akt/mTOR-dependent mechanisms. Induction the Akt/mTOR signaling pathway promotes radioresistance in various cancers, including NSCLC. Therefore, the current study suggested the therapeutic potential of combination therapy of celecoxib and radiation in the prevention of radioresistance.

Klíčová slova:

Apoptosis – Cancer treatment – Cell cycle and cell division – Mouse models – Non-small cell lung cancer – NSAIDs – Radiation therapy – COX-2 inhibitors


Zdroje

1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. doi: 10.3322/caac.21387 28055103.

2. Eberhardt WE. Concurrent chemoradiotherapy in stage III non-small-cell lung cancer: what is the best regimen? J Clin Oncol. 2015;33(6):532–3. doi: 10.1200/JCO.2014.58.9812 25559800.

3. Multhoff G, Radons J. Radiation, inflammation, and immune responses in cancer. Front Oncol. 2012;2:58. doi: 10.3389/fonc.2012.00058 22675673; PubMed Central PMCID: PMC3366472.

4. Molla M, Panes J. Radiation-induced intestinal inflammation. World J Gastroenterol. 2007;13(22):3043–6. doi: 10.3748/wjg.v13.i22.3043 17589918; PubMed Central PMCID: PMC4172609.

5. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–7. doi: 10.1038/nature01322 12490959; PubMed Central PMCID: PMC2803035.

6. Cheki M, Yahyapour R, Farhood B, Rezaeyan A, Shabeeb D, Amini P, et al. COX-2 in Radiotherapy: A Potential Target for Radioprotection and Radiosensitization. Curr Mol Pharmacol. 2018;11(3):173–83. Epub 2018/02/23. doi: 10.2174/1874467211666180219102520 29468988.

7. DuBois RN, Tsujii M, Bishop P, Awad JA, Makita K, Lanahan A. Cloning and characterization of a growth factor-inducible cyclooxygenase gene from rat intestinal epithelial cells. Am J Physiol. 1994;266(5 Pt 1):G822–7. doi: 10.1152/ajpgi.1994.266.5.G822 8203528.

8. Han ZQ, Liao H, Shi F, Chen XP, Hu HC, Tian MQ, et al. Inhibition of cyclooxygenase-2 sensitizes lung cancer cells to radiation-induced apoptosis. Oncol Lett. 2017;14(5):5959–65. doi: 10.3892/ol.2017.6940 29113232; PubMed Central PMCID: PMC5661612.

9. Cho SJ, Kim N, Kim JS, Jung HC, Song IS. The anti-cancer effect of COX-2 inhibitors on gastric cancer cells. Dig Dis Sci. 2007;52(7):1713–21. doi: 10.1007/s10620-007-9787-3 17393325.

10. Brown JR, DuBois RN. COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol. 2005;23(12):2840–55. doi: 10.1200/JCO.2005.09.051 15837998.

11. Sung JJ, Leung WK, Go MY, To KF, Cheng AS, Ng EK, et al. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol. 2000;157(3):729–35. doi: 10.1016/S0002-9440(10)64586-5 10980112; PubMed Central PMCID: PMC1885697.

12. Kismet K, Akay MT, Abbasoglu O, Ercan A. Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention. Cancer Detect Prev. 2004;28(2):127–42. doi: 10.1016/j.cdp.2003.12.005 15068837.

13. Needleman P, Isakson PC. The discovery and function of COX-2. J Rheumatol Suppl. 1997;49:6–8. 9249644.

14. Hida T, Kozaki K, Ito H, Miyaishi O, Tatematsu Y, Suzuki T, et al. Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a selective cyclooxygenase 2 inhibitor, JTE-522, and conventional anticancer agents. Clin Cancer Res. 2002;8(7):2443–7. 12114451.

15. Elder DJ, Halton DE, Hague A, Paraskeva C. Induction of apoptotic cell death in human colorectal carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug: independence from COX-2 protein expression. Clin Cancer Res. 1997;3(10):1679–83. 9815550.

16. Arico S, Pattingre S, Bauvy C, Gane P, Barbat A, Codogno P, et al. Celecoxib induces apoptosis by inhibiting 3-phosphoinositide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J Biol Chem. 2002;277(31):27613–21. doi: 10.1074/jbc.M201119200 12000750.

17. Liu R, Tan Q, Luo Q. Decreased expression level and DNA-binding activity of specificity protein 1 via cyclooxygenase-2 inhibition antagonizes radiation resistance, cell migration and invasion in radiation-resistant lung cancer cells. Oncol Lett. 2018;16(3):3029–37. Epub 2018/08/22. doi: 10.3892/ol.2018.9035 30127893; PubMed Central PMCID: PMC6096147.

18. Xu XT, Hu WT, Zhou JY, Tu Y. Celecoxib enhances the radiosensitivity of HCT116 cells in a COX-2 independent manner by up-regulating BCCIP. Am J Transl Res. 2017;9(3):1088–100. Epub 2017/04/08. 28386336; PubMed Central PMCID: PMC5376001.

19. Huang J, Yuan X, Pang Q, Zhang H, Yu J, Yang B, et al. Radiosensitivity enhancement by combined treatment of nimotuzumab and celecoxib on nasopharyngeal carcinoma cells. Drug Des Devel Ther. 2018;12:2223–31. Epub 2018/07/25. doi: 10.2147/DDDT.S163595 30038488; PubMed Central PMCID: PMC6052925.

20. Kang KB, Wang TT, Woon CT, Cheah ES, Moore XL, Zhu C, et al. Enhancement of glioblastoma radioresponse by a selective COX-2 inhibitor celecoxib: inhibition of tumor angiogenesis with extensive tumor necrosis. Int J Radiat Oncol Biol Phys. 2007;67(3):888–96. Epub 2007/02/13. doi: 10.1016/j.ijrobp.2006.09.055 17293239.

21. Xue WP, Bai SM, Luo M, Bi ZF, Liu YM, Wu SK. Phase I clinical trial of nasopharyngeal radiotherapy and concurrent celecoxib for patients with locoregionally advanced nasopharyngeal carcinoma. Oral Oncol. 2011;47(8):753–7. Epub 2011/06/29. doi: 10.1016/j.oraloncology.2011.06.002 21708478.

22. Sun J, Liu NB, Zhuang HQ, Zhao LJ, Yuan ZY, Wang P. Celecoxib-erlotinib combination treatment enhances radiosensitivity in A549 human lung cancer cell. Cancer Biomark. 2017;19(1):45–50. Epub 2017/03/12. doi: 10.3233/CBM-160323 28282799.

23. Zhang SX, Qiu QH, Chen WB, Liang CH, Huang B. Celecoxib enhances radiosensitivity via induction of G(2)-M phase arrest and apoptosis in nasopharyngeal carcinoma. Cell Physiol Biochem. 2014;33(5):1484–97. Epub 2014/05/24. doi: 10.1159/000358713 24854838.

24. Kim B, Kim J, Kim YS. Celecoxib induces cell death on non-small cell lung cancer cells through endoplasmic reticulum stress. Anat Cell Biol. 2017;50(4):293–300. Epub 2018/01/23. doi: 10.5115/acb.2017.50.4.293 29354301; PubMed Central PMCID: PMC5768566.

25. Jendrossek V. Targeting apoptosis pathways by Celecoxib in cancer. Cancer Lett. 2013;332(2):313–24. Epub 2011/02/25. doi: 10.1016/j.canlet.2011.01.012 21345578.

26. Masferrer JL, Leahy KM, Koki AT, Zweifel BS, Settle SL, Woerner BM, et al. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000;60(5):1306–11. 10728691.

27. Hou LC, Huang F, Xu HB. Does celecoxib improve the efficacy of chemotherapy for advanced non-small cell lung cancer? Br J Clin Pharmacol. 2016;81(1):23–32. doi: 10.1111/bcp.12757 26331772; PubMed Central PMCID: PMC4693572.

28. Chen M, Yu L, Gu C, Zhong D, Wu S, Liu S. Celecoxib antagonizes the cytotoxic effect of cisplatin in human gastric cancer cells by decreasing intracellular cisplatin accumulation. Cancer Lett. 2013;329(2):189–96. doi: 10.1016/j.canlet.2012.10.030 23142285.

29. Cataldi A, Zauli G, Di Pietro R, Castorina S, Rana R. Involvement of the pathway phosphatidylinositol-3-kinase/AKT-1 in the establishment of the survival response to ionizing radiation. Cell Signal. 2001;13(5):369–75. doi: 10.1016/s0898-6568(01)00147-4 11369519.

30. Rudner J, Elsaesser SJ, Muller AC, Belka C, Jendrossek V. Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on celecoxib-induced apoptosis. Biochem Pharmacol. 2010;79(1):10–20. doi: 10.1016/j.bcp.2009.07.021 19665451.

31. Wu T, Leng J, Han C, Demetris AJ. The cyclooxygenase-2 inhibitor celecoxib blocks phosphorylation of Akt and induces apoptosis in human cholangiocarcinoma cells. Mol Cancer Ther. 2004;3(3):299–307. 15026550.

32. Belka C, Rudner J, Wesselborg S, Stepczynska A, Marini P, Lepple-Wienhues A, et al. Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis. Oncogene. 2000;19(9):1181–90. doi: 10.1038/sj.onc.1203401 10713706.

33. Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H, et al. Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma. Cancer Res. 2006;66(14):7059–66. doi: 10.1158/0008-5472.CAN-06-0325 16849551.

34. Alloza I, Baxter A, Chen Q, Matthiesen R, Vandenbroeck K. Celecoxib inhibits interleukin-12 alphabeta and beta2 folding and secretion by a novel COX2-independent mechanism involving chaperones of the endoplasmic reticulum. Mol Pharmacol. 2006;69(5):1579–87. doi: 10.1124/mol.105.020669 16467190.

35. Schonthal AH. Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy. Br J Cancer. 2007;97(11):1465–8. doi: 10.1038/sj.bjc.6604049 17955049; PubMed Central PMCID: PMC2360267.


Článek vyšel v časopise

PLOS One


2019 Číslo 10