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Preventative effect of celecoxib in dimethylbenz[a]anthracene-induced ovarian cancer in rats

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

The present study investigated the preventive effect of the cyclooxygenase (COX)-2 inhibitor, celecoxib, in 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer in a rat model.

Methods

A diet containing celecoxib (1500 ppm) was started 2 weeks before the introduction of DMBA. DMBA-soaked cotton threads were surgically applied to induce ovarian cancer in female Wistar rats. Tumor growth and survival were observed for 24 weeks.

Results

During the study period, an overall tumor incidence of 97.5% was observed and 65% of tumors were ovarian adenocarcinoma. The celecoxib diet significantly reduced the incidence and size of DMBA-induced ovarian cancers and significantly improved survival of tumor-bearing rats. The preventive effect of celecoxib was associated with increased apoptosis.

Conclusion

DMBA-induced ovarian cancer in rats recapitulates many pathophysiological features of the human counterpart. Our results provide supportive evidence that celecoxib has a preventive effect on development of ovarian cancer in a rat model.

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Abbreviations

COX:

Cyclooxygenase

DMBA:

7,12-Dimethylbenz[a]anthracene

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210

    Article  CAS  PubMed  Google Scholar 

  2. American Cancer Society (2016) Cancer facts and figures 2016. American Cancer Society, Atlanta

    Google Scholar 

  3. Bobbs AS, Cole JM, Cowden Dahl KD (2015) Emerging and evolving ovarian cancer animal models. Cancer Growth Metastasis 8(Suppl 1):29–36. https://doi.org/10.4137/CGM.S21221

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nishida T, Sugiyama T, Kataoka A, Ushijima K, Yakushiji M (1998) Histologic characterization of rat ovarian carcinoma induced by intraovarian insertion of a 7,12-dimethylbenz[a]anthracene-coated suture: common epithelial tumors of the ovary in rats? Cancer 83(5):965–970

    Article  CAS  PubMed  Google Scholar 

  5. Crist KA, Zhang Z, You M, Gunning WT, Conran PB, Steele VE, Lubet RA (2005) Characterization of rat ovarian adenocarcinomas developed in response to direct instillation of 7,12-dimethylbenz[a]anthracene (DMBA) coated suture. Carcinogenesis 26(5):951–957. https://doi.org/10.1093/carcin/bgi039

    Article  CAS  PubMed  Google Scholar 

  6. Khan AA (2017) Pro-apoptotic activity of nano-escheriosome based oleic acid conjugate against 7,12-dimethylbenz(a)anthracene (DMBA) induced cutaneous carcinogenesis. Biomed Pharmacother 90:295–302. https://doi.org/10.1016/j.biopha.2017.03.061

    Article  CAS  PubMed  Google Scholar 

  7. Huang Y, Jiang W, Wang Y, Zheng Y, Cong Q, Xu C (2012) Enhanced efficacy and specificity of epithelial ovarian carcinogenesis by embedding a DMBA-coated cloth strip in the ovary of rat. J Ovarian Res 5(1):21. https://doi.org/10.1186/1757-2215-5-21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu L, Hu Z, Zhang H, Hou Y, Zhang Z, Zhou G, Li B (2016) Vitamin D postpones the progression of epithelial ovarian cancer induced by 7, 12-dimethylbenz [a] anthracene both in vitro and in vivo. OncoTargets Ther 9:2365–2375. https://doi.org/10.2147/OTT.S100581

    Article  CAS  Google Scholar 

  9. Lee JY, Myung SK, Song YS (2013) Prognostic role of cyclooxygenase-2 in epithelial ovarian cancer: a meta-analysis of observational studies. Gynecol Oncol 129(3):613–619. https://doi.org/10.1016/j.ygyno.2013.02.011

    Article  CAS  PubMed  Google Scholar 

  10. Li W, Jiang HR, Xu XL, Wang J, Zhang J, Liu ML, Zhai LY (2010) Cyclin D1 expression and the inhibitory effect of celecoxib on ovarian tumor growth in vivo. Int J Mol Sci 11(10):3999–4013. https://doi.org/10.3390/ijms11103999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li W, Xu XL, Zhang J, Cai JH, Tang YX (2012) Effects of cyclooxygenase inhibitors on survival time in ovarian cancer xenograft-bearing mice. Oncol Lett 4(6):1269–1273. https://doi.org/10.3892/ol.2012.929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Suri A, Sheng X, Schuler KM, Zhong Y, Han X, Jones HM, Gehrig PA, Zhou C, Bae-Jump VL (2016) The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer. Oncotarget 7(26):39582–39594. https://doi.org/10.18632/oncotarget.8659

    Article  PubMed  PubMed Central  Google Scholar 

  13. Khan AA, Jabeen M, Khan AA, Owais M (2013) Anticancer efficacy of a novel propofol-linoleic acid-loaded escheriosomal formulation against murine hepatocellular carcinoma. Nanomedicine 8(8):1281–1294. https://doi.org/10.2217/nnm.12.166

    Article  CAS  PubMed  Google Scholar 

  14. Khan AA, Alanazi AM, Jabeen M, Hassan I, Bhat MA (2016) Targeted nano-delivery of novel omega-3 conjugate against hepatocellular carcinoma: regulating COX-2/bcl-2 expression in an animal model. Biomed Pharmacother 81:394–401. https://doi.org/10.1016/j.biopha.2016.04.033

    Article  CAS  PubMed  Google Scholar 

  15. Morin PJ, Weeraratna AT (2016) Genetically-defined ovarian cancer mouse models. J Pathol 238(2):180–184. https://doi.org/10.1002/path.4663

    Article  PubMed  Google Scholar 

  16. Hennequart M, Pilotte L, Cane S, Hoffmann D, Stroobant V, Plaen E, Eynde B (2017) Constitutive IDO1 expression in human tumors is driven by cyclooxygenase-2 and mediates intrinsic immune resistance. Cancer Immunol Res 5(8):695–709. https://doi.org/10.1158/2326-6066.CIR-16-0400

    Article  CAS  PubMed  Google Scholar 

  17. Salehifar E, Hosseinimehr SJ (2016) The use of cyclooxygenase-2 inhibitors for improvement of efficacy of radiotherapy in cancers. Drug Discov Today 21(4):654–662. https://doi.org/10.1016/j.drudis.2016.02.019

    Article  CAS  PubMed  Google Scholar 

  18. Kim HJ, Yim GW, Nam EJ, Kim YT (2014) Synergistic effect of COX-2 inhibitor on paclitaxel-induced apoptosis in the human ovarian cancer cell line OVCAR-3. Cancer Res Treat 46(1):81–92. https://doi.org/10.4143/crt.2014.46.1.81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li W, Wang J, Jiang HR, Xu XL, Zhang J, Liu ML, Zhai LY (2011) Combined effects of cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on ovarian carcinoma in vivo. Int J Mol Sci 12(1):668–681. https://doi.org/10.3390/ijms12010668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Eitsuka T, Tatewaki N, Nishida H, Nakagawa K, Miyazawa T (2016) Synergistic anticancer effect of tocotrienol combined with chemotherapeutic agents or dietary components: a review. Int J Mol Sci. https://doi.org/10.3390/ijms17101605

    Article  PubMed  PubMed Central  Google Scholar 

  22. Thill M, Woeste A, Reichert K, Fischer D, Rody A, Friedrich M, Koster F (2015) Vitamin D inhibits ovarian cancer cell line proliferation in combination with celecoxib and suppresses cyclooxygenase-2 expression. Anticancer Res 35(2):1197–1203

    CAS  PubMed  Google Scholar 

  23. Webb T, Carter J, Roberts JL, Poklepovic A, McGuire WP, Booth L, Dent P (2015) Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance. Cancer Biol Ther 16(11):1660–1670. https://doi.org/10.1080/15384047.2015.1099769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu R, Zheng J, Li C, Pang Y, Zheng Q, Xu X, Liu P (2015) Celecoxib induces epithelial-mesenchymal transition in epithelial ovarian cancer cells via regulating ZEB1 expression. Arch Gynecol Obstet 291(6):1361–1369. https://doi.org/10.1007/s00404-014-3555-3

    Article  CAS  PubMed  Google Scholar 

  25. Reyners AK, de Munck L, Erdkamp FL, Smit WM, Hoekman K, Lalisang RI, de Graaf H, Wymenga AN, Polee M, Hollema H, van Vugt MA, Schaapveld M, Willemse PH, DoCaCel Study G (2012) A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: the DoCaCel study. Ann Oncol 23(11):2896–2902. https://doi.org/10.1093/annonc/mds107

    Article  CAS  PubMed  Google Scholar 

  26. Legge F, Paglia A, D’Asta M, Fuoco G, Scambia G, Ferrandina G (2011) Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients. BMC Cancer 11:214. https://doi.org/10.1186/1471-2407-11-214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen J, Shen P, Zhang XC, Zhao MD, Zhang XG, Yang L (2014) Efficacy and safety profile of celecoxib for treating advanced cancers: a meta-analysis of 11 randomized clinical trials. Clin Ther 36(8):1253–1263. https://doi.org/10.1016/j.clinthera.2014.06.015

    Article  CAS  PubMed  Google Scholar 

  28. Reddy BS, Hirose Y, Lubet R, Steele V, Kelloff G, Paulson S, Seibert K, Rao CV (2000) Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Can Res 60(2):293–297

    CAS  Google Scholar 

  29. Harris RE, Alshafie GA, Abou-Issa H, Seibert K (2000) Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Can Res 60(8):2101–2103

    CAS  Google Scholar 

  30. Grubbs CJ, Lubet RA, Koki AT, Leahy KM, Masferrer JL, Steele VE, Kelloff GJ, Hill DL, Seibert K (2000) Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats. Can Res 60(20):5599–5602

    CAS  Google Scholar 

  31. Cai F, Chen M, Zha D, Zhang P, Zhang X, Cao N, Wang J, He Y, Fan X, Zhang W, Fu Z, Lai Y, Hua ZC, Zhuang H (2017) Curcumol potentiates celecoxib-induced growth inhibition and apoptosis in human non-small cell lung cancer. Oncotarget 8(70):115526–115545. https://doi.org/10.18632/oncotarget.23308

    Article  PubMed  PubMed Central  Google Scholar 

  32. Guo Q, Liu X, Lu L, Yuan H, Wang Y, Chen Z, Ji R, Zhou Y (2017) Comprehensive evaluation of clinical efficacy and safety of celecoxib combined with chemotherapy in management of gastric cancer. Medicine 96(51):e8857. https://doi.org/10.1097/MD.0000000000008857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yu J, Tang BD, Leung WK, To KF, Bai AH, Zeng ZR, Ma PK, Go MY, Hu PJ, Sung JJ (2005) Different cell kinetic changes in rat stomach cancer after treatment with celecoxib or indomethacin: implications on chemoprevention. World J Gastroenterol 11(1):41–45

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Gupta S, Adhami VM, Subbarayan M, MacLennan GT, Lewin JS, Hafeli UO, Fu P, Mukhtar H (2004) Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. Can Res 64(9):3334–3343

    Article  CAS  Google Scholar 

  35. Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS (2002) Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med 8(3):289–293. https://doi.org/10.1038/nm0302-289

    Article  CAS  PubMed  Google Scholar 

  36. Jendrossek V (2013) Targeting apoptosis pathways by celecoxib in cancer. Cancer Lett 332(2):313–324. https://doi.org/10.1016/j.canlet.2011.01.012

    Article  CAS  PubMed  Google Scholar 

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Funding

This research is supported by Foundations of Medicine and Hygiene Science and Technology Planning Project of Zhejiang Province (2012KYB031) and Zhejiang Natural Science Foundation (LY14H160010).

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Authors and Affiliations

  1. Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, China

    Zhuyan Shao, Qiang Wen & Tao Zhu

  2. Department of Obstetrics and Gynecology of Shanghai Medical School and Institute of Biomedical Sciences, Fudan University, Shanghai, China

    Wei Jiang, Yu Kang & Conjian Xu

  3. Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, USA

    Shihua Wang

Authors
  1. Zhuyan Shao
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  2. Qiang Wen
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  3. Tao Zhu
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  4. Wei Jiang
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  5. Yu Kang
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  6. Conjian Xu
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  7. Shihua Wang
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Contributions

XC and SZ designed the study. SZ, WQ, ZT, JW and KY participated in animal studies and related experiments. SZ, WS and XC analyzed data and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Conjian Xu or Shihua Wang.

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Ethics approval

This study was approved by the Biomedical Research Ethics Committee of Shanghai Institute for Biological Science of Chinese Academy.

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Not applicable.

Conflict of interest

The authors declare no competing interests.

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Cite this article

Shao, Z., Wen, Q., Zhu, T. et al. Preventative effect of celecoxib in dimethylbenz[a]anthracene-induced ovarian cancer in rats. Arch Gynecol Obstet 298, 981–989 (2018). https://doi.org/10.1007/s00404-018-4898-y

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