DOI QR코드

DOI QR Code

Evaluation of Cytotoxicity Effects of Chalcone Epoxide Analogues as a Selective COX-II Inhibitor in the Human Liver Carcinoma Cell Line

  • Makhdoumi, Pouran (Student Research Committee, Department of Pharmacodynamics and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences) ;
  • Zarghi, Afshin (Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences) ;
  • Daraei, Bahram (Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University) ;
  • Karimi, Gholamreza (Pharmaceutical Research Center, Mashhad University of Medical Sciences)
  • 투고 : 2017.04.27
  • 심사 : 2017.09.04
  • 발행 : 2017.09.30

초록

Objectives: Study of the mechanisms involved in cancer progression suggests that cyclooxygenase enzymes play an important role in the induction of inflammation, tumor formation, and metastasis of cancer cells. Thus, cyclooxygenase enzymes could be considered for cancer chemotherapy. Among these enzymes, cyclooxygenase 2 (COX-2) is associated with liver carcinogenesis. Various COX-2 inhibitors cause growth inhibition of human hepatocellular carcinoma cells, but many of them act in the COX-2 independent mechanism. Thus, the introduction of selective COX-2 inhibitors is necessary to achieve a clear result. The present study was aimed to determine the growth-inhibitory effects of new analogues of chalcone epoxide as selective COX-2 inhibitors on the human hepatocellular carcinoma (HepG2) cell line. Methods: Estimation of both cell growth and the amount of prostaglandin E2 (PGE2) production were used to study the effect of selective COX-2 inhibitors on the hepatocellular carcinoma cell. Cell growth determination has done by MTT assay in 24 h, 48 h and 72 h, and PGE2 production has estimated by using ELYSA kit in 48 h and 72 h. Results: The results showed growth inhibition of the HepG2 cell line in a concentration and time-dependent manner, as well as a reduction in the formation of PGE2 as a product of COX-2 activity. Among the compounds those analogues with methoxy and hydrogen group showed more inhibitory effect than others. Conclusion: The current in-vitro study indicates that the observed significant growth-inhibitory effect of chalcone-epoxide analogues on the HepG2 cell line may involve COX-dependent mechanisms and the PGE2 pathway parallel to the effect of celecoxib. It can be said that these analogues might be efficient compounds in chemotherapy of COX-2 dependent carcinoma specially preventing and treatment of hepatocellular carcinomas.

참고문헌

  1. Schiff ER, Maddrey WC, Sorrell MF. Schiff's diseases of the liver. Philadelphia: Lippincott-Raven Publishers; 1999. p. 1281-304.
  2. Kew MC. Hepatic tumors and cysts. Sleisenger & Fordtran's gastrointestinal and liver disease: pathology/diagnosis/management. Philadelphia: Saunders; 1998. p. 1365-87.
  3. Okuda K, Fujimoto I, Hanai A, Urano Y. Changing incidence of hepatocellular carcinoma in Japan. Cancer research. 1987;47(18):4967-72.
  4. Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC. Increase in primary liver cancer in the UK, 1979-94. Lancet. 1997;350(9085):1142-3.
  5. Deuffic S, Poynard T, Buffat L, Valleron AJ. Trends in primary liver cancer. Lancet. 1998;351(9097):214-5.
  6. El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology. 2001;33(1):62-5. https://doi.org/10.1053/jhep.2001.21041
  7. Hu KQ. Rationale and feasibility of chemoprovention of hepatocellular carcinoma by cyclooxygenase-2 inhibitors. J Lab Clin Med. 2002;139(4):234-43. https://doi.org/10.1067/mlc.2002.122281
  8. Williams CS, Smalley W, DuBois RN. Aspirin use and potential mechanisms for colorectal cancer prevention. J Clin Invest. 1997;100(6):1325-9. https://doi.org/10.1172/JCI119651
  9. Buttar NS, Wang KK, editors. The "aspirin" of the new millennium: cyclooxygenase-2 inhibitors. Mayo Clin Proc. 2000;75(10):1027-38. https://doi.org/10.4065/75.10.1027
  10. Fosslien E. Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci. 2000;37(5):431-502. https://doi.org/10.1080/10408360091174286
  11. Pai R, Soreghan B, Szabo IL, Pavelka M, Baatar D, Tarnawski AS. Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat Med. 2002;8(3):289-93. https://doi.org/10.1038/nm0302-289
  12. Cheng J, Imanishi H, Iijima H, Shimomura S, Yamamoto T, Amuro Y, et al. Expression of cyclooxygenase 2 and cytosolic phospholipase A(2) in the liver tissue of patients with chronic hepatitis and liver cirrhosis. Hepatol Res. 2002;23(3):185-95. https://doi.org/10.1016/S1386-6346(01)00177-2
  13. Weddle DL, Tithoff P, Williams M, Schuller HM. ${\beta}$-adrenergic growth regulation of human cancer cell lines derived from pancreatic ductal carcinomas. Carcinogenesis. 2001;22(3):473-9. https://doi.org/10.1093/carcin/22.3.473
  14. Davies G, Martin LA, Sacks N, Dowsett M. Cyclooxygenase-2 (COX-2), aromatase and breast cancer: a possible role for COX-2 inhibitors in breast cancer chemoprevention. Ann Oncol. 2002;13(5):669-78. https://doi.org/10.1093/annonc/mdf125
  15. Hosomi Y, Yokose T, Hirose Y, Nakajima R, Nagai K, Nishiwaki Y, et al. Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung. Lung Cancer. 2000;30(2):73-81. https://doi.org/10.1016/S0169-5002(00)00132-X
  16. Seno H, Oshima M, Ishikawa T-o, Oshima H, Takaku K, Chiba T, et al. Cyclooxygenase 2-and prostaglandin $E_2$ receptor $EP_2$-dependent angiogenesis in $Apc^{{\Delta}716}$ mouse intestinal polyps. Cancer research. 2002;62(2):506-11.
  17. Richter M, Weiss M, Weinberger I, Fürstenberger G, Marian B. Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors. Carcinogenesis. 2001;22(1):17-25. https://doi.org/10.1093/carcin/22.1.17
  18. Wu GS, Zou SQ, Liu ZR, Tang ZH, Wang JH. Celecoxib inhibits proliferation and induces apoptosis via prostaglandin E2 pathway in human cholangiocarcinoma cell lines. World J Gastroenterol. 2003;9(6):1302-6. https://doi.org/10.3748/wjg.v9.i6.1302
  19. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294(5548):1871-5. https://doi.org/10.1126/science.294.5548.1871
  20. Rigas B, Goldman IS, Levine L. Altered eicosanoid levels in human colon cancer. J Lab Clin Med. 1993;122(5):518-23.
  21. Harizi H, Gualde N. The impact of eicosanoids on the crosstalk between innate and adaptive immunity: the key roles of dendritic cells. Tissue Antigens. 2005;65(6):507-14. https://doi.org/10.1111/j.1399-0039.2005.00394.x
  22. Karin M. Nuclear factor-${\kappa}B$ in cancer development and progression. Nature. 2006;441(7092):431-6. https://doi.org/10.1038/nature04870
  23. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-99. https://doi.org/10.1016/j.cell.2010.01.025
  24. Cheng J, Imanishi H, Amuro Y, Hada T. Ns-398, a selective cyclooxygenase 2 inhibitor, inhibited cell growth and induced cell cycle arrest in human hepatocellular carcinoma cell lines. Int J Cancer. 2002;99(5):755-61. https://doi.org/10.1002/ijc.10409
  25. Cui W, Yu CH, Hu KQ. In vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells. Clinical cancer research. 2005;11(22):8213-21. https://doi.org/10.1158/1078-0432.CCR-05-1044
  26. Heiduschka G, Erovic BM, Vormittag L, Skoda C, Martinek H, Brunner M, et al. $7{\beta}$-hydroxycholesterol induces apoptosis and regulates cyclooxygenase 2 in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2009;135(3):261-7. https://doi.org/10.1001/archoto.2008.558
  27. Park W, Oh YT, Han JH, Pyo H. Antitumor enhancement of celecoxib, a selective Cyclooxygenase-2 inhibitor, in a Lewis lung carcinoma expressing Cyclooxygenase-2. J Exp Clin Cancer Res. 2008;27(1):66. https://doi.org/10.1186/1756-9966-27-66
  28. Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, Song CW, et al. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer. 2007;97(11):1523-31. https://doi.org/10.1038/sj.bjc.6604057
  29. Futaki N, Arai I, Hamasaka Y, Takahashi S, Higuchi S, Otomo S. Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation. J Pharm Pharmacol. 1993;45(8):753-5. https://doi.org/10.1111/j.2042-7158.1993.tb07103.x
  30. Gans KR, Galbraith W, Roman RJ, Haber SB, Kerr JS, Schmidt WK, et al. Anti-inflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor. J Pharmacol Exp Ther. 1990;254(1):180-7.
  31. Mejza F, Nizankowska E. [Selective inhibitors of cyclooxygenase-2 (COX-2)]. Postepy Hig Med Dosw. 2001;55(2):287-302. Polish.
  32. Zarghi A, Sabakhi I, Topuzyan V, Hajimahdi Z, Daraie B. Design, synthesis and biological evaluation of 5-oxo-1, 4, 5, 6, 7, 8 hexahydroquinoline derivatives as selective cyclooxygenase-2 inhibitors. Iran J Pharm Res. 2014;13:61-9. https://doi.org/10.18579/jpcrkc/2014/13/2/78403
  33. Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 1999;18(55):7908-16. https://doi.org/10.1038/sj.onc.1203286
  34. Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology. 1999;29(3):688-96. https://doi.org/10.1002/hep.510290355
  35. Hu KQ, Yu CH, Mineyama Y, McCracken JD, Hillebrand DJ, Hasan M. Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398, a selective COX-2 inhibitor. Int J Oncol. 2003;22(4):757-63.
  36. Rahman MA, Dhar DK, Masunaga R, Yamanoi A, Kohno H, Nagasue N. Sulindac and exisulind exhibit a significant antiproliferative effect and induce apoptosis in human hepatocellular carcinoma cell lines. Cancer Res. 2000;60(8):2085-9.
  37. Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG, et al. Expression of cyclooxygenase-2 (COX-2) in hepatocellular carcinoma and growth inhibition of hepatoma cell lines by a COX-2 inhibitor, NS-398. Clin Cancer Res. 2001;7(5):1410-8.
  38. Yamamoto Y, Yin MJ, Lin KM, Gaynor RB. Sulindac inhibits activation of the $NF-{\kappa}B$ pathway. J Biol Chem. 1999;274(38):27307-14. https://doi.org/10.1074/jbc.274.38.27307
  39. Herrmann C, Block C, Geisen C, Haas K, Weber C, Winde G, et al. Sulindac sulfide inhibits Ras signaling. Oncogene. 1998;17(14):1769-76. https://doi.org/10.1038/sj.onc.1202085
  40. Waddell WR, Miesfeld RL. Adenomatous polyposis coli, protein kinases, protein tyrosine phosphatase: the effect of sulindac. J Surg Oncol. 1995;58(4):252-6. https://doi.org/10.1002/jso.2930580411
  41. Piazza GA, Rahm AK, Finn TS, Fryer BH, Li H, Stoumen AL, et al. Apoptosis primarily accounts for the growthinhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxy-genase inhibition, cell cycle arrest, and p53 induction. Cancer Res. 1997;57(12):2452-9.
  42. Park MK, Kim MK, Kim JC, Sung YK. Pattern of apoptosis by NS398, a selective COX-2 inhibitor, in hepatocellular carcinoma cell lines. Cancer Res Treat. 2005;37(5):313-7. https://doi.org/10.4143/crt.2005.37.5.313
  43. Cheng AS, Chan HL, Leung WK, Wong N, Johnson PJ, Sung JJ. Specific COX-2 inhibitor, NS-398, suppresses cellular proliferation and induces apoptosis in human hepatocellular carcinoma cells. Int J Oncol. 2003;23(1):113-9.