The report aims to investigate the relationship between the expression of cyclin D1 and Cyclooxgenase-2 (COX-2), thus to explore the molecular mechanisms of the antitumor efficacy of Celecoxib, a COX-2 inhibitor. Human ovarian SKOV-3 carcinoma cell xenograft-bearing mice were treated with Celecoxib by infusing gaster (i.g.) twice/day for 21 days. The mRNA levels of COX-2 and cyclin D1 were determined by RT-PCR. The expression of cyclin D1 at the protein level was detected by immunohistochemistry, while COX-2 protein expression was determined by Western blot. A high-dose of Celecoxib (100？mg/kg) significantly inhibited tumor growth ( P < 0.05), and the expression of cyclin D1 was reduced by 61%. Celecoxib decreased the proliferation cell index by 40% ( P < 0.001) and increased apoptotic index by 52% ( P < 0.05) in high-dose Celecoxib treated group. Our results suggest that the antitumor efficacy of Celecoxib against ovarian cancer in mice may in part be mediated through suppression of cyclin D1, which may contribute to its ability to suppress proliferation.
References
[1]
Yokoyama, Y; Sakamoto, T; Sato, S; Saito, Y. Evaluation of cytoreductive surgery with pelvic and paraaortic lymphadenectomy and intermittent cisplatin-based combination chemotherapy for improvement of long-term survival in ovarian cancer. Eur. J. Gynaecol. Oncol？1999, 20, 361–366.
[2]
Williams, CS; Mann, M; DuBois, RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene？1999, 18, 7908–7916.
[3]
Dempke, W; Rie, C; Grothey, A; Schmoll, HJ. Cyclooxygenase-2: A novel target for cancer chemotherapy? J. Cancer Res. Clin. Oncol？2001, 127, 411–417.
[4]
Li, S; Miner, K; Fannin, R; Barrett, JC; Davis, BJ. Cyclooxygenase-1 and 2 in normal and malignant human ovarian epithelium. Gynecol. Oncol？2004, 92, 622–627.
[5]
Denkert, C; K？bel, M; Pest, S; Koch, I; Berger, S; Schwabe, M; Siegert, A; Reles, A; Klosterhalfen, B; Hauptmann, S. Expression of cyclooxygenase-2 is an independent prognostic factor in human ovarian carcinoma. Am. J. Pathol？2002, 160, 893–903.
[6]
Erkinheimo, TL; Lassus, H; Finne, P; van Rees, BP; Leminen, A; Ylikorkala, O; Haglund, C; Butzow, R; Ristim？ki, A. Elevated cyclooxygenase-2 expression is associated with altered expression of p53 and SMAD4, amplification of HER-2/neu, and poor outcome in serous ovarian carcinoma. Clin. Cancer Res？2004, 10, 538–545.
[7]
Arico, S; Pattingre, S; Bauvy, C; Gane, P; Barbat, A; Codogno, P; Ogier-Denis, E. Celecoxib induces apoptosis by inhibiting 3-phosphoino-sitide-dependent protein kinase-1 activity in the human colon cancer HT-29 cell line. J. Biol. Chem？2002, 277, 27613–27621.
[8]
Xin, B; Yokoyama, Y; Shigeto, T; Mizunuma, H. Anti-tumor effect of non-steroidal antiinflammatory drugs on human ovarian cancers. Pathol. Oncol. Res？2007, 13, 365–369.
[9]
Xin, B; Yokoyama, Y; Shigeto, T; Futagami, M; Mizunuma, H. Inhibitory effect of meloxicam, a selective cyclooxygenase-2 inhibitor, and Ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, on the growth of human ovarian cancers. Cancer？2007, 110, 791–800.
[10]
Uddin, S; Ahmed, M; Hussain, A; Assad, L; Al-Dayel, F; Bavi, P; Al-Kuraya, KS; Munkarah, A. Cyclooxygenase-2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancer. Int. J. Cancer？2010, 126, 386–394.
Basu, GD; Pathangey, LB; Tinder, TL; Lagioia, M; Gendler, SJ; Mukherjee, P. Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol. Cancer Res？2004, 2, 632–642.
[13]
Wang, L; Chen, W; Xie, X; He, Y; Bai, X. Celecoxib inhibits tumor growth and angiogenesis in an orthotopic implantation tumor model of human colon cancer. Exp. Oncol？2008, 30, 42–51.
[14]
Leahy, KM; Ornberg, RL; Wang, Y; Zweifel, BS; Koki, AT; Masferrer, JL. Cyclooxygenase-2 inhibition by Celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res？2002, 62, 625–631.
[15]
Wu, GQ; Xie, D; Yang, GF; Liao, YJ; Mai, SJ; Deng, HX; Sze, J; Guan, XY; Zeng, YX; Lin, MC; Kung, HF. Cell cycle-related kinase supports ovarian carcinoma cell proliferation via regulation of cyclin D1 and is a predictor of outcome in patients with ovarian carcinoma. Int. J. Cancer？2009, 125, 2631–2642.
[16]
Barbieri, F; Lorenzi, P; Ragni, N; Schettini, G; Bruzzo, C; Pedullà, F; Alama, A. Overexpression of cyclin D1 is associated with poor survival in epithelial ovarian cancer. Oncology？2004, 66, 310–315.
[17]
Ferrara, N; Leung, DW; Cachianes, G; Winer, J; Henzel, WL. Purification and cloning of vascular endothelial growth factor secreted by pituitary folliculostellate cells. Methods Enzymol？1991, 198, 391–405.
[18]
Denkert, C; K？bel, M; Pest, S; Koch, I; Berger, S; Schwabe, M; Siegert, A; Reles, A; Klosterhalfen, B; Hauptmann, S. Expression of cyclooxygenase 2 is an independent prognostic factor in human ovarian carcinoma. Am. J. Pathol？2002, 160, 893–903.
[19]
Symowicz, J; Adley, BP; Woo, MM; Auersperg, N; Hudson, LG; Stack, MS. Cyclooxygenase-2 functions as a downstream mediator of lysophosphatidic acid to promote aggressive behavior in ovarian carcinoma cells. Cancer Res？2005, 65, 2234–2242.
[20]
Worsley, SD; Ponder, BA; Davies, BR. Overexpression of cyclin D1 in epithelial ovarian cancers. Gynecol. Oncol？1997, 64, 189–195.
[21]
Masamha, CP; Benbrook, DM. Cyclin D1 degradation is sufficient to induce G1 cell cycle arrest despite constitutive expression of cyclin E2 in ovarian cancer cells. Cancer Res？2009, 69, 6565–6572.
[22]
Vital-Reyes, V; Rodríguez-Burford, C; Chhieng, DC; Oelschlager, DK; Reyes-Fuentes, A; Barnes, M; Grizzle, WE. Celecoxib inhibits cellular growth, decreases Ki-67 expression and modifies apoptosis in ovarian cancer cell lines. Arch. Med. Res？2006, 37, 689–695.
[23]
Arnold, A; Papanikolaou, A. Cyclin D1 in breast cancer pathogenesis. J. Clin. Oncol？2005, 23, 4215–4224.
[24]
Schiffmann, S; Maier, TJ; Wobst, I; Janssen, A; Corban-Wilhelm, H; Angioni, C; Geisslinger, G; Gr？sch, S. The anti-proliferative potency of celecoxib is not a class effect of coxibs. Biochem. Pharmacol？2008, 76, 179–187.
[25]
Soh, JW; Kazi, JU; Li, H; Thompson, WJ; Weinstein, IB. Celecoxib-induced growth inhibition in SW480 colon cancer cells is associated with activation of protein kinase G. Mol. Carcinog？2008, 47, 519–525.
[26]
D’Andrilli, G; Kumar, C; Scambia, G; Giordano, A. Cell cycle genes in ovarian cancer: steps toward earlier diagnosis and novel therapies. Clin. Cancer Res？2004, 10, 8132–8141.
[27]
Macaluso, M; Paggi, MG; Giordano, A. Genetic and epigenetic alterations as hallmarks of the intricate road to cancer. Oncogene？2003, 22, 6472–6478.
[28]
Narayanan, BA; Condon, MS; Bosland, MC; Narayanan, NK; Reddy, BS. Suppression of N-methyl-N-nitrosourea/testosterone-induced rat prostate cancer growth by celecoxib: effects on cyclooxygenase-2, cell cycle regulation, and apoptosis mechanism(s). Clin. Cancer Res？2003, 15, 3503–3513.
[29]
Gastman, BR. Apoptosis and its clinical impact. Head Neck？2001, 23, 409–425.
[30]
Song, YC; Kim, SH; Juhnn, YS; Song, YS. Apoptotic effect of celecoxib dependent upon p53 status in human ovarian cancer cells. Ann. N.Y. Acad. Sci？2007, 1095, 26–34.
[31]
Olson, TA; Mohanraj, D; Carson, LF; Ramakrishnan, S. Vascular permeability factor gene expression in normal and neoplastic ovaries. Cancer Res？1994, 54, 276–280.
[32]
Yoneda, J; Kuniyasu, H; Crispens, MA; Price, JE; Bucana, CD; Fidler, IJ. Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. J. Natl. Cancer Inst？1998, 90, 447–454.
[33]
Hartenbach, EM; Olson, TA; Goswitz, JJ; Mohanraj, D; Twiggs, LB; Carson, LF; Ramakrishnan, S. Vascular endothelial growth factor expression and survival in human epithelial ovarian carcinomas. Cancer Lett？1997, 121, 169–175.
[34]
Paley, PJ; Staskus, KA; Gebhard, K; Mohanraj, D; Twiggs, LB; Carson, LF; Ramakrishnan, S. Vascular endothelial growth factor expression in early stage ovarian carcinomas. Cancer？1997, 80, 98–106.
[35]
Yamamoto, S; Konishi, I; Mandai, M; Kuroda, H; Komatsu, T; Nanbu, K; Sakahara, H; Mori, T. Expression of vascular endothelial growth factor (VEGF) in epithelia ovarian neoplasms: correlation with clinicopathology and patient survival and analysis of serum VEGF levels. Br. J. Cancer？1997, 76, 1221–1227.
[36]
Lee, JS; Choi, YD; Lee, JH; Nam, JH; Choi, C; Lee, MC; Park, CS; Juhng, SW; Min, KW. Expression of cyclooxygenase-2 in epithelial ovarian tumors and its relation to vascular endothelial growth factor and p53 expression. Int. J. Gynecol. Cancer？2006, 16, 247–253.
[37]
Fujimoto, J; Toyoki, H; Sakaguchi, H; Jahan, I; Alam, SM; Tamaya, T. Clinical implications of expression of cyclooxygenase-2 related to angiogenesis in ovarian cancer. Oncol. Rep？2006, 15, 21–25.
[38]
Gavrieli, Y; Sherman, Y; Ben-Sasson, SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol？1992, 119, 493–501.
[39]
Del-Vecchio, MT; Leoncinel, L; Buerdi, K; Kraft, R; Megha, T; Barbini, P; Tosi, P; Cottier, H. Diffuse controcytic and/or centroblastic malignant non-Hodgkins lymphomas: comparison of mitotic and pyknotic (apoptotic) indices. Int. J. Cancer？1991, 47, 38–43.
