Treatment strategies for ovarian cancer focusing on prostaglandins

This work aims to researching the potential of anti-inflammatory therapy as an adjuvant in the antiblastic treatment for ovarian cancers. Drugs commonly used for dyslipidemia and diabetes mellitus and anti-inflammatory drugs have tumorsuppressing effects via anti-angiogenic and apoptosis-inducing actions. Proinflammatory prostaglandins (PGs) promote angiogenesis and suppress apoptosis. A therapeutic agent for dyslipidemia, Clofibric acid increases carbonyl reductase 1 (CBR1), which inactivates PGs in the tumor, and exerts a tumor shrinkage effect. Oral hypoglycemic agents, ciglitazone and pioglitazone reduce PG synthase and cyclooxygenase (COX) 2 in tumors and shrink them. A selective COX-2 inhibitor, Meloxicam directly inhibits PG production and shrinks tumors. These facts remind us of the importance of drug repositioning. Considering that the safety has been established including side effects, these drugs have the potential to be used not only to treat ovarian cancer but also human solid cancers in general as a combination adjuvant drug with other anticancer agents or to be applied to tumor dormancy therapy with different properties from anticancer agents.

Ovarian cancer; Prostaglandins; Clofibric acid; Carbonyl reductase; Oral hypo-glycemic agents

[1] Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, et al. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGFR-3 as a prognostic factor in endometrial carcinoma. Clinical Cancer Research. 2003; 9: 1361–1369.

[2] Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hast-ings JM, Holland CM, et al. Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. British Journal of Cancer. 2003; 88: 237–244.

[3] Umemoto M, Yokoyama Y, Sato S, Al-Mulla F, Tsuchida S, Saito

Y. Carbonyl reductase as a significant predictor of survival and metastasis in epithelial ovarian cancer. British Journal of Cancer. 2001; 85: 1032–1036.

[4] Sakamoto A, Yokoyama Y, Umemoto M, Futagami M, Sakamoto T, Bing X, et al. Clinical implication of expression of cyclooxygenase-2 and peroxisome proliferator activated-receptor γ in epithelial ovarian tumours. British Journal of Cancer. 2004; 91: 633–638.

[5] Yokoyama Y, Xin B, Shigeto T, Umemoto M, Kasai-Sakamoto A, Futagami M, et al. Clofibric acid, a peroxisome proliferator-activated receptor α ligand, inhibits growth of human ovarian cancer. Molecular Cancer Therapeutics. 2007; 6: 1379–1386.

[6] 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.

[7] Shigeto T, Yokoyama Y, Xin B, Mizunuma H. Peroxisome proliferator-activated receptor alpha and gamma inhibit growth of human ovarian cancer. Oncology Reports. 2007; 18: 833–840.

[8] Bräutigam K, Biernath-Wüpping J, Bauerschlag DO, von Kaisen-berg CS, Jonat W, Maass N, et al. Combined treatment with TRAIL and PPARγ ligands overcomes chemoresistance of ovarian cancer cell lines. Journal of Cancer Research and Clinical Oncol-ogy. 2011; 137: 875–886.

[9] Kobayashi Y, Kashima H, Rahmanto YS, Banno K, Yu Y, Matoba Y, et al. Drug repositioning of mevalonate pathway inhibitors as antitumor agents for ovarian cancer. Oncotarget. 2017; 8: 72147–72156.

[10] Pozzi A, Ibanez MR, Gatica AE, Yang S, Wei S, Mei S, et al. Peroxi-somal proliferator-activated receptor-alpha-dependent inhibition of endothelial cell proliferation and tumorigenesis. The Journal of Biological Chemistry. 2007; 282: 17685–17695.

[11] Panigrahy D, Kaipainen A, Huang S, Butterfield CE, Barnés CM, Fannon M, et al. PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105: 985–990.

[12] Miura R, Yokoyama Y, Shigeto T, Futagami M, Mizunuma H. In-hibitory effect of carbonyl reductase 1 on ovarian cancer growth via tumor necrosis factor signaling. International Journal of Oncology. 2015; 47: 2173–2180.

[13] Osawa Y, Yokoyama Y, Shigeto T, Futagami M, Mizunuma H. Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation. International Journal of Oncology. 2015; 46: 1252–1258.

[14] Kobayashi A, Yokoyama Y, Osawa Y, Miura R, Mizunuma H. Gene therapy for ovarian cancer using carbonyl reductase 1 DNA with a polyamidoamine dendrimer in mouse models. Cancer Gene Therapy. 2016; 23: 24–28.