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The importance of 15-lipoxygenase inhibitors in cancer treatment

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Abstract

Cancer-targeted therapy is an expanding and successful approach in treatment of many types of cancers. One of the main categories of targeted therapy is use of small molecule inhibitors. 15-Lipoxygenase (15-LOX) is an enzyme which reacts with polyunsaturated fatty acids and produces metabolites that are implicated in many important human diseases, such as cancer. Considering the role of 15-LOX (mainly 15-LOX-1) in the progression of some cancers, the discovery of 15-LOX inhibitors could potentially lead to development of novel cancer therapeutics and it can be claimed that 15-LOX inhibitors might be suitable as chemotherapy agents in the near future. This article reviews relevant publications on 15-LOX inhibitors with focus on their anticancer activities in vitro and in vivo. Many 15-LOX inhibitors have been reported for which separate studies have shown their anticancer activities. This review paves the way to further explore the mechanism of their antiproliferative effects via 15-LOX inhibition.

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References

  1. Bray, F., & Moller, B. (2006). Predicting the future burden of cancer. Nature Reviews. Cancer, 6(1), 63–74. https://doi.org/10.1038/nrc1781.

    Article  PubMed  CAS  Google Scholar 

  2. Aggarwal, B. B., Vijayalekshmi, R. V., & Sung, B. (2009). Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clinical Cancer Research, 15(2), 425–430. https://doi.org/10.1158/1078-0432.ccr-08-0149.

    Article  PubMed  CAS  Google Scholar 

  3. Prasad, S., Phromnoi, K., Yadav, V. R., Chaturvedi, M. M., & Aggarwal, B. B. (2010). Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer. Planta Medica, 76(11), 1044–1063. https://doi.org/10.1055/s-0030-1250111.

    Article  PubMed  CAS  Google Scholar 

  4. Burdick, A. D., Kim, D. J., Peraza, M. A., Gonzalez, F. J., & Peters, J. M. (2006). The role of peroxisome proliferator-activated receptor-beta/delta in epithelial cell growth and differentiation. Cellular Signalling, 18(1), 9–20. https://doi.org/10.1016/j.cellsig.2005.07.009.

    Article  PubMed  CAS  Google Scholar 

  5. Kasibhatla, S., & Tseng, B. (2003). Why target apoptosis in cancer treatment? Molecular Cancer Therapeutics, 2(6), 573–580.

    PubMed  CAS  Google Scholar 

  6. Salimi, V., Tavakoli-Yaraki, M., Mahmoodi, M., Shahabi, S., Gharagozlou, M. J., Shokri, F., et al. (2013). The oncolytic effect of respiratory syncytial virus (RSV) in human skin cancer cell line, A431. Iranian Red Crescent Medical Journal, 15(1), 62–67. https://doi.org/10.5812/ircmj.4722.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hyde, C. A., & Missailidis, S. (2009). Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis. International Immunopharmacology, 9(6), 701–715. https://doi.org/10.1016/j.intimp.2009.02.003.

    Article  PubMed  CAS  Google Scholar 

  8. Burke, J. E., & Dennis, E. A. (2009). Phospholipase A2 biochemistry. Cardiovascular Drugs and Therapy, 23(1), 49–59. https://doi.org/10.1007/s10557-008-6132-9.

    Article  PubMed  CAS  Google Scholar 

  9. Orafaie, A., Sadeghian, H., Bahrami, A. R., Saboormaleki, S., & Matin, M. M. (2017). 5-Farnesyloxycoumarin: a potent 15-LOX-1 inhibitor, prevents prostate cancer cell growth. Medicinal Chemistry Research, 26(1), 227–234. https://doi.org/10.1007/s00044-016-1737-1.

    Article  CAS  Google Scholar 

  10. Yamamoto, S. (1992). Mammalian lipoxygenases: molecular structures and functions. Biochimica et Biophysica Acta, 1128(2–3), 117–131.

    Article  PubMed  CAS  Google Scholar 

  11. Kuhn, H., & Thiele, B. J. (1999). The diversity of the lipoxygenase family. Many sequence data but little information on biological significance. FEBS Letters, 449(1), 7–11.

    Article  PubMed  CAS  Google Scholar 

  12. Sadeghian, H., & Jabbari, A. (2016). 15-Lipoxygenase inhibitors: a patent review. Expert Opinion on Therapeutic Patents, 26(1), 65–88. https://doi.org/10.1517/13543776.2016.1113259.

    Article  PubMed  CAS  Google Scholar 

  13. Brash, A. R., Boeglin, W. E., & Chang, M. S. (1997). Discovery of a second 15S-lipoxygenase in humans. Proceedings of the National Academy of Sciences of the United States of America, 94(12), 6148–6152.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Grullich, C., Duvoisin, R. M., Wiedmann, M., & van Leyen, K. (2001). Inhibition of 15-lipoxygenase leads to delayed organelle degradation in the reticulocyte. FEBS Letters, 489(1), 51–54.

    Article  PubMed  CAS  Google Scholar 

  15. Kroschwald, P., Kroschwald, A., Kuhn, H., Ludwig, P., Thiele, B. J., Hohne, M., et al. (1989). Occurrence of the erythroid cell specific arachidonate 15-lipoxygenase in human reticulocytes. Biochemical and Biophysical Research Communications, 160(2), 954–960.

    Article  PubMed  CAS  Google Scholar 

  16. Vijayvergiya, C., De Angelis, D., Walther, M., Kuhn, H., Duvoisin, R. M., Smith, D. H., et al. (2004). High-level expression of rabbit 15-lipoxygenase induces collapse of the mitochondrial pH gradient in cell culture. Biochemistry, 43(48), 15296–15302. https://doi.org/10.1021/bi048745v.

    Article  PubMed  CAS  Google Scholar 

  17. Maccarrone, M., Melino, G., & Finazzi-Agro, A. (2001). Lipoxygenases and their involvement in programmed cell death. Cell Death and Differentiation, 8(8), 776–784. https://doi.org/10.1038/sj.cdd.4400908.

    Article  PubMed  CAS  Google Scholar 

  18. Nadel, J. A., Conrad, D. J., Ueki, I. F., Schuster, A., & Sigal, E. (1991). Immunocytochemical localization of arachidonate 15-lipoxygenase in erythrocytes, leukocytes, and airway cells. The Journal of Clinical Investigation, 87(4), 1139–1145. https://doi.org/10.1172/jci115110.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. van Leyen, K., Duvoisin, R. M., Engelhardt, H., & Wiedmann, M. (1998). A function for lipoxygenase in programmed organelle degradation. Nature, 395(6700), 392–395. https://doi.org/10.1038/26500.

    Article  PubMed  Google Scholar 

  20. Yokota, S., Oda, T., & Fahimi, H. D. (2001). The role of 15-lipoxygenase in disruption of the peroxisomal membrane and in programmed degradation of peroxisomes in normal rat liver. The Journal of Histochemistry and Cytochemistry, 49(5), 613–622. https://doi.org/10.1177/002215540104900508.

    Article  PubMed  CAS  Google Scholar 

  21. Comba, A., Maestri, D. M., Berra, M. A., Garcia, C. P., Das, U. N., Eynard, A. R., et al. (2010). Effect of omega-3 and omega-9 fatty acid rich oils on lipoxygenases and cyclooxygenases enzymes and on the growth of a mammary adenocarcinoma model. Lipids in Health and Disease, 9, 112. https://doi.org/10.1186/1476-511x-9-112.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Suraneni, M. V., Moore, J. R., Zhang, D., Badeaux, M., Macaluso, M. D., DiGiovanni, J., et al. (2014). Tumor-suppressive functions of 15-lipoxygenase-2 and RB1CC1 in prostate cancer. Cell Cycle, 13(11), 1798–1810. https://doi.org/10.4161/cc.28757.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Spindler, S. A., Sarkar, F. H., Sakr, W. A., Blackburn, M. L., Bull, A. W., LaGattuta, M., et al. (1997). Production of 13-hydroxyoctadecadienoic acid (13-HODE) by prostate tumors and cell lines. Biochemical and Biophysical Research Communications, 239(3), 775–781. https://doi.org/10.1006/bbrc.1997.7471.

    Article  PubMed  CAS  Google Scholar 

  24. Kelavkar, U. P., Cohen, C., Kamitani, H., Eling, T. E., & Badr, K. F. (2000). Concordant induction of 15-lipoxygenase-1 and mutant p53 expression in human prostate adenocarcinoma: correlation with Gleason staging. Carcinogenesis, 21(10), 1777–1787.

    Article  PubMed  CAS  Google Scholar 

  25. Kelavkar, U., Lin, Y., Landsittel, D., Chandran, U., & Dhir, R. (2006). The yin and yang of 15-lipoxygenase-1 and delta-desaturases: dietary omega-6 linoleic acid metabolic pathway in prostate. J Carcinog, 5, 9. https://doi.org/10.1186/1477-3163-5-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Kelavkar, U. P., Glasgow, W., Olson, S. J., Foster, B. A., & Shappell, S. B. (2004). Overexpression of 12/15-lipoxygenase, an ortholog of human 15-lipoxygenase-1, in the prostate tumors of TRAMP mice. Neoplasia, 6(6), 821–830.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kelavkar, U. P., Parwani, A. V., Shappell, S. B., & Martin, W. D. (2006). Conditional expression of human 15-lipoxygenase-1 in mouse prostate induces prostatic intraepithelial neoplasia: the FLiMP mouse model. Neoplasia, 8(6), 510–522. https://doi.org/10.1593/neo.06202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Sen, M., McHugh, K., Hutzley, J., Philips, B. J., Dhir, R., Parwani, A. V., & Kelavkar, U. P. (2006). Orthotopic expression of human 15-lipoxygenase (LO)-1 in the dorsolateral prostate of normal wild-type C57BL/6 mouse causes PIN-like lesions. Prostaglandins & Other Lipid Mediators, 81(1–2), 1–13. https://doi.org/10.1016/j.prostaglandins.2006.05.024.

    Article  CAS  Google Scholar 

  29. Kelavkar, U. P., Nixon, J. B., Cohen, C., Dillehay, D., Eling, T. E., & Badr, K. F. (2001). Overexpression of 15-lipoxygenase-1 in PC-3 human prostate cancer cells increases tumorigenesis. Carcinogenesis, 22(11), 1765–1773.

    Article  PubMed  CAS  Google Scholar 

  30. Kelavkar, U. P., Harya, N. S., Hutzley, J., Bacich, D. J., Monzon, F. A., Chandran, U., Dhir, R., & O’Keefe, D. S. (2007). DNA methylation paradigm shift: 15-lipoxygenase-1 upregulation in prostatic intraepithelial neoplasia and prostate cancer by atypical promoter hypermethylation. Prostaglandins & Other Lipid Mediators, 82(1–4), 185–197. https://doi.org/10.1016/j.prostaglandins.2006.05.015.

    Article  CAS  Google Scholar 

  31. Das, S., Roth, C. P., Wasson, L. M., & Vishwanatha, J. K. (2007). Signal transducer and activator of transcription-6 (STAT6) is a constitutively expressed survival factor in human prostate cancer. Prostate, 67(14), 1550–1564. https://doi.org/10.1002/pros.20640.

    Article  PubMed  CAS  Google Scholar 

  32. Iranshahi, M., Jabbari, A., Orafaie, A., Mehri, R., Zeraatkar, S., Ahmadi, T., Alimardani, M., & Sadeghian, H. (2012). Synthesis and SAR studies of mono O-prenylated coumarins as potent 15-lipoxygenase inhibitors. European Journal of Medicinal Chemistry, 57, 134–142. https://doi.org/10.1016/j.ejmech.2012.09.006.

    Article  PubMed  CAS  Google Scholar 

  33. Musa, M. A., Cooperwood, J. S., & Khan, M. O. (2008). A review of coumarin derivatives in pharmacotherapy of breast cancer. Current Medicinal Chemistry, 15(26), 2664–2679.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Roussaki, M., Zelianaios, K., Kavetsou, E., Hamilakis, S., Hadjipavlou-Litina, D., Kontogiorgis, C., Liargkova, T., & Detsi, A. (2014). Structural modifications of coumarin derivatives: determination of antioxidant and lipoxygenase (LOX) inhibitory activity. Bioorganic & Medicinal Chemistry, 22(23), 6586–6594. https://doi.org/10.1016/j.bmc.2014.10.008.

    Article  CAS  Google Scholar 

  35. Iranshahi, M., Askari, M., Sahebkar, A., & Adjipavlou-Litina, D. (2009). Evaluation of antioxidant, anti-inflammatory and lipoxygenase inhibitory activities of the prenylated coumarin umbelliprenin. DARU&58; Journal of Pharmaceutical Sciences, 17(2), 99–103.

    CAS  Google Scholar 

  36. Barthomeuf, C., Lim, S., Iranshahi, M., & Chollet, P. (2008). Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis. Phytomedicine, 15(1–2), 103–111. https://doi.org/10.1016/j.phymed.2007.04.001.

    Article  PubMed  CAS  Google Scholar 

  37. Hosseinymehr, M., Matin, M. M., Sadeghian, H., Bahrami, A. R., & Kaseb-Mojaver, N. (2016). 8-Farnesyloxycoumarin induces apoptosis in PC-3 prostate cancer cells by inhibition of 15-lipoxygenase-1 enzymatic activity. Anti-Cancer Drugs, 27(9), 854–862. https://doi.org/10.1097/cad.0000000000000399.

    Article  PubMed  CAS  Google Scholar 

  38. Jun, M., Bacay, A. F., Moyer, J., Webb, A., & Carrico-Moniz, D. (2014). Synthesis and biological evaluation of isoprenylated coumarins as potential anti-pancreatic cancer agents. Bioorganic & Medicinal Chemistry Letters, 24(19), 4654–4658. https://doi.org/10.1016/j.bmcl.2014.08.038.

    Article  CAS  Google Scholar 

  39. Aliabadi, A., Mohammadi-farani, A., Seydi-kangarshahi, S., & Ahmadi, F. (2017). Discovery of 2-(1,3-dioxoisoindolin-2-yl)-n-phenylacetamide derivatives as probable 15-lipoxygenase-1 inhibitors with potential anticancer effects. FARMACIA, 65(2), 268–274.

    Google Scholar 

  40. Aliabadi, A., Mohammadi-Farani, A., Roodabeh, S., & Ahmadi, F. (2017). Synthesis and biological evaluation of N-(5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl)benzamide derivatives as lipoxygenase inhibitor with potential anticancer activity. Iran J Pharm Res, 16(1), 165–172.

    PubMed  PubMed Central  Google Scholar 

  41. Bakavoli, M., Nikpour, M., Rahimizadeh, M., Saberi, M. R., & Sadeghian, H. (2007). Design and synthesis of pyrimido[4,5-b][1,4]benzothiazine derivatives, as potent 15-lipoxygenase inhibitors. Bioorganic & Medicinal Chemistry, 15(5), 2120–2126. https://doi.org/10.1016/j.bmc.2006.12.022.

    Article  CAS  Google Scholar 

  42. Cornicelli, J., Padia, J., & Lane, Y. (1997). Method for treating and preventing inflammation and atherosclerosis.

  43. Kelavkar, U., Glasgow, W., & Eling, T. E. (2002). The effect of 15-lipoxygenase-1 expression on cancer cells. Current Urology Reports, 3(3), 207–214.

    Article  PubMed  Google Scholar 

  44. Ma, J., Zhang, L., Zhang, J., Liu, M., Wei, L., Shen, T., Ma, C., Wang, Y., Chen, Y., & Zhu, D. (2013). 15-Lipoxygenase-1/15-hydroxyeicosatetraenoic acid promotes hepatocellular cancer cells growth through protein kinase B and heat shock protein 90 complex activation. The International Journal of Biochemistry & Cell Biology, 45(6), 1031–1041. https://doi.org/10.1016/j.biocel.2013.02.018.

    Article  CAS  Google Scholar 

  45. Simpson, J., Forrester, R., Tisdale, M. J., Billington, D. C., & Rathbone, D. L. (2003). Effect of catechol derivatives on cell growth and lipoxygenase activity. Bioorganic & Medicinal Chemistry Letters, 13(15), 2435–2439.

    Article  CAS  Google Scholar 

  46. Matsuyama, M., Yoshimura, R., Mitsuhashi, M., Hase, T., Tsuchida, K., Takemoto, Y., Kawahito, Y., Sano, H., & Nakatani, T. (2004). Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors. International Journal of Oncology, 24(4), 821–827.

    PubMed  CAS  Google Scholar 

  47. Yoshinaga, M., Buchanan, F. G., & DuBois, R. N. (2004). 15-LOX-1 inhibits p21 (Cip/WAF 1) expression by enhancing MEK-ERK 1/2 signaling in colon carcinoma cells. Prostaglandins & Other Lipid Mediators, 73(1–2), 111–122.

    Article  CAS  Google Scholar 

  48. Kashyap, D., Mittal, S., Sak, K., Singhal, P., & Tuli, H. S. (2016). Molecular mechanisms of action of quercetin in cancer: recent advances. Tumour Biology, 37(10), 12927–12939. https://doi.org/10.1007/s13277-016-5184-x.

    Article  PubMed  CAS  Google Scholar 

  49. Malterud, K. E., & Rydland, K. M. (2000). Inhibitors of 15-lipoxygenase from orange peel. Journal of Agricultural and Food Chemistry, 48(11), 5576–5580.

    Article  PubMed  CAS  Google Scholar 

  50. Park, H. J., Kim, M. J., Ha, E., & Chung, J. H. (2008). Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine, 15(1–2), 147–151. https://doi.org/10.1016/j.phymed.2007.07.061.

    Article  PubMed  CAS  Google Scholar 

  51. Lee, C. J., Wilson, L., Jordan, M. A., Nguyen, V., Tang, J., & Smiyun, G. (2010). Hesperidin suppressed proliferations of both human breast cancer and androgen-dependent prostate cancer cells. Phytotherapy Research, 24(Suppl 1), S15–S19. https://doi.org/10.1002/ptr.2856.

    Article  PubMed  Google Scholar 

  52. Luo, G., Guan, X., & Zhou, L. (2008). Apoptotic effect of citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer Biology & Therapy, 7(6), 966–973.

    Article  CAS  Google Scholar 

  53. Morley, K. L., Ferguson, P. J., & Koropatnick, J. (2007). Tangeretin and nobiletin induce G1 cell cycle arrest but not apoptosis in human breast and colon cancer cells. Cancer Letters, 251(1), 168–178. https://doi.org/10.1016/j.canlet.2006.11.016.

    Article  PubMed  CAS  Google Scholar 

  54. Zhang, J., Wu, Y., Zhao, X., Luo, F., Li, X., Zhu, H., Sun, C., & Chen, K. (2014). Chemopreventive effect of flavonoids from Ougan (Citrus reticulata cv. Suavissima) fruit against cancer cell proliferation and migration. Journal of Functional Foods, 10, 511–519. https://doi.org/10.1016/j.jff.2014.08.006.

    Article  CAS  Google Scholar 

  55. Bracke, M. E., Depypere, H. T., Boterberg, T., Van Marck, V. L., Vennekens, K. M., Vanluchene, E., et al. (1999). Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer. Journal of the National Cancer Institute, 91(4), 354–359.

    Article  PubMed  CAS  Google Scholar 

  56. Arafa el, S. A., Zhu, Q., Barakat, B. M., Wani, G., Zhao, Q., El-Mahdy, M. A., et al. (2009). Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway. Cancer Research, 69(23), 8910–8917. https://doi.org/10.1158/0008-5472.can-09-1543.

    Article  Google Scholar 

  57. Du, Q., & Chen, H. (2010). The methoxyflavones in Citrus reticulata Blanco cv. ponkan and their antiproliferative activity against cancer cells. Food Chemistry, 119(2), 567–572. https://doi.org/10.1016/j.foodchem.2009.06.059.

    Article  CAS  Google Scholar 

  58. Thangapazham, R. L., Singh, A. K., Sharma, A., Warren, J., Gaddipati, J. P., & Maheshwari, R. K. (2007). Green tea polyphenols and its constituent epigallocatechin gallate inhibits proliferation of human breast cancer cells in vitro and in vivo. Cancer Letters, 245(1–2), 232–241. https://doi.org/10.1016/j.canlet.2006.01.027.

    Article  PubMed  CAS  Google Scholar 

  59. Liao, S., Umekita, Y., Guo, J., Kokontis, J. M., & Hiipakka, R. A. (1995). Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Letters, 96(2), 239–243.

    Article  PubMed  CAS  Google Scholar 

  60. Masuda, M., Suzui, M., Lim, J. T., & Weinstein, I. B. (2003). Epigallocatechin-3-gallate inhibits activation of HER-2/neu and downstream signaling pathways in human head and neck and breast carcinoma cells. Clinical Cancer Research, 9(9), 3486–3491.

    PubMed  CAS  Google Scholar 

  61. Shimizu, M., Deguchi, A., Lim, J. T., Moriwaki, H., Kopelovich, L., & Weinstein, I. B. (2005). (−)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clinical Cancer Research, 11(7), 2735–2746. https://doi.org/10.1158/1078-0432.ccr-04-2014.

    Article  PubMed  CAS  Google Scholar 

  62. Baek, S. J., Kim, J. S., Jackson, F. R., Eling, T. E., McEntee, M. F., & Lee, S. H. (2004). Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells. Carcinogenesis, 25(12), 2425–2432. https://doi.org/10.1093/carcin/bgh255.

    Article  PubMed  CAS  Google Scholar 

  63. Dinicola, S., Pasqualato, A., Cucina, A., Coluccia, P., Ferranti, F., Canipari, R., Catizone, A., Proietti, S., D’Anselmi, F., Ricci, G., Palombo, A., & Bizzarri, M. (2014). Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion. European Journal of Nutrition, 53(2), 421–431. https://doi.org/10.1007/s00394-013-0542-6.

    Article  PubMed  Google Scholar 

  64. Lewandowska, U., Szewczyk, K., Owczarek, K., Hrabec, Z., Podsedek, A., Sosnowska, D., et al. (2013). Procyanidins from evening primrose (Oenothera paradoxa) defatted seeds inhibit invasiveness of breast cancer cells and modulate the expression of selected genes involved in angiogenesis, metastasis, and apoptosis. Nutrition and Cancer, 65(8), 1219–1231. https://doi.org/10.1080/01635581.2013.830314.

    Article  PubMed  CAS  Google Scholar 

  65. Ye, X., Krohn, R. L., Liu, W., Joshi, S. S., Kuszynski, C. A., McGinn, T. R., Bagchi, M., Preuss, H. G., Stohs, S. J., & Bagchi, D. (1999). The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Molecular and Cellular Biochemistry, 196(1–2), 99–108.

    Article  PubMed  CAS  Google Scholar 

  66. Chatelain, K., Phippen, S., McCabe, J., Teeters, C. A., O'Malley, S., & Kingsley, K. (2011). Cranberry and grape seed extracts inhibit the proliferative phenotype of oral squamous cell carcinomas. Evidence-based Complementary and Alternative Medicine, 2011, 467691. https://doi.org/10.1093/ecam/nen047.

    Article  PubMed  Google Scholar 

  67. Tyagi, A., Agarwal, R., & Agarwal, C. (2003). Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis. Oncogene, 22(9), 1302–1316. https://doi.org/10.1038/sj.onc.1206265.

    Article  PubMed  CAS  Google Scholar 

  68. Agarwal, C., Singh, R. P., & Agarwal, R. (2002). Grape seed extract induces apoptotic death of human prostate carcinoma DU145 cells via caspases activation accompanied by dissipation of mitochondrial membrane potential and cytochrome c release. Carcinogenesis, 23(11), 1869–1876.

    Article  PubMed  CAS  Google Scholar 

  69. Liu, J., Zhang, W. Y., Kong, Z. H., & Ding, D. G. (2016). Induction of cell cycle arrest and apoptosis by grape seed procyanidin extract in human bladder cancer BIU87 cells. European Review for Medical and Pharmacological Sciences, 20(15), 3282–3291.

    PubMed  CAS  Google Scholar 

  70. Dinicola, S., Cucina, A., Pasqualato, A., D'Anselmi, F., Proietti, S., Lisi, E., et al. (2012). Antiproliferative and apoptotic effects triggered by grape seed extract (GSE) versus epigallocatechin and procyanidins on colon cancer cell lines. International Journal of Molecular Sciences, 13(1), 651–664. https://doi.org/10.3390/ijms13010651.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Kaur, M., Mandair, R., Agarwal, R., & Agarwal, C. (2008). Grape seed extract induces cell cycle arrest and apoptosis in human colon carcinoma cells. Nutrition and Cancer, 60(Suppl 1), 2–11. https://doi.org/10.1080/01635580802381295.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Owczarek, K., Hrabec, E., Fichna, J., Sosnowska, D., Koziolkiewicz, M., Szymanski, J., et al. (2017). Flavanols from Japanese quince (Chaenomeles japonica) fruit suppress expression of cyclooxygenase-2, metalloproteinase-9, and nuclear factor-kappaB in human colon cancer cells. Acta Biochimica Polonica, 64(3), 567–576. https://doi.org/10.18388/abp.2017_1599.

    Article  PubMed  CAS  Google Scholar 

  73. Malterud, K. E., Farbrot, T. L., Huse, A. E., & Sund, R. B. (1993). Antioxidant and radical scavenging effects of anthraquinones and anthrones. Pharmacology, 47(Suppl 1), 77–85. https://doi.org/10.1159/000139846.

    Article  PubMed  CAS  Google Scholar 

  74. Fernand, V. E., Losso, J. N., Truax, R. E., Villar, E. E., Bwambok, D. K., Fakayode, S. O., Lowry, M., & Warner, I. M. (2011). Rhein inhibits angiogenesis and the viability of hormone-dependent and -independent cancer cells under normoxic or hypoxic conditions in vitro. Chemico-Biological Interactions, 192(3), 220–232. https://doi.org/10.1016/j.cbi.2011.03.013.

    Article  PubMed  CAS  Google Scholar 

  75. Trybus, W., Krol, G., Trybus, E., Stachurska, A., Kopacz-Bednarska, A., & Krol, T. (2017). Aloe-emodin influence on the lysosomal compartment of Hela cells. Asian Pacific Journal of Cancer Prevention, 18(12), 3273–3279. https://doi.org/10.22034/apjcp.2017.18.12.3273.

    Article  PubMed  Google Scholar 

  76. Pecere, T., Gazzola, M. V., Mucignat, C., Parolin, C., Vecchia, F. D., Cavaggioni, A., Basso, G., Diaspro, A., Salvato, B., Carli, M., & Palù, G. (2000). Aloe-emodin is a new type of anticancer agent with selective activity against neuroectodermal tumors. Cancer Research, 60(11), 2800–2804.

    PubMed  CAS  Google Scholar 

  77. Takeda, S., Jiang, R., Aramaki, H., Imoto, M., Toda, A., Eyanagi, R., Amamoto, T., Yamamoto, I., & Watanabe, K. (2011). Delta9-tetrahydrocannabinol and its major metabolite delta9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors. Journal of Pharmaceutical Sciences, 100(3), 1206–1211. https://doi.org/10.1002/jps.22354.

    Article  PubMed  CAS  Google Scholar 

  78. Ruiz, L., Miguel, A., & Diaz-Laviada, I. (1999). Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Letters, 458(3), 400–404.

    Article  PubMed  CAS  Google Scholar 

  79. Caffarel, M. M., Sarrio, D., Palacios, J., Guzman, M., & Sanchez, C. (2006). Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Research, 66(13), 6615–6621. https://doi.org/10.1158/0008-5472.can-05-4566.

    Article  PubMed  CAS  Google Scholar 

  80. Greenhough, A., Patsos, H. A., Williams, A. C., & Paraskeva, C. (2007). The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. International Journal of Cancer, 121(10), 2172–2180. https://doi.org/10.1002/ijc.22917.

    Article  PubMed  CAS  Google Scholar 

  81. Sadeghian, H., Seyedi, S. M., Saberi, M. R., Arghiani, Z., & Riazi, M. (2008). Design and synthesis of eugenol derivatives, as potent 15-lipoxygenase inhibitors. Bioorganic & Medicinal Chemistry, 16(2), 890–901. https://doi.org/10.1016/j.bmc.2007.10.016.

    Article  CAS  Google Scholar 

  82. Pisano, M., Pagnan, G., Loi, M., Mura, M. E., Tilocca, M. G., Palmieri, G., Fabbri, D., Dettori, M. A., Delogu, G., Ponzoni, M., & Rozzo, C. (2007). Antiproliferative and pro-apoptotic activity of eugenol-related biphenyls on malignant melanoma cells. Molecular Cancer, 6, 8. https://doi.org/10.1186/1476-4598-6-8.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kim, G., Choi, D., Lim, J., Jeong, H., Kim, I., Lee, M., et al. (2006). Caspases-dependent apoptosis in human melanoma cell by eugenol. Korean Journal of Anatomy, 39(3), 245–253.

    Google Scholar 

  84. Ghosh, R., Nadiminty, N., Fitzpatrick, J. E., Alworth, W. L., Slaga, T. J., & Kumar, A. P. (2005). Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity. The Journal of Biological Chemistry, 280(7), 5812–5819. https://doi.org/10.1074/jbc.M411429200.

    Article  PubMed  CAS  Google Scholar 

  85. Pal, D., Banerjee, S., Mukherjee, S., Roy, A., Panda, C. K., & Das, S. (2010). Eugenol restricts DMBA croton oil induced skin carcinogenesis in mice: downregulation of c-Myc and H-ras, and activation of p53 dependent apoptotic pathway. Journal of Dermatological Science, 59(1), 31–39. https://doi.org/10.1016/j.jdermsci.2010.04.013.

    Article  PubMed  CAS  Google Scholar 

  86. Kaur, G., Athar, M., & Alam, M. S. (2010). Eugenol precludes cutaneous chemical carcinogenesis in mouse by preventing oxidative stress and inflammation and by inducing apoptosis. Molecular Carcinogenesis, 49(3), 290–301. https://doi.org/10.1002/mc.20601.

    Article  PubMed  CAS  Google Scholar 

  87. Shin, S. H., Park, J. H., & Kim, G. C. (2007). The mechanism of apoptosis induced by eugenol in human osteosarcoma cells. J. Korean Oral Maxillofac. Surg., 33, 20–27.

    Google Scholar 

  88. Yoo, C. B., Han, K. T., Cho, K. S., Ha, J., Park, H. J., Nam, J. H., Kil, U. H., & Lee, K. T. (2005). Eugenol isolated from the essential oil of Eugenia caryophyllata induces a reactive oxygen species-mediated apoptosis in HL-60 human promyelocytic leukemia cells. Cancer Letters, 225(1), 41–52. https://doi.org/10.1016/j.canlet.2004.11.018.

    Article  PubMed  CAS  Google Scholar 

  89. Manikandan, P., Vinothini, G., Vidya Priyadarsini, R., Prathiba, D., & Nagini, S. (2011). Eugenol inhibits cell proliferation via NF-kappaB suppression in a rat model of gastric carcinogenesis induced by MNNG. Investigational New Drugs, 29(1), 110–117. https://doi.org/10.1007/s10637-009-9345-2.

    Article  PubMed  CAS  Google Scholar 

  90. Ghosh, R., Ganapathy, M., Alworth, W. L., Chan, D. C., & Kumar, A. P. (2009). Combination of 2-methoxyestradiol (2-ME2) and eugenol for apoptosis induction synergistically in androgen independent prostate cancer cells. The Journal of Steroid Biochemistry and Molecular Biology, 113(1–2), 25–35. https://doi.org/10.1016/j.jsbmb.2008.11.002.

    Article  PubMed  CAS  Google Scholar 

  91. Carrasco, A. H., Espinoza, C. L., Cardile, V., Gallardo, C., Cardona, W., Lombardo, L., et al. (2008). Eugenol and its synthetic analogues inhibit cell growth of human cancer cells (part I). Journal of the Brazilian Chemical Society, 19, 543–548.

    Article  Google Scholar 

  92. Jaganathan, S. K., Mondhe, D., Wani, Z. A., Pal, H. C., & Mandal, M. (2010). Effect of honey and eugenol on Ehrlich ascites and solid carcinoma. Journal of Biomedicine & Biotechnology, 2010, 989163–989165. https://doi.org/10.1155/2010/989163.

    Article  CAS  Google Scholar 

  93. Hampson, A. J., Axelrod, J., & Grimaldi, M. (2003). Cannabinoids as antioxidants and neuroprotectants. US6630507B1.

  94. Takeda, S., Usami, N., Yamamoto, I., & Watanabe, K. (2009). Cannabidiol-2′,6′-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Drug Metabolism and Disposition, 37(8), 1733–1737. https://doi.org/10.1124/dmd.109.026930.

    Article  PubMed  CAS  Google Scholar 

  95. Carracedo, A., Gironella, M., Lorente, M., Garcia, S., Guzman, M., Velasco, G., et al. (2006). Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Research, 66(13), 6748–6755. https://doi.org/10.1158/0008-5472.can-06-0169.

    Article  PubMed  CAS  Google Scholar 

  96. Vara, D., Morell, C., Rodriguez-Henche, N., & Diaz-Laviada, I. (2013). Involvement of PPARgamma in the antitumoral action of cannabinoids on hepatocellular carcinoma. Cell Death & Disease, 4, e618. https://doi.org/10.1038/cddis.2013.141.

    Article  CAS  Google Scholar 

  97. Casanova, M. L., Blazquez, C., Martinez-Palacio, J., Villanueva, C., Fernandez-Acenero, M. J., Huffman, J. W., et al. (2003). Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. The Journal of Clinical Investigation, 111(1), 43–50. https://doi.org/10.1172/jci16116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Blazquez, C., Casanova, M. L., Planas, A., Gomez Del Pulgar, T., Villanueva, C., Fernandez-Acenero, M. J., et al. (2003). Inhibition of tumor angiogenesis by cannabinoids. The FASEB Journal, 17(3), 529–531. https://doi.org/10.1096/fj.02-0795fje.

    Article  PubMed  CAS  Google Scholar 

  99. Blazquez, C., Gonzalez-Feria, L., Alvarez, L., Haro, A., Casanova, M. L., & Guzman, M. (2004). Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas. Cancer Research, 64(16), 5617–5623. https://doi.org/10.1158/0008-5472.can-03-3927.

    Article  PubMed  CAS  Google Scholar 

  100. Portella, G., Laezza, C., Laccetti, P., De Petrocellis, L., Di Marzo, V., & Bifulco, M. (2003). Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. The FASEB Journal, 17(12), 1771–1773. https://doi.org/10.1096/fj.02-1129fje.

    Article  PubMed  CAS  Google Scholar 

  101. Kuroiwa, S., Maruyama, S., Suzuki, Y., & Yamazaki, H. (2006). Use of 3,5-diphenylpyrazole analogue as anti-tumor agent. WO2006109680A1: Google Patents.

  102. Armstrong, M. M., Freedman, C. J., Jung, J. E., Zheng, Y., Kalyanaraman, C., Jacobson, M. P., Simeonov, A., Maloney, D. J., van Leyen, K., Jadhav, A., & Holman, T. R. (2016). A potent and selective inhibitor targeting human and murine 12/15-LOX. Bioorganic & Medicinal Chemistry, 24(6), 1183–1190. https://doi.org/10.1016/j.bmc.2016.01.042.

    Article  CAS  Google Scholar 

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Orafaie, A., Matin, M.M. & Sadeghian, H. The importance of 15-lipoxygenase inhibitors in cancer treatment. Cancer Metastasis Rev 37, 397–408 (2018). https://doi.org/10.1007/s10555-018-9738-9

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