Gökhan TEMELTAŞ, Funda KOSAVA, Özlem TEMİZ ARPACI, İbrahim TUĞLU

Investigation of the effect on prostate cancer purine base analog of the newly developed compound

Prostate cancer is an important cause of death in men. This malignant disease is known for excessive proliferation, decreased apoptosis, and uncontrolled proliferation of cells. In the light of this knowledge, our aim was to examine potential compounds for their effects on NF-κB and angiogenesis proteins (VGEF, MMP, ES, TSP-1) in a prostate cancer line. In this study, we planned that the purine base analogue with anti-cancer potential has synthesized new compounds, and those with anti-cancer potential has selected by screening with MTT testing. We analysed VEGF, MMP, Endostatin (ES), Thrombospondin-1 (TSP-1) and NF-κB protein levels in a prostate cancer line by the Elisa method. MMA-MEP caused a significant decrease especially for VEGF-A, NF-kB, Endostatin, Thrombospondin -1 and MMP levels compared to other compounds. This suggests that this heterocyclic compound is more effective compared to others. This compound could be more effective for patients with prostate cancer, depending on time and amount. In line with these results, we want to continue our work by applying this heterocyclic compound in different amounts at different time periods.

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1. Arısoy M, Temiz-Arpacı O, Yıldız İ, et al. Synthesis, Antimicrobial activity and QSAR studies of 2,5-disubstituted benzoxazoles, SAR & QSAR Environ. Res. 2008;19;589-612.

2. Arısoy M, Temiz-Arpacı O, Kaynak-Onurdag F, et al. Synthesis and antimicrobial evaluation of 2-(p-SubstitutedPhenyl)-5-[(4-substituted piperazin-1-yl)acetamido]-benzoxazoles. Z Naturforsch. 2014;69;368-74.

3. Temiz-Arpaci O, Doğanç F, Saç D, et al. Synthesis and antimicrobial evaluation of some sulfonylamido-benzoxazoles. Acta Biol. Hung. 2016;67:75-84.

4. Brown RN, Cameron R, Chalmers DK, et al. 2-Ethoxybenzoxazole as a bioisosteric replacement of an ethyl benzoate group in a human rhinovirus (HRV) capsid binder. Bioorg Med Chem Letters. 2005;15:2051-5.

5. Rida SM, Ashour FA, El-Hawash SAM, et al. Synthesis of some novel benzoxazole derivatives as anticancer, anti-HIV-1 and antimicrobial agents. Eur J Med Chem. 2005;40:949-59.

6. Oksuzoglu E, Tekiner-Gulbas B, Alper S, et al. Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitors. J Enzyme Inhib Med Chem 2008;23:37–42.

7. Pınar A, Yurdakul P, Yıldız I, et al. Some fused heterocyclic compounds as eukaryotic topoisomerase II inhibitors. Biochem Biophys Res Commun. 2004;317:670.

8. Oksuzoglu E, Temiz-Arpaci O, Tekiner-Gulbas B, et al. A study on the genotoxic activities of some new benzoxazoles. Med Chem Res. 2007;16:1-14.

9. Varga A, Akı-Sener E, et al. Induction of apoptosis and necrosis by resistance benzazoles and benzoxazines on tumour cell line mouselymphoma L5718 Mdr+cells. In Vivo. 2005;19:1087-92.

10. Temiz-Arpaci O, Coban T, Tekiner-Gulbas B, et al. A study on the antioxidant activities of some new benzazole derivatives. Acta Biol Hungarica. 2006;57:201-9.

11. Gungorduk K, Ertas IE, Sahbaz A, et al. Immunolocalization of ERK1/2 and p-AKT in normal endometrium, endometrial hyperplasia, and early and advanced stage endometrioid endometrial adenocancer and their prognostic signifi cance in malignant group. Eur J Obstet Gynecol Reprod Biol. 2014;179:147–52.

12. Muvaffak A , Gurhan I , Gunduz U , et al. Preparation and characterization of a biodegradable drug targeting system for anticancer drug delivery: microsphereantibody conjugate. J Drug Targ. 2005;13:151–9 .

13. Wiśniewski T, Żyromska A, Makarewicz R, et al. Osteopontin and angiogenic factors as new biomarkers of prostate cancer. Urological Oncology. 2019;16:134-40.

14. Heidtmann HH, Nettelbeck DM, Mingels A, et al. Generation of angiostatinlike fragments from plasminogen by prostate-specific antigen. Br J Cancer. 1999;81:1269–73

15. Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control. 2002, 9(2 Suppl):36–44.

16. Ucuzian AA, Gassman AA, East AT, et al. Molecular mediators of angiogenesis. J Burn Care Res 2010;31:158–75.

17. Carmen Stanca Melincovici, Adina Bianca Boşca, Sergiu Şuşman, et al. Vascular endothelial growth factor (VEGF) – key factor in normal and pathological angiogenesis, Rom J Morphol Embryol. 2018;59:455–67.

18. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611.

19. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.

20. Samson M, Peale FV Jr, Frantz G, et al. Human endocrine gland-derived vascular endothelial growth factor: expression early in development and in Leydig cell tumors suggests roles in normal and pathological testis angiogenesis. J Clin Endocrinol Metab. 2004;89:4078–88.

21. Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/ VEGF receptor system and its role under physiological and pathological conditions. Clin Sci (Lond). 2005;109:227–41.

22. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13:9–22.

23. Duffy AM, Bouchier-Hayes DJ, Harmey JH. Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signalling by VEGF. In: Madame Curie Bioscience Database (formerly, Eurekah Bioscience Database). Angiogenesis. Landes Bioscience, Austin (TX), USA, 2000–2013. https:// www.ncbi.nlm.nih.gov/books/NBK6482/

24. Miron L, Gafton B, Marinca M. Angiogeneza tumorală – implicaţii în terapia cancerelor. Jurnalul de Chirurgie Iaşi. 2010;6:104–10.

25. Raza A, Franklin MJ, Dudek AZ. Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol. 2010;85:593–8.

26. Yana I, Sagara H, Takaki S, et al. Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells. J Cell Sci, 2007;120(Pt 9):1607–14.

27. A Medina-González, N Eiró Díaz , JM Fernández Gómez, et al. Barmadahc, Comparative analysis of the expression of metalloproteases (MMP-2, MMP-9, MMP-11 and MMP-13) and the tissue inhibitor of metalloprotease 3 (TIMP3) between previous negative biopsies and radical prostatectomies. Actas Urol Esp. 2019;pii:S0210-4806:30192-5.

28. RJA. van Moorselaar a, EE. Voest, Angiogenesis in prostate cancer: its role in disease progression and possible therapeutic approaches, Molecular Cellular Endocrinol. 2002;197:239-50.

29. Po-Chun Chen, Chih-Hsin Tang, Liang-Wei Lin, et al. Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression, J Hematol Oncol. 2017;10:130.

30. Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med. 2012;2:a006627. 31. Chen H, Strickland DK, Mosher DF. Metabolism of thrombospondin 2. Binding and degradation by 3 t3 cells and glycosaminoglycan-variant Chinese hamster ovary cells. J Biol Chem. 1996;271:15993–9.

32. Yang Z, Strickland DK, Bornstein P. Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J Biol Chem. 2001;276:8403–8.

33. O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88.277285.

34. LM. Coussens, Z Werb. Inflammation and cancer. Nature. 2002;420:860–7. 35. Y Ben-Neriah, M Karin. Inflammation meets cancer, withNFκBasthematchmaker. Nature Immunol. 2011;12:715–23.

36. Bonacini M, Negri A, Davalli P, et al, Clusterin silencing in prostate cancer induces matrix metalloproteinases by an NF-κB-dependent mechanism. J Oncol. 2019;2019:4081624.

37. Huang S, Pettaway CA, Uehara H, et al. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 2001;20:4188–97.

38. Kosova F, Temiz Arpaci O, Olmez E, et al. Synthesis and the effect of a novel benzoxazole compound on breast cancer cell line. Medicine Sci. 2019;8:186- 91.

39. Kosova F, Kurt FO, Olmez E, et al. Effects of caffeic acid phenethyl ester on matrix molecules and angiogenetic and anti-angiogenetic factors in gastric cancer cells cultured on different substrates. Biotechnic & Histochemistry. 2015;2:1-10.

40. Kosova F, Arpaci ÖT, Kurt FO ve ark. 2014. Özgün heterosiklik bileşiklerin kanser dizin hücrelerinde apoptotik faktörler üzerindeki etkilerinin araştırılması, TÜBİTAK Projesi, 111S290, Proje Yürütücüsü.