PC3 Insan Prostat Kanseri, Hela Servikal Kanser ve SKOV-3 Over Kanseri Hücre Hatlarında, Spesifik Küçük Moleküllü Polo Benzeri Kinaz 1 Inhibitörü NMS-P937'nin Antitümör Aktivitesi

Year 2023, , 6 - 12, 16.04.2023

Nazan Yurtcu , Aylin Gökhan

https://doi.org/10.46332/aemj.960806

Abstract

Amaç: Spesifik küçük molekül polo benzeri kinaz 1 (PLK1) inhibitörü olan NMS-P937'nin PC3 insan prostat kanseri, HeLa servikal kanser ve SKOV-3 over kanseri hücre hatlarında antitümör aktivitesini araştırmayı amaçladık.

Araçlar ve Yöntem: PC3, HeLa ve SKOV-3 hücreleri, 48 saat boyunca NMS-P937 ile muamele edildi. Canlılık, XTT kolorimetrik tahlil ile analiz edildi ve PC3'ün en hassas hücre dizisi olduğu bulunduğundan, toplam oksidan status (TOS) değerleri, NMS-P937 ile tedavi edilmiş ve edilmemiş PC3 hücrelerinde TOS tahlili ile değerlendirildi.

Bulgular: Kanser hücre hatlarının proliferasyonu, konsantrasyondaki artışla bağlantılı olarak NMS-P937 tarafından orta derecede inhibe edildi. NMS-P937'nin PC3, HeLa ve SKOV-3 hücrelerindeki 48s IC50 değerleri 27.3, 69.7 ve 79.3 μM olarak kaydedildi. TOS, kontrol ve NMS-P937 ile muamele edilmiş PC3 hücrelerinde ölçüldü ve sırasıyla 3.15±0.36 ve 4.49±0.64 μmol H2O2 Equiv./L olarak hesaplandı, bu da çalışma bileşiğinin etkisi altında artan oksidatif stresi gösterdi (p=0.035).

Sonuç: PLK1 inhibitörü NMS-P937, PC3 insan prostat kanseri, HeLa servikal kanser ve SKOV-3 over kanserinden oluşan kanser hücre hatlarının aktivitesini doza bağlı bir şekilde azaltır. Bu bileşik oksidatif stresi arttırır ve bu da bileşiğin PC3 hücrelerinde sitotoksik aktivitesinde çok önemli bir rol oynayabilir. Ancak yine de farklı kanser hücre dizileri ve tümör modellerini içeren hem in vitro hem de in vivo çalışmaların yapılmasına ve gelişebilecek olumsuz etkilerin ortaya çıkarılmasına ihtiyaç vardır.

Keywords

PLK1 inhibisyonu, NMS-P937, kanser hücre hatları, sitotoksisite, oksidatif stres

Supporting Institution

Yok

Project Number

Değil

Antitumor Activity of NMS-P937 Specific Small-Molecule Polo-Like Kinase 1 Inhibitor, in PC3 Human Prostate Cancer, Hela Cervical Cancer, and SKOV-3 Ovarian Cancer Cell Lines

Abstract

Purpose: We aimed to investigate the antitumor activity of NMS-P937, a specific small-molecule polo-like kinase 1 (PLK1) inhibitor, in PC3 human prostate cancer, HeLa cervical cancer, and SKOV-3 ovarian cancer cell lines.

Materials and methods: PC3, HeLa, and SKOV-3 cells were treated with NMS-P937 for 48 h. The viability was analyzed by XTT colorimetric assay. Since PC3 was found to be the most sensitive cell line, total oxidant status (TOS) values were evaluated in NMS-P937-treated and non-treated PC3 cells via TOS assay.

Results: The proliferation of cancer cell lines was moderately inhibited by NMS-P937 in conjunction with the increase in concentration. The IC50 values of NMS-P937 in PC3, HeLa, and SKOV-3 cells were recorded as 27.3, 69.7, and 79.3 μM, respectively, for 48 h. TOS was measured in control and NMS-P937-treated PC3 cells and calculated as 3.15±0.36 and 4.49±0.64 μmol H2O2 Equiv./L, respectively, indicating the increased oxidative stress under the influence of the study compound (p=0.035).

Conclusion: The PLK1 inhibitor NMS-P937 reduces the activity of cancer cell lines consisting of PC3 human prostate cancer, HeLa cervical cancer, and SKOV-3 ovarian cancer in a dose-dependent manner. This compound increases oxidative stress, which may play a pivotal role in the cytotoxic activity of the compound in PC3 cells. However, there is still a need to carry out both in vitro and in vivo studies, including different cancer cell lines and tumor models, and to reveal the adverse effects that may develop.

Keywords

cancer cell lines, cytotoxicity, NMS-P937, PLK1 inhibition, oxidative stress

Project Number

Değil

References

• 1. Mattiuzzi C, Lippi G. Current cancer epidemiology. J Epidemiol Glob Health. 2019;9(4):217-222.
• 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
• 3. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33.
• 4. Van Vugt MATM, Medema RH. Checkpoint adaptation and recovery: Back with polo after the break. Cell Cycle. 2004;3(11):1383-1386.
• 5. Lee S-Y, Jang C, Lee K-A. Polo-Like Kinases (Plks), a Key Regulator of Cell Cycle and New Potential Target for Cancer Therapy. Dev Reprod. 2014;18(1):65-71.
• 6. Lane HA, Nigg EA. Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol. 1996;135(6 Pt 2):1701-1713.
• 7. Karsenti P, Lascar G, Salama J, Coste T. Thrombopenic purpura and hepatitis B: arguments favoring peripheral destruction of blood platelets. Gastroenterol Clin Biol. 1984;8(8-9):683-684.
• 8. Dumontet C, Jordan MA. Microtubule-binding agents: A dynamic field of cancer therapeutics. Nat Rev Drug Discov. 2010;9(10):790-803.
• 9. Jackson JR, Patrick DR, Dar MM, Huang PS. Targeted anti-mitotic therapies: Can we improve on tubulin agents? Nat Rev Cancer. 2007;7(2):107-117.
• 10. Valsasina B, Beria I, Alli C, et al. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther. 2012;11(4):1006-1016.
• 11. Dastan T, Kocyigit UM, Durna Dastan S, et al. Investigation of acetylcholinesterase and mammalian DNA topoisomerases, carbonic anhydrase inhibition profiles, and cytotoxic activity of novel bis(α-aminoalkyl)phosphinic acid derivatives against human breast cancer. J Biochem Mol Toxicol. 2017;31(11):e21971.
• 12. Ergul M, Bakar-Ates F. A specific inhibitor of polo-like kinase 1, GSK461364A, suppresses proliferation of Raji Burkitt’s lymphoma cells through mediating cell cycle arrest, DNA damage, and apoptosis. Chem Biol Interact. 2020;332:109288.
• 13. Sarac K, Orek C, Cetin A, et al. Synthesis and in vitro antioxidant evaluation of new bis (α-aminoalkyl) phosphinic acid derivatives. Phosphorus, Sulfur Silicon Relat Elem. 2016;191(9):1284-1289.
• 14. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38 (12):1103-1111.
• 15. Zhang H, Zhang K, Xu Z, et al. MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation. BMC Cancer. 2021;21(1):163.
• 16. Ergul M, Bakar-Ates F. RO3280: A Novel PLK1 Inhibitor, Suppressed the Proliferation of MCF-7 Breast Cancer Cells Through the Induction of Cell Cycle Arrest at G2/M Point. Anticancer Agents Med Chem. 2019;19(15):1846-1854.
• 17. Huang X, Xie Z, Liao C. Developing polo-like kinase 1 inhibitors. Future Med Chem. 2020;12(10):869-871.
• 18. National Center for Biotechnology Information. PubChem Compound Summary for CID 49792852. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/nms-1286937. Published 2004. Accessed date April 29, 2021.
• 19. Zhang Z, Hou X, Shao C, et al. Plk1 inhibition enhances the efficacy of androgen signaling blockade in castration-resistant prostate cancer. Cancer Res. 2014;74(22): 6635-6647.
• 20. Li J, Wang R, Kong Y, et al. Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer. Mol Cancer Ther. 2017;16(3):469-479.
• 21. Xu Y, Wang Q, Xiao K, et al. Novel dual BET and PLK1 inhibitor WNY0824 exerts potent antitumor effects in CRPC by inhibiting transcription factor function and inducing mitotic abnormality. Mol Cancer Ther. 2020;19(6):1221-1231.
• 22. Gao L, Pang Y-YY, Guo X-YY, et al. Polo like kinase 1 expression in cervical cancer tissues generated from multiple detection methods. Peer J. 2020;8:e10458.
• 23. Guo N, Gao C, Chen L. Knockdown of Polo-like kinase 1 (PLK1) inhibits the growth of cervical cancer HeLa cells. Chinese journal of cellular and molecular immunology. 2018;34(4):334-340.
• 24. Parrilla A, Barber M, Majem B, et al. Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer. Cancers (Basel). 2020;12(4):886.
• 25. Ma S, Rong X, Gao F, Yang Y, Wei L. TPX2 promotes cell proliferation and migration via PLK1 in OC. Cancer Biomarkers. 2018;22(3):443-451.
• 26. Raab M, Sanhaji M, Zhou S, et al. Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability. Neoplasia. 2019;21(4):363-375.
• 27. Affatato R, Carrassa L, Chilà R, Lupi M, Restelli V, Damia G. Identification of PLK1 as a new therapeutic target in mucinous ovarian carcinoma. Cancers (Basel). 2020;12(3):672.
• 28. Raab M, Krämer A, Hehlgans S, et al. Mitotic arrest and slippage induced by pharmacological inhibition of Polo-like kinase 1. Mol Oncol. 2015;9(1):140-154.
• 29. Gutteridge REA, Ndiaye MA, Liu X, Ahmad N. Plk1 inhibitors in cancer therapy: From laboratory to clinics. Mol Cancer Ther. 2016;15(7):1427-1435.
• 30. Kumar S, Kim J. PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis. Biomed Res Int. 2015;2015:1-21.
• 31. Casolaro A, Golay J, Albanese C, et al. The Polo-Like Kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia. Bertolini F, ed. PLoS One. 2013;8(3):e58424.
• 32. Zeidan AM, Ridinger M, Lin TL, et al. A phase ib study of onvansertib, a novel oral PLK1 inhibitor, in combination therapy for patients with relapsed or refractory acute myeloid leukemia. Clin Cancer Res. 2020;26(23): 6132-6140.