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Kenpaullone (CDK2 Inhibitor dan GSK-3? Inhibitor) sebagai agen otoprotektif pada pasien kemoterapi berbasis cisplatin: tinjauan pustaka



Abstract

Background: Malignancies are one of the diseases with the most sufferers, almost all country in the world has a number of these diseases. Cisplatin-based chemotherapy regimens have long been the gold standard in the treatment of various soft tissue malignancies. Despite many beneficial cisplatin features, it also has serious side effects, which are nephrotoxicity, neurotoxicity, and ototoxicity. This literature study aims to theoretically review the role of kenpaullone (CDK2 Inhibitor and GSK-3? Inhibitor) as an autoprotective agent in cisplatin-based chemotherapy patients.

Methods: The literature review approach is used in this study. Sources of reading come from relevant and appropriate journals and books from PubMed and Google Scholar.

Results: Cisplatin is thought to selectively damages the outer hair cells within the organ of Corti, spiral ganglion cells, and cells within the stria vascularis. It is reducing the formation of free radicals as otoprotective strategies by maintaining glutathione levels and antioxidant activity. Kenpaullone provided significant protection against cisplatin-induced ototoxicity when delivered by tran tympanic injection in zebrafish, mice, and rats. Kenpaullone has proven to directly inhibit cyclin-dependent kinase 2 (CDK2) and Glycogen synthesis kinase-3, thereby attenuating cisplatin-induced mitochondrial ROS production caspase 3/7-mediated cell death. Cisplatin can cause ototoxicity in the manifestation of hearing loss; thus, an otoprotector is needed to prevent this side effect. Kenpaullone is a CDK2 inhibitor and GSK-3 inhibitor that can reduce damage to outer hair cells induced by cisplatin to prevent ototoxic hearing loss.

Conclusion: The results of this study indicate that various literature studies show that kenpaullone (CDK2 Inhibitor and GSK-3? Inhibitor) can be used as an autoprotective agent in cisplatin-based chemotherapy patients.

 

 

Latar Belakang: Keganasan merupakan salah satu penyakit yang memiliki jumlah pasien terbanyak, hampir seluruh negara di dunia memiliki jumlah penderita penyakit tersebut. Kemoterapi berbasis cisplatin telah lama menjadi baku emas untuk terapi pada beberapa keganasan jaringan lunak. Selain memberikan banyak keuntungan, cisplatin juga menimbulkan efek samping yang berat seperti nefrotoksik, neurotoksik, dan ototoksik. Studi tinjauan pustaka ini bertujuan untuk meninjau secara teoritis peran kenpaullone (CDK2 Inhibitor dan GSK-3? Inhibitor) sebagai agen otoprotektif pada pasien kemoterapi berbasis cisplatin.

Metode: Dalam penulisan ini digunakan metode tinjauan pustaka. Sumber bacaan berasal jurnal-jurnal dan buku-buku yang relevan dan sesuai dari PubMed maupun Google Scholar.

Hasil: Diduga bahwa cisplatin secara selektif merusak bagian sel luar disertai organ korti, sel ganglia spiral, dan sel dengan stria vaskularis. Strategi otoprotektif termasuk menurunkan pembentukan radikal bebas dengan menjaga level gluthione dan aktivitas antioksidan. Kenpaullone memberikan efek protektif signifikan terhadap ototoksisitas akibat terapi cisplatin ketika dinjeksikan secara transtimpani pada ikan zebra, dan tikus. Kenpaullone terbukti secara langsung menginhibisi Cyclin-Dependent Kinase 2 (CDK-2) dan Glycogen Synthesis Kinase-3 (GSK-3), menurukan produksi ROS mitokondria yang diinduksi oleh cisplatin serta caspase 3/7 yang memediasi kematian sel. Sehingga hal tersebut dapat mencegah terjadinya gangguan pendengaran akibat ototoksik.

Kesimpulan: Hasil tinjauan pustaka ini menunjukkan bahwa berbagai studi literatur menunjukkan bahwa kenpaullone (CDK2 Inhibitor dan GSK-3? Inhibitor) dapat dipergunakan sebagai agen otoprotektif pada pasien kemoterapi berbasis cisplatin.

Keywords: Otoprotektor Cisplatin CDK GSK3 Kenpaullone

References

  1. Paken J, Govender CD, Pillay M, Sewram V. Cisplatin-Associated Ototoxicity: A Review for the Health Professional. J Toxicol. 2016;2016.
  2. The International Agency for Research on Cancer (IARC) report W. Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. Int Agency Res Cancer [Internet]. 2018;(September):13–5. Tersedia pada: http://gco.iarc.fr/,
  3. Kusurkar RA, Vos CMP, Westers P, Croiset G. How motivation affects academic performance : a structural equation modelling analysis. 2013;57–69.
  4. Greene JB, Standring R, Siddiqui F, Ahsan SF. Incidence of Cisplatin Induced Ototoxicity in Adults with Head and Neck Cancer. Adv Otolaryngol. 2015;2015:1–4.
  5. Edward ED, Rosdiana N, Farhat F, Siregar OR, Lubis B. Prevalence and risk factors of hearing loss in children with solid tumors treated with platinum-based chemotherapy. Paediatr Indones. 2015;55(3):121.
  6. Park HJ, Kim HJ, Bae GS, Seo SW, Kim DY, Jung WS, et al. Selective GSK-3β inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells. Hear Res [Internet]. 2009;257(1–2):53–62. Tersedia pada: http://dx.doi.org/10.1016/j.heares.2009.08.001
  7. van den Berg JH, Beijnen JH, Balm AJM, Schellens JHM. Future opportunities in preventing cisplatin induced ototoxicity. Cancer Treat Rev. 2006;32(5):390–7.
  8. Teitz T, Jie F, Asli N G, Justine D B, Shiyong D, Robert H, et al. CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. J Exp Med [Internet]. 2018;215(4):1187–203. Tersedia pada: http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L621545193%0Ahttp://dx.doi.org/10.1084/jem.20172246
  9. Cicenas J, Kalyan K, Sorokinas A, Jatulyte A, Valiunas D, Kaupinis A, et al. Highlights of the latest advances in research on CDK inhibitors. Cancers (Basel). 2014;6(4):2224–42.
  10. Shen DW, Pouliot LM, Hall MD, Gottesman MM. Cisplatin resistance: A cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev. 2012;64(3):706–21.
  11. Gómez-Ruiz S, Maksimović-Ivanić D, Mijatović S, Kaluderović GN. On the discovery, biological effects, and use of cisplatin and metallocenes in anticancer chemotherapy. Bioinorg Chem Appl. 2012;2012:15–7.
  12. Spreckelmeyer S, Orvig C, Casini A. Cellular transport mechanisms of cytotoxic metallodrugs: An overview beyond cisplatin. Molecules. 2014;19(10):15584–610.
  13. Tsang RY, Al-Fayea T, Au HJ. Cisplatin overdose: Toxicities and management. Drug Saf. 2009;32(12):1109–22.
  14. Karasawa T, Steyger PS. An integrated view of cisplatin-induced nephrotoxicity and ototoxicity. Toxicol Lett [Internet]. 2015;237(3):219–27. Tersedia pada: http://dx.doi.org/10.1016/j.toxlet.2015.06.012
  15. Mukherjea D, Rybak LP. Pharmacogenomics of cisplatin-induced ototoxicity R eview. 2011;12:1039–50.
  16. Joo HC, Choi JW, Moon H, Lee CY, Yoo KJ, Kim SW, et al. Protective effects of kenpaullone on cardiomyocytes following H2O2-induced oxidative stress are attributed to inhibition of connexin 43 degradation by SGSM3. Biochem Biophys Res Commun [Internet]. 2018;499(2):368–73. Tersedia pada: https://doi.org/10.1016/j.bbrc.2018.03.166
  17. Hodeify R, Tarcsafalvi A, Megyesi J, Safirstein RL, Price PM. Cdk2-dependent phosphorylation of p21 regulates the role of Cdk2 in cisplatin cytotoxicity. Am J Physiol - Ren Physiol. 2011;300(5):1171–9.
  18. Koutsandrea EG, Fousteris MA, Nikolaropoulos SS. Synthesis of new tetracyclic paullone derivatives as potential CDK inhibitors. Heterocycl Commun. 2012;18(4):169–79.
  19. Kitabayashi T, Dong Y, Furuta T, Sabit H, Jiapaer S, Zhang J, et al. Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma. Sci Rep. 2019;9(1):1–12.
  20. Li N, Wang LJ, Jiang B, Guo SJ, Li XQ, Chen XC, et al. Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors. Bioorganic Med Chem Lett [Internet]. 2018;28(12):2131–5. Tersedia pada: http://dx.doi.org/10.1016/j.ejmech.2009.12.026
  21. Malumbres M. Cyclin-dependent kinases. 2014;1–10.
  22. Ly PTT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, et al. Inhibition of GSK3 b -mediated BACE1 expression reduces Alzheimer-associated phenotypes Find the latest version : Inhibition of GSK3 β -mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest. 2013;123(1):224–35.
  23. Jacobs KM, Bhave SR, Ferraro DJ, Jaboin JJ, Hallahan DE, Thotala D. GSK-3β: A bifunctional role in cell death pathways. Int J Cell Biol. 2012;2012(Figure 1).
  24. Tolle N, Kunick C. Paullones as Inhibitors of Protein Kinases. Curr Top Med Chem. 2011;11(11):1320–32.
  25. Anello L, Cavalieri V, Di Bernardo M. Developmental effects of the protein kinase inhibitor kenpaullone on the sea urchin embryo. Comp Biochem Physiol Part - C Toxicol Pharmacol [Internet]. 2018;204(November 2017):36–44. Tersedia pada: https://doi.org/10.1016/j.cbpc.2017.11.001
  26. Kim H-J, Lee Y-R, Nguyen DH, Lee H-B, Kim E-K. Effect of Kenpaullone, a Specific Inhibitor of GSK3β, on Melanin Synthesis in B16 Melanoma and Human Melanocytes. J Soc Cosmet Sci Korea. 2011;37(3):211–8.

How to Cite

Widiarta, I. B. W., Umam, A. K., & Dewantara, I. P. S. (2020). Kenpaullone (CDK2 Inhibitor dan GSK-3? Inhibitor) sebagai agen otoprotektif pada pasien kemoterapi berbasis cisplatin: tinjauan pustaka. Intisari Sains Medis, 11(3), 1258–1263. https://doi.org/10.15562/ism.v11i3.686
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Ida Bagus Wisnu Widiarta
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Anbiya Khairul Umam
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I Putu Santhi Dewantara
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