POTENSI KOMBINASI RUXOLITINIB DENGAN INHIBITOR PI3K/mTOR BEZ235 TERENKAPSULASI NANOKRISTAL KALSIUM KARBONAT PADA PENDERITA POLISITEMIA VERA
Abstract
ABSTRAK
Pendahuluan: Polisitemia vera (PV) merupakan kondisi di mana janus kinase 2 (JAK2) pada sel hematopoietik mengalami hiperaktivasi sehingga terjadi fosforilasi signal transducer and activator of transcription 5 (STAT5) tanpa adanya ligan yang berikatan pada reseptor. Kondisi tersebut menyebabkan terjadinya produksi sel darah yang berlebihan, terutama eritrosit. Hiperaktivasi tersebut disebabkan oleh adanya mutasi V617F pada JAK2 yang mengganggu interaksi domain jak homology 1 (JH1) dengan jak homology 2 (JH2). Polisitemia vera dapat menyebabkan komplikasi berupa thrombosis, hipertensi, dan splenomegaly. Jika berkepanjangan, polisitemia vera dapat berkembang menjadi myelofibrosis. Selain itu, hiperaktivasi JAK2 juga menyebabkan meningkatnya aktivitas phosphatidylinositol 3-kinase (PI3K) yang juga berujung pada fosforilasi STAT5.
Pembahasan: Saat ini, terapi polisitemia vera yang banyak digunakan adalah ruxolitinib. Namun, ruxolitinib memiliki kekurangan, yaitu tidak dapat menghambat fosforilasi STAT5 secara sempurna dan dapat meningkatkan risiko reaktivasi herpes zoster yang dapat dihambat oleh inhibitor PI3K. Oleh karena itu, diperlukan suatu terapi alternatif, yaitu kombinasi ruxolitinib dengan PI3K inhibitor, salah satunya adalah dengan BEZ235. BEZ235 merupakan inhibitor PI3K/Mammalian Target of Rapamycin (mTOR) yang berpotensi untuk dikombinasikan dengan ruxolitinib. BEZ235 mampu mencegah inhibisi fosforilasi STAT5 yang tidak sempurna. Akan tetapi, BEZ235 memiliki bioavailibilitas yang rendah sehingga perlu dilakukan upaya enkapsulasi, salah satunya dengan menggunakan nanokristal CaCO3. Secara keseluruhan, kombinasi ruxolitinib dengan BEZ235 menunjukkan hasil yang lebih baik dibandingkan dengan pemberian obat tanpa kombinasi.
Simpulan: Oleh karena itu, penulis ingin mengkaji lebih dalam mengenai potensi BEZ235 terenkapsulasi nanokristal CaCO3 yang dikombinasikan dengan ruxolitinib terhadap potensinya sebagai terapi polisitemia vera
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References
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25. Chen E, Mullally A. How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematology (United States) 2014;2014(1):268–76.
26. Marcellino BK, Hoffman R. Recent advances in prognostication and treatment of polycythemia vera. Fac Rev [Internet] 2021 [cited 2023 Mar 9];10. Available from: /pmc/articles/PMC8009192/
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30. Hammarén HM, Ungureanu D, Grisouard J, Skoda RC, Hubbard SR, Silvennoinen O. ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proc Natl Acad Sci U S A [Internet] 2015 [cited 2023 Mar 9];112(15):4642–7. Available from: https://www.pnas.org/doi/abs/10.1073/pnas.1423201112
31. Puleo DE, Kucera K, Hammarén HM, Ungureanu D, Newton AS, Silvennoinen O, et al. Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders. ACS Med Chem Lett [Internet] 2017 [cited 2023 Mar 9];8(6):618–21. Available from: /pmc/articles/PMC5467198/
32. Karim S, Malik IR, Nazeer Q, Zaheer A, Farooq M, Mahmood N, et al. Molecular analysis of V617F mutation in Janus kinase 2 gene of breast cancer patients. Saudi J Biol Sci 2019;26(6):1123–8.
33. Leroy E, Balligand T, Pecquet C, Mouton C, Colau D, Shiau AK, et al. Differential effect of inhibitory strategies of the V617 mutant of JAK2 on cytokine receptor signaling. Journal of Allergy and Clinical Immunology 2019;144(1):224–35.
34. Leroy E, Dusa A, Colau D, Motamedi A, Cahu X, Mouton C, et al. Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix. Biochemical Journal [Internet] 2016 [cited 2023 Mar 9];473(11):1579. Available from: /pmc/articles/PMC4888464/
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40. Vergaro V, Civallero M, Citti C, Cosenza M, Baldassarre F, Cannazza G, et al. Cell-Penetrating CaCO3 Nanocrystals for Improved Transport of NVP-BEZ235 across Membrane Barrier in T-Cell Lymphoma. Cancers 2018, Vol 10, Page 31 [Internet] 2018 [cited 2023 Mar 9];10(2):31. Available from: https://www.mdpi.com/2072-6694/10/2/31/htm
41. Trushina DB, Borodina TN, Belyakov S, Antipina MN. Calcium carbonate vaterite particles for drug delivery: Advances and challenges. Mater Today Adv 2022;14:100214.
42. Kamba AS, Ismail M, Azmi Tengku Ibrahim T, Zakaria ZAB. Biocompatibility of bio based calcium carbonate nanocrystals aragonite polymorph on NIH 3T3 fibroblast cell line. African Journal of Traditional, Complementary and Alternative Medicines [Internet] 2014 [cited 2023 Mar 9];11(4):31–8. Available from: https://www.ajol.info/index.php/ajtcam/article/view/106316
43. Wang CQ, Gong MQ, Wu JL, Zhuo RX, Cheng SX. Dual-functionalized calcium carbonate based gene delivery system for efficient gene delivery. RSC Adv [Internet] 2014 [cited 2023 Mar 9];4(73):38623–9. Available from: https://pubs.rsc.org/en/content/articlehtml/2014/ra/c4ra05468g
44. Idris SB, Abdul Kadir A, Abdullah JFF, Ramanoon SZ, Basit MA, Abubakar MZZA. Pharmacokinetics of Free Oxytetracycline and Oxytetracycline Loaded Cockle Shell Calcium Carbonate-Based Nanoparticle in BALB/c Mice. Front Vet Sci [Internet] 2020 [cited 2023 Mar 9];7. Available from: /pmc/articles/PMC7308650/
45. Gao YY, Hu LS, Han HJ, Song CY, Huang YX, Guo KY. [NVP-BEZ235 inhibits proliferation and colony-forming capability of CD34(+)CD38(-) human acute myeloid leukemia stem cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi [Internet] 2013 [cited 2023 Mar 9];21(2):334–8. Available from: https://pubmed.ncbi.nlm.nih.gov/23628027/
2. Moulard O, Mehta J, Fryzek J, Olivares R, Iqbal U, Mesa RA. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 2014;92(4):289–97.
3. Spivak JL. Polycythemia Vera. Curr Treat Options Oncol 2018;19(2).
4. Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J 2018;8(2):15.
5. Dores GM, Curtis RE, Linet MS, Morton LM. Cause-specific mortality following polycythemia vera, essential thrombocythemia, and primary myelofibrosis in the US population, 2001–2017. Am J Hematol 2021;96(12):E451–4.
6. Cahyanur R, Rinaldi I. Pendekatan Klinis Polisitemia. Jurnal Penyakit Dalam Indonesia 2019;6(3):156.
7. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol 2020;95(12):1599–613.
8. Cuthbert D, Stein BL. Polycythemia vera-associated complications: Pathogenesis, clinical manifestations, and effects on outcomes. J Blood Med 2019;10:359–71.
9. Mahariski PA, Meilani NM, Dharmayuda TG. Polisitemia Vera. Simdos Unud 2016;15(2):65–70.
10. Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera: historical oversights, diagnostic details, and therapeutic views. Leukemia 2021;35(12):3339–51.
11. de Freitas RM, da Costa Maranduba CM. Myeloproliferative neoplasms and the JAK/STAT signaling pathway: An overview. Rev Bras Hematol Hemoter 2015;37(5):348–53.
12. Recio C, Guerra B, Guerra-Rodríguez M, Aranda-Tavío H, Martín-Rodríguez P, de Mirecki-Garrido M, et al. Signal transducer and activator of transcription (STAT)-5: an opportunity for drug development in oncohematology. Oncogene 2019;38(24):4657–68.
13. Gerds AT, Bartalucci N, Assad A, Yacoub A. Targeting the PI3K pathway in myeloproliferative neoplasms. Expert Rev Anticancer Ther 2022;22(8):835–43.
14. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. New England Journal of Medicine 2015;372(5):426–35.
15. Materials S. Inhibitors of the PI3K / mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A / CIP2A axis. Oncotarget Supplementary Materials 2017;1:1.
16. Guvenir Celik E, Eroglu O. Combined treatment with ruxolitinib and MK-2206 inhibits the JAK2/STAT5 and PI3K/AKT pathways via apoptosis in MDA-MB-231 breast cancer cell line. Mol Biol Rep 2023;50(1):319–29.
17. Bellozi PMQ, Gomes GF, De Oliveira LR, Olmo IG, Vieira ÉLM, Ribeiro FM, et al. NVP-BEZ235 (dactolisib) has protective effects in a transgenic mouse model of Alzheimer’s disease. Front Pharmacol [Internet] 2019 [cited 2023 Mar 9];10. Available from: /pmc/articles/PMC6864823/
18. Hsu CM, Lin PM, Tsai Y Te, Tsai MS, Tseng CH, Lin SF, et al. NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin. Cell Death Discovery 2018 4:1 [Internet] 2018 [cited 2023 Mar 9];4(1):1–10. Available from: https://www.nature.com/articles/s41420-018-0060-7
19. Civallero M, Cosenza M, Pozzi S, Bari A, Ferri P, Sacchi S. Activity of BKM120 and BEZ235 against Lymphoma Cells. Biomed Res Int [Internet] 2015 [cited 2023 Mar 9];2015. Available from: /pmc/articles/PMC4628710/
20. Wise-Draper TM, Moorthy G, Salkeni MA, Karim NA, Thomas HE, Mercer CA, et al. A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies. Target Oncol 2017;12(3):323–32.
21. Esmaeili A, Asgari A. In vitro release and biological activities of Carum copticum essential oil (CEO) loaded chitosan nanoparticles. Elsevier B.V.; 2015.
22. Zhao P, Tian Y, You J, Hu X, Liu Y. Recent Advances of Calcium Carbonate Nanoparticles for Biomedical Applications. Bioengineering 2022;9(11):691.
23. Bryan JC, Verstovsek S. Overcoming treatment challenges in myelofibrosis and polycythemia vera: the role of ruxolitinib. Cancer Chemotherapy and Pharmacology 2016 77:6 [Internet] 2016 [cited 2023 Mar 9];77(6):1125–42. Available from: https://link.springer.com/article/10.1007/s00280-016-3012-z
24. Lu X, Chang R. Polycythemia Vera. Treasure Island (FL): 2022.
25. Chen E, Mullally A. How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematology (United States) 2014;2014(1):268–76.
26. Marcellino BK, Hoffman R. Recent advances in prognostication and treatment of polycythemia vera. Fac Rev [Internet] 2021 [cited 2023 Mar 9];10. Available from: /pmc/articles/PMC8009192/
27. Arya Y, Syal A, Gupta M, Gaba S. Advances in the Treatment of Polycythemia Vera: Trends in Disease Management. Cureus [Internet] 2021 [cited 2023 Mar 9];13(3). Available from: /pmc/articles/PMC8084584/
28. Sadjadian P, Wille K, Griesshammer M. Ruxolitinib-Associated Infections in Polycythemia Vera: Review of the Literature, Clinical Significance, and Recommendations. Cancers (Basel) [Internet] 2020 [cited 2023 Mar 9];12(11):1–14. Available from: /pmc/articles/PMC7693745/
29. Akram AM, Kausar H, Chaudhary A, Khalid AM, Shahzad MM, Akhtar MW, et al. Detection of Exon 12 and 14 Mutations in Janus Kinase 2 Gene Including a Novel Mutant in V617F Negative Polycythemia Vera Patients from Pakistan. J Cancer [Internet] 2018 [cited 2023 Mar 9];9(23):4341–5. Available from: http://www.jcancer.org
30. Hammarén HM, Ungureanu D, Grisouard J, Skoda RC, Hubbard SR, Silvennoinen O. ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proc Natl Acad Sci U S A [Internet] 2015 [cited 2023 Mar 9];112(15):4642–7. Available from: https://www.pnas.org/doi/abs/10.1073/pnas.1423201112
31. Puleo DE, Kucera K, Hammarén HM, Ungureanu D, Newton AS, Silvennoinen O, et al. Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders. ACS Med Chem Lett [Internet] 2017 [cited 2023 Mar 9];8(6):618–21. Available from: /pmc/articles/PMC5467198/
32. Karim S, Malik IR, Nazeer Q, Zaheer A, Farooq M, Mahmood N, et al. Molecular analysis of V617F mutation in Janus kinase 2 gene of breast cancer patients. Saudi J Biol Sci 2019;26(6):1123–8.
33. Leroy E, Balligand T, Pecquet C, Mouton C, Colau D, Shiau AK, et al. Differential effect of inhibitory strategies of the V617 mutant of JAK2 on cytokine receptor signaling. Journal of Allergy and Clinical Immunology 2019;144(1):224–35.
34. Leroy E, Dusa A, Colau D, Motamedi A, Cahu X, Mouton C, et al. Uncoupling JAK2 V617F activation from cytokine-induced signalling by modulation of JH2 αC helix. Biochemical Journal [Internet] 2016 [cited 2023 Mar 9];473(11):1579. Available from: /pmc/articles/PMC4888464/
35. Bartalucci N, Guglielmelli P, Vannucchi AM. Rationale for targeting the PI3K/Akt/mTOR pathway in myeloproliferative neoplasms. Clin Lymphoma Myeloma Leuk [Internet] 2013 [cited 2023 Mar 9];13 Suppl 2(SUPPL. 2). Available from: https://pubmed.ncbi.nlm.nih.gov/24290217/
36. Maurer B, Kollmann S, Pickem J, Hoelbl-Kovacic A, Sexl V. STAT5A and STAT5B—Twins with Different Personalities in Hematopoiesis and Leukemia. Cancers (Basel) [Internet] 2019 [cited 2023 Mar 9];11(11). Available from: /pmc/articles/PMC6895831/
37. Bartalucci N, Calabresi L, Balliu M, Martinelli S, Rossi MC, Villeval JL, et al. Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis. Oncotarget [Internet] 2017 [cited 2023 Mar 9];8(57):96710–24. Available from: https://pubmed.ncbi.nlm.nih.gov/29228564/
38. Bartalucci N, Tozzi L, Bogani C, Martinelli S, Rotunno G, Villeval JL, et al. Co-targeting the PI3K/mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms. J Cell Mol Med [Internet] 2013 [cited 2023 Mar 9];17(11):1385. Available from: /pmc/articles/PMC4117551/
39. Liu XQ, Cohen JI. The Role of PI3K/Akt in Human Herpesvirus Infection: from the Bench to the Bedside. Virology [Internet] 2015 [cited 2023 Mar 9];0:568. Available from: /pmc/articles/PMC4424147/
40. Vergaro V, Civallero M, Citti C, Cosenza M, Baldassarre F, Cannazza G, et al. Cell-Penetrating CaCO3 Nanocrystals for Improved Transport of NVP-BEZ235 across Membrane Barrier in T-Cell Lymphoma. Cancers 2018, Vol 10, Page 31 [Internet] 2018 [cited 2023 Mar 9];10(2):31. Available from: https://www.mdpi.com/2072-6694/10/2/31/htm
41. Trushina DB, Borodina TN, Belyakov S, Antipina MN. Calcium carbonate vaterite particles for drug delivery: Advances and challenges. Mater Today Adv 2022;14:100214.
42. Kamba AS, Ismail M, Azmi Tengku Ibrahim T, Zakaria ZAB. Biocompatibility of bio based calcium carbonate nanocrystals aragonite polymorph on NIH 3T3 fibroblast cell line. African Journal of Traditional, Complementary and Alternative Medicines [Internet] 2014 [cited 2023 Mar 9];11(4):31–8. Available from: https://www.ajol.info/index.php/ajtcam/article/view/106316
43. Wang CQ, Gong MQ, Wu JL, Zhuo RX, Cheng SX. Dual-functionalized calcium carbonate based gene delivery system for efficient gene delivery. RSC Adv [Internet] 2014 [cited 2023 Mar 9];4(73):38623–9. Available from: https://pubs.rsc.org/en/content/articlehtml/2014/ra/c4ra05468g
44. Idris SB, Abdul Kadir A, Abdullah JFF, Ramanoon SZ, Basit MA, Abubakar MZZA. Pharmacokinetics of Free Oxytetracycline and Oxytetracycline Loaded Cockle Shell Calcium Carbonate-Based Nanoparticle in BALB/c Mice. Front Vet Sci [Internet] 2020 [cited 2023 Mar 9];7. Available from: /pmc/articles/PMC7308650/
45. Gao YY, Hu LS, Han HJ, Song CY, Huang YX, Guo KY. [NVP-BEZ235 inhibits proliferation and colony-forming capability of CD34(+)CD38(-) human acute myeloid leukemia stem cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi [Internet] 2013 [cited 2023 Mar 9];21(2):334–8. Available from: https://pubmed.ncbi.nlm.nih.gov/23628027/
Published
2023-12-02
How to Cite
ARIAWAN, I Wayan Tegar Raharja; DIVASTA, I G Mahapraja; MAHARANI, Putu Ayu Pradnya Gita.
POTENSI KOMBINASI RUXOLITINIB DENGAN INHIBITOR PI3K/mTOR BEZ235 TERENKAPSULASI NANOKRISTAL KALSIUM KARBONAT PADA PENDERITA POLISITEMIA VERA.
Essential: Essence of Scientific Medical Journal, [S.l.], v. 21, n. 1, p. 64-72, dec. 2023.
ISSN 2655-6472.
Available at: <https://ojs.unud.ac.id/index.php/essential/article/view/100185>. Date accessed: 28 apr. 2024.
doi: https://doi.org/10.24843/essential.v21i1.100185.
Section
Artikel Tinjauan Pustaka
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