Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells

Hande Nur ŞAHİN, (Abdullah Gül Üniversitesi, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Bölümü Biyoloji ve Genetik, Kayseri, Türkiye)
Aysun ADAN (Abdullah Gül Üniversitesi, Yaşam ve Doğa Bilimleri Fakültesi, Moleküler Bölümü Biyoloji ve Genetik, Kayseri, Türkiye)
Türk Biyokimya Dergisi
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Yıl: 2022 Cilt: 47 Sayı: 1 Sayfa Aralığı: 49 - 58 Metin Dili: İngilizce DOI: 10.1515/tjb-2021-0152 İndeks Tarihi: 17-05-2023

Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells

Öz:
Objectives: Therapeutic potential of clinically approved FLT3 inhibitor midostaurin has been neglected in wild-type FLT3 positive acute myeloid leukemia (AML). Sphingosine kinase-1 (SK-1) having anti-proliferative functions is studied in various cancers, but not in FLT3 wild-type AML. We aimed to develop new therapeutic strategies to combat FLT3 wild-type AML by combining midostaurin with SK-1 inhibitor (SKI II) in THP1 cells. Methods: The anti-proliferative effects of midostaurin, SKI II and in combination on THP1 cells were determined by MTT assay. The combination indexes were calculated using calcusyn software. SK-1 expression and PARP cleavage were checked by western blot. Cell cycle distributions (PI staining) and apoptosis (annexin-V/PI dual staining) were assessed by flow cytometry for each agent alone and in combinations. Results: Midostaurin decreased SK-1 protein level. Midostaurin, SKI II and certain combinations decreased cell viability in a dose dependent manner. The combined antileukemic effects of the aforementioned drug combination afforded additive effect. Co-administration induced both necrosis and apoptosis via phosphatidylserine externalization, PARP cleavage and cell cycle arrest at G0/G1 and S phases. Conclusions: Targeting sphingosine kinase-1 together with FLT3 inhibition could be a novel mechanism to increase limited clinic response to midostaurin in wild-type FLT3 overexpressing AML after further pre-clinical studies.
Anahtar Kelime:

FMS benzeri tirozin kinaz 3 (FLT3) yabanıl tip akut miyeloid lösemi hücrelerinde midostaurin ve sfingozin kinaz-1 inhibitörünün kombine etkisi

Öz:
Amaç: Klinik olarak onaylanmış FLT3 inhibitörü olan midostaurinin yabanıl tip FLT3 pozitif akut miyeloid lösemide (AML)’deki terapötik potansiyeli ihmal edilmiştir. Anti-proliferatif rolleri olan sfingozin kinaz-1 (SK-1) bir çok kanserde çalışılmış fakat yabanıl tip FLT3 AML’deki rolü bilinmemektedir. Bu çalışmada, midostaurinin sfingozin kinaz-1 inhibitörü (SKI II) ile kombinasyonunun THP1 hücrelerindeki etkisinin belirlenmesi ile yeni bir tedavi yaklaşımının araştırılması amaçlanmıştır. Yöntem: Midostaurin, SKI II ve kombinasyonların THP1 hücreleri üzerindeki anti-proliferatif etkisi MTT testi ile saptanmıştır. Kombinasyon indeksleri Calcusyn programı ile hesaplanmıştır. SK-1 and PARP kesimi western blot ile belirlenmiştir. Midostaurin, SKI II ve kombinasyonlarının hücre döngüsü dağılımları PI boyaması, apoptoz ise aneksin V/PI ikili boyaması yapılarak akım sitometresi ile saptanmıştır. Bulgular: Midostaurin SK-1 ifadesini azaltmıştır. Midostaurin, SKI II ve belirli konsantrasyonlardaki kombinasyonlar hücre canlılığını doza bağlı olarak azaltmıştır. Midostaurinin SKI II ile kombinasyonu aditif etki göstermiştir. Kombinasyonmuamelesi fosfatidilserinin dışmembran yüzeyine translokasyonunu ve PARP aktifleşmesi ile apoptozu tetiklerken aynı zamanda nekroza ve hücre döngüsünün G0/G1 ve S fazlarında tutulumlara neden olmuştur. Sonuç: Klinik öncesi detaylı calışmalar ile desteklendikten sonra sfingozin kinaz-1’in FLT3 ile birlikte hedeflenmesi yabanıl tip FLT3 ifadesine sahip AML’de midostaurinin klinikte görülen sınırlı etkisinin arttırılması açısından yeni bir yaklaşım olabilecektir.
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
  • 1. Grove CS, Vassiliou GS. Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis Model Mech 2014;8: 941–51.
  • 2. Martelli MP, Sportoletti P, Tiacci E, Martelli MF, Falini B. Mutational landscape of AML with normal cytogenetics: biological and clinical implications. Blood Rev 2013;1: 13–22.
  • 3. Testa U, Pelosi E. The Impact of FLT3 mutations on the development of acute myeloid leukemias. Leuk Res Treatment 2013;2013:1–14.
  • 4. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 2019;33:299–312.
  • 5. Antar AI, Otrock ZK, Jabbour E, Mohty M, Bazarbachi A. FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Leukemia 2020;34:682–96.
  • 6. Estey EH. Acute myeloid leukemia: 2019 update on riskstratification and management. Am J Hematol 2018;93:1267–91.
  • 7. Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377: 454–64.
  • 8. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, et al. Phase IIB trial of oral midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010;28:4339–45.
  • 9. Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 2012;26: 2061–8.
  • 10. Weisberg E, Meng C, Case AE, Tiv HL, Gokhale PC, Buhrlage SJ, et al. Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia. J Cell Mol Med 2020;24:2968–80.
  • 11. Morales ML, Arenas A, Ortiz-Ruiz A, Leivas A, Rapado I, Rodríguez- García A, et al. MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia. Sci Rep 2019;9: 18630.
  • 12. Kroll A, Cho HE, Kang MH. Antineoplastic agents targeting targeting sphingolipid pathways. Front Oncol 2020;10:833.
  • 13. Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 2004;8:604–16.
  • 14. Truman JP, Garcia-Barros M, Obeid LM, Hannun YA. Evolving concepts in cancer therapy through targeting sphingolipid metabolism. Biochim Biophys Acta 2014;1841:1174–88.
  • 15. Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 2012;13:51–65.
  • 16. Giussani P, Tringali C, Riboni L, Viani P, Venerando B. Sphingolipids: key regulators of apoptosis and pivotal players in cancer drug resistance. Int J Mol Sci 2014;15:4356–92.
  • 17. Adan-Gokbulut A, Kartal-Yandim M, Iskender G, Baran Y. Novel agents targeting bioactive sphingolipids for the treatment of cancer. Curr Med Chem 2013;20:108–22.
  • 18. Li Y, Gao Y, Liang B, Nie W, Zhao L, Wang L. Combined effects on leukemia cell growth by targeting sphingosine kinase 1 and sirtuin 1 signaling. Exp Ther Med 2020;6:262.
  • 19. LeBlanc FR, Pearson JM, Tan SF, Cheon H, Xing JC, Dunton W, et al. Sphingosine kinase-2 is overexpressed in large granular lymphocyte leukaemia and promotes survival through Mcl-1. Br J Haematol 2020;190:405–17.
  • 20. Powell JA, Lewis AC, Zhu W, Toubia J, Pitman MR, Wallington- Beddoe CT. et al. Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia. Blood 2017;129:771–82.
  • 21. Adan A, Baran Y. The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks. Tumor Biol 2015;36:8973–84.
  • 22. Baran Y, Salas A, Senkal CE, Gunduz U, Bielawski J, Obeid LM, et al. Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells. J Biol Chem 2007;282:10922–34.
  • 23. Chou TC. Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Res 2010; 70:440–6.
  • 24. Casagrande N, Borghese C, Favero A, Vicenzetto C, Aldinucci D. Trabectedin overcomes doxorubicin-resistance, counteracts tumor-immunosuppressive reprogramming of monocytes and decreases xenograft growth in Hodgkin lymphoma. Cancer Lett 2021;500:182–93.
  • 25. Levis M. Midostaurin approved for FLT3-mutated AML. Blood 2017;129:3403–6.
  • 26. Dohner H, Sierra J, Stone R, Hoenekopp A, Berkowitz N, Sachs C, et al. Trial in progress: a phase 3, randomized, doubleblind study ofmidostaurin in combination with chemotherapy and as single-agent maintenance therapy in newly diagnosed patients with FLT3 mutation-negative acute myeloid leukemia (AML). Clin Lymphoma, Myeloma & Leukemia 2018;18: S206–7.
  • 27. Wallington-Beddoe CT, Xie V, TongD, Powell JA, Lewis AC, Davies L, et al. Identification of sphingosine kinase 1 as a therapeutic target in B-lineage acute lymphoblastic leukaemia. Br J Haematol 2019; 184:443–7.
  • 28. Lupino L, Perry T, Margielewska S, Hollows R, Ibrahim M, Care M, et al. Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma. Leukemia 2019;33:2884–97.
  • 29. Beljanski V, Lewis CS, Smith CD. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther 2011;11: 524–34.
  • 30. El Hassouni B, Mantini G, Li Petri G, Capula M, Boyd L, Weinstein HNW, et al. To combine or not combine: drug interactions and tools for their analysis. Reflections from the EORTC-PAMM course on preclinical and early-phase clinical pharmacology. Anticancer Res 2019;39:3303–9.
  • 31. Almejún MB, Borge M, Colado A, Elías EE, Podaza E, Risnik D, et al. Sphingosine kinase 1 participates in the activation, proliferation and survival of chronic lymphocytic leukemia cells. Haematologica 2017;102:e257–60.
  • 32. Yang L, Weng W, Sun ZX, Fu XJ, Ma J, Zhuang W-F. SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo. BiochemBiophys Res Commun 2015; 460:903–8.
  • 33. Evangelisti C, Evangelisti C, Teti G, Chiarini F, Falconi M, Melchionda F, et al. Assessment of the effect of sphingosine kinase inhibitors on apoptosis, unfolded protein response and autophagy of T-cell acute lymphoblastic leukemia cells; indications for novel therapeutics. Oncotarget 2014;5:7886–901.
  • 34. Odgerel T, Kikuchi J, Wada T, Shimizu R, Futaki K, Kano Y, et al. The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations. Oncogene 2008;27:3102–10.
APA Şahin H, adan a (2022). Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. , 49 - 58. 10.1515/tjb-2021-0152
Chicago Şahin Hande Nur,adan aysun Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. (2022): 49 - 58. 10.1515/tjb-2021-0152
MLA Şahin Hande Nur,adan aysun Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. , 2022, ss.49 - 58. 10.1515/tjb-2021-0152
AMA Şahin H,adan a Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. . 2022; 49 - 58. 10.1515/tjb-2021-0152
Vancouver Şahin H,adan a Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. . 2022; 49 - 58. 10.1515/tjb-2021-0152
IEEE Şahin H,adan a "Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells." , ss.49 - 58, 2022. 10.1515/tjb-2021-0152
ISNAD Şahin, Hande Nur - adan, aysun. "Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells". (2022), 49-58. https://doi.org/10.1515/tjb-2021-0152
APA Şahin H, adan a (2022). Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. Türk Biyokimya Dergisi, 47(1), 49 - 58. 10.1515/tjb-2021-0152
Chicago Şahin Hande Nur,adan aysun Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. Türk Biyokimya Dergisi 47, no.1 (2022): 49 - 58. 10.1515/tjb-2021-0152
MLA Şahin Hande Nur,adan aysun Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. Türk Biyokimya Dergisi, vol.47, no.1, 2022, ss.49 - 58. 10.1515/tjb-2021-0152
AMA Şahin H,adan a Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. Türk Biyokimya Dergisi. 2022; 47(1): 49 - 58. 10.1515/tjb-2021-0152
Vancouver Şahin H,adan a Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells. Türk Biyokimya Dergisi. 2022; 47(1): 49 - 58. 10.1515/tjb-2021-0152
IEEE Şahin H,adan a "Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells." Türk Biyokimya Dergisi, 47, ss.49 - 58, 2022. 10.1515/tjb-2021-0152
ISNAD Şahin, Hande Nur - adan, aysun. "Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells". Türk Biyokimya Dergisi 47/1 (2022), 49-58. https://doi.org/10.1515/tjb-2021-0152
Sayfa Oluşturulma Tarihi
24-04-2024 7:9

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