Combined effect of midostaurin and sphingosine kinase-1 inhibitor on FMS-like tyrosine kinase 3 (FLT3) wild type acute myeloid leukemia cells FMS benzeri tirozin kinaz 3 (FLT3) yabanıl tip akut miyeloid lösemi hücrelerinde midostaurin ve sfingozin kinaz-1 inhibitörünün kombine etkisi

Şahin H. N., ADAN A.

Turkish Journal of Biochemistry, vol.47, no.1, pp.49-58, 2022 (SCI-Expanded) identifier

  • Publication Type: Article / Article
  • Volume: 47 Issue: 1
  • Publication Date: 2022
  • Doi Number: 10.1515/tjb-2021-0152/html
  • Journal Name: Turkish Journal of Biochemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, EMBASE, Food Science & Technology Abstracts, Directory of Open Access Journals
  • Page Numbers: pp.49-58
  • Keywords: apoptosis, FLT3 wild type AML, midostaurin, sphingosine kinase, sphingosine kinase inhibitor
  • Kayseri University Affiliated: No

Abstract

© 2022 Hande Nur Şahin and Aysun AdanObjectives: 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 anti-leukemic 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.