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

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Sahin H. N., Adan A.

TURKISH JOURNAL OF BIOCHEMISTRY-TURK BIYOKIMYA DERGISI, vol.47, no.1, pp.49-58, 2022 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 47 Issue: 1
  • Publication Date: 2022
  • Doi Number: 10.1515/tjb-2021-0152
  • Journal Name: TURKISH JOURNAL OF BIOCHEMISTRY-TURK BIYOKIMYA DERGISI
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, EMBASE, TR DİZİN (ULAKBİM)
  • Page Numbers: pp.49-58
  • Keywords: apoptosis, FLT3 wild type AML, midostaurin, sphingosine kinase, sphingosine kinase inhibitor, apoptoz, FLT3 yabanil tip AML, midostaurin, sfingozin kinaz, sfingozin kinaz inhibitoru, APOPTOSIS, SPHINGOLIPIDS, CHEMOTHERAPY, COMBINATION, RESISTANCE, THERAPY, PKC412, GROWTH, TRIAL
  • Abdullah Gül University Affiliated: Yes

Abstract

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 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.